Assessment of methods and indexes of insulin sensitivity | Revista Portuguesa de Endocrinologia, Diabetes e Metabolismo

array:24 ["pii" => "S1646343913000734" "issn" => "16463439" "doi" => "10.1016/j.rpedm.2013.10.004" "estado" => "S300" "fechaPublicacion" => "2014-01-01" "aid" => "25" "copyright" => "Sociedade Portuguesa de Endocrinologia, Diabetes e Metabolismo" "copyrightAnyo" => "2012" "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/3.0/" "subdocumento" => "ssu" "cita" => "Rev Port Endocrinol Diabetes Metab. 2014;9:65-73" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 16662 "formatos" => array:3 [ "EPUB" => 129 "HTML" => 14012 "PDF" => 2521 ] ] "itemSiguiente" => array:19 [ "pii" => "S164634391400008X" "issn" => "16463439" "doi" => "10.1016/j.rpedm.2014.03.001" "estado" => "S300" "fechaPublicacion" => "2014-01-01" "aid" => "33" "copyright" => "Sociedade Portuguesa de Endocrinologia, Diabetes e Metabolismo" "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/3.0/" "subdocumento" => "ssu" "cita" => "Rev Port Endocrinol Diabetes Metab. 2014;9:74-8" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 5122 "formatos" => array:3 [ "EPUB" => 124 "HTML" => 4199 "PDF" => 799 ] ] "pt" => array:12 [ "idiomaDefecto" => true "cabecera" => "Revisão" "titulo" => "Sobrecarga de ferro e diabetes mellitus" "tienePdf" => "pt" "tieneTextoCompleto" => "pt" "tieneResumen" => array:2 [ 0 => "pt" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "74" "paginaFinal" => "78" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Iron overload and diabetes mellitus" ] ] "contieneResumen" => array:2 [ "pt" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "pt" => true ] "contienePdf" => array:1 [ "pt" => true ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Sofia Gouveia, Cristina Ribeiro, Francisco Carrilho" "autores" => array:3 [ 0 => array:2 [ "nombre" => "Sofia" "apellidos" => "Gouveia" ] 1 => array:2 [ "nombre" => "Cristina" "apellidos" => "Ribeiro" ] 2 => array:2 [ "nombre" => "Francisco" "apellidos" => "Carrilho" ] ] ] ] ] "idiomaDefecto" => "pt" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S164634391400008X?idApp=UINPBA00004N" "url" => "/16463439/0000000900000001/v1_201407280026/S164634391400008X/v1_201407280026/pt/main.assets" ] "itemAnterior" => array:19 [ "pii" => "S1646343914000029" "issn" => "16463439" "doi" => "10.1016/j.rpedm.2013.12.001" "estado" => "S300" "fechaPublicacion" => "2014-01-01" "aid" => "27" "copyright" => "Sociedade Portuguesa de Endocrinologia, Diabetes e Metabolismo" "documento" => "article" "crossmark" => 0 "licencia" => "http://creativecommons.org/licenses/by-nc-nd/3.0/" "subdocumento" => "ssu" "cita" => "Rev Port Endocrinol Diabetes Metab. 2014;9:59-64" "abierto" => array:3 [ "ES" => true "ES2" => true "LATM" => true ] "gratuito" => true "lecturas" => array:2 [ "total" => 31669 "formatos" => array:3 [ "EPUB" => 146 "HTML" => 30097 "PDF" => 1426 ] ] "pt" => array:13 [ "idiomaDefecto" => true "cabecera" => "Revisão" "titulo" => "Hiperplasia congénita da suprarrenal não clássica – aspetos relevantes para a prática clínica" "tienePdf" => "pt" "tieneTextoCompleto" => "pt" "tieneResumen" => array:2 [ 0 => "pt" 1 => "en" ] "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "59" "paginaFinal" => "64" ] ] "titulosAlternativos" => array:1 [ "en" => array:1 [ "titulo" => "Nonclassical congenital adrenal hyperplasia – relevant aspects for clinical practice" ] ] "contieneResumen" => array:2 [ "pt" => true "en" => true ] "contieneTextoCompleto" => array:1 [ "pt" => true ] "contienePdf" => array:1 [ "pt" => true ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Figura 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 445 "Ancho" => 1672 "Tamanyo" => 62912 ] ] "descripcion" => array:1 [ "pt" => "Valores de referência para diagnóstico de hiperplasia congénita suprarrenal através da prova de estimulação com ACTH." ] ] ] "autores" => array:1 [ 0 => array:2 [ "autoresLista" => "Teresa Azevedo, Teresa Martins, Manuel Carlos Lemos, Fernando Rodrigues" "autores" => array:4 [ 0 => array:2 [ "nombre" => "Teresa" "apellidos" => "Azevedo" ] 1 => array:2 [ "nombre" => "Teresa" "apellidos" => "Martins" ] 2 => array:2 [ "nombre" => "Manuel Carlos" "apellidos" => "Lemos" ] 3 => array:2 [ "nombre" => "Fernando" "apellidos" => "Rodrigues" ] ] ] ] ] "idiomaDefecto" => "pt" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1646343914000029?idApp=UINPBA00004N" "url" => "/16463439/0000000900000001/v1_201407280026/S1646343914000029/v1_201407280026/pt/main.assets" ] "en" => array:20 [ "idiomaDefecto" => true "cabecera" => "Revisão" "titulo" => "Assessment of methods and indexes of insulin sensitivity" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "65" "paginaFinal" => "73" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Rita S. Patarrão, Wilford Wayne Lautt, Maria Paula Macedo" "autores" => array:3 [ 0 => array:4 [ "nombre" => "Rita S." "apellidos" => "Patarrão" "email" => array:1 [ 0 => "rita.patarrao@fcm.unl.pt" ] "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Wilford" "apellidos" => "Wayne Lautt" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "b" "identificador" => "aff0010" ] ] ] 2 => array:3 [ "nombre" => "Maria" "apellidos" => "Paula Macedo" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "c" "identificador" => "aff0015" ] 1 => array:2 [ "etiqueta" => "d" "identificador" => "aff0020" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "CEDOC, Área de Ensino e Investigação de Medicina Celular e Molecular, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal" "etiqueta" => "a" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba R3E OW3, Canada" "etiqueta" => "b" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "CEDOC, Departamento de Fisiologia, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal" "etiqueta" => "c" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "APDP-ERC Portuguese Diabetes Association Education and Research Center, Rua do Salitre, 118-120, 1250-203 Lisbon, Portugal" "etiqueta" => "d" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "⁎" "correspondencia" => "Corresponding author." ] ] ] ] "titulosAlternativos" => array:1 [ "pt" => array:1 [ "titulo" => "Métodos de avaliação e índices de sensibilidade à insulina" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 789 "Ancho" => 2143 "Tamanyo" => 97102 ] ] "descripcion" => array:1 [ "en" => "(A) Mean profile using the dynamic analysis of the pattern of glucose infusion during the Rapid Insulin Sensitivity Test (RIST). The mean RIST curves were obtained by averaging glucose infusion rates at 0.1-min intervals throughout the test (Postprandial RIST (bold line) and the RIST obtained after 24h-fast (simple line)). (B) Calculation of the area under the curve during the 24 h-fast and postprandial RIST, that corresponds to the total amount of glucose infused to maintain euglycemia over the test period, which is terminated when no further glucose infusion is required (RIST index).<a class="elsevierStyleCrossRef" href="#bib0280">56</a>" ] ] ] "textoCompleto" => "IntroductionMeasurements of insulin sensitivity provide clinicians and researchers with excellent instruments to objectively evaluate the efficiency of both current and potentially useful interventional tools.It is of great importance to develop tools for quantifying insulin sensitivity/resistance in humans, which may be used to appropriately investigate the epidemiology, pathophysiologic mechanisms, outcomes of therapeutic interventions, and clinical course of patients with insulin resistance.Methods of insulin sensitivity/resistance assessmentHyperinsulinemic Euglycemic Glucose ClampThe Hyperinsulinemic Euglycemic Clamp (HIEC), originally developed by DeFronzo, is widely accepted as the “gold standard” for directly determining metabolic insulin sensitivity in humans.<a class="elsevierStyleCrossRef" href="#bib0005">1</a> After an overnight fast, insulin is infused intravenously at a constant rate that may range from 5 to 120mU/m2/min (dose per body surface area per minute, during 180min). This constant insulin infusion results in a new steady-state insulin level that is above the fasting level (hyperinsulinemic). Consequently, glucose disposal in skeletal muscle and adipose tissue is increased while hepatic glucose production (HGP) is suppressed. Under these conditions, a glucose analyzer is used to frequently monitor blood glucose levels at 5–10min intervals, while 20% dextrose is given intravenously at a variable rate in order to “clamp” blood glucose concentrations in the normal range (euglycemic). After several hours of constant insulin infusion, steady-state conditions are typically achieved for plasma insulin, blood glucose, and the glucose infusion rate (GIR). Assuming that the hyperinsulinemic state is sufficient to completely suppress HGP, and since there is no net change in blood glucose concentrations under steady-state clamp conditions, the GIR must be equal to the glucose disposal rate (M). Thus, whole body glucose disposal at a given level of hyperinsulinemia can be directly determined. M is typically normalized to body weight or fat-free mass to generate an estimate of insulin sensitivity. Alternatively, an insulin sensitivity index (SI) derived from clamp data can be defined as SIClamp=MG×ΔI, where M is normalized for G (steady-state blood glucose concentration) and ΔI (difference between fasting and steady-state plasma insulin concentrations).<a class="elsevierStyleCrossRef" href="#bib0010">2</a>The validity of glucose clamp measurements of insulin sensitivity depends on achieving steady-state conditions. “Steady-state” is often defined as a period greater than 30min (at least 1h after initiation of insulin infusion) during which the coefficients of variation for blood glucose, plasma insulin, and GIR are less than 5%.<a class="elsevierStyleCrossRef" href="#bib0010">2</a> It is possible to use a radiolabeled glucose tracer under clamp conditions to estimate hepatic glucose production, so that appropriate corrections can be made to M in the event HGP is not completely suppressed.<a class="elsevierStyleCrossRefs" href="#bib0015">3–5</a> An alternative approach is to use an insulin infusion rate sufficiently high to completely suppress HGP according to the insulin sensitivity/resistance of the population to be studied.M is routinely obtained at only a single insulin infusion rate, and therefore comparisons between M or SIClamp among different subjects is valid only if the same insulin infusion rate is used for all subjects.The principal advantage of the glucose clamp in humans is that it directly measures whole body glucose disposal at a given level of insulinemia under steady-state conditions. Conceptually, the approach is straightforward but there is a limited number of assumptions that are clearly defined. In research settings where assessing insulin sensitivity/resistance is of primary interest and feasibility is not an issue, it is appropriate to use the glucose clamp technique.The main limitations of the HIEC approach are that it is time-consuming, labor intensive, expensive, and requires an experienced operator to manage technical difficulties. Another limitation is that the clamp utilizes steady-state insulin levels that may be supraphysiological. This results in a reversal of the normal portal to peripheral insulin gradient. Thus, the glucose clamp may not accurately reflect insulin action and glucose dynamics under physiological conditions that a dynamic test, such as, an oral meal or oral glucose load may determine. Further, in the HIEC insulin sensitivity is measured only under a steady-state condition, and therefore, the test does not realistically portray dynamic conditions such as those occurring after normal meals. Because HIEC is dependent on steady-state conditions, insulin infusion is continuous for ≈3h, and the subjects are in the fasted state. The results of the HIEC may be limited by these restraints, because insulin release is pulsatile,<a class="elsevierStyleCrossRefs" href="#bib0030">6–8</a> and insulin action is sensitized in the postprandial state.<a class="elsevierStyleCrossRef" href="#bib0045">9</a> Nevertheless, it should be remembered that the HIEC measures insulin-stimulated glucose disposal only at insulin levels in the upper physiological range; information on the effects of insulin on glucose uptake and production in the basal condition, which is physiologically very important, is not provided (unless tracers are used).<a class="elsevierStyleCrossRef" href="#bib0050">10</a>Insulin Tolerance TestThe Insulin Tolerance Test (ITT) was one of the first methods developed to assess insulin sensitivity in vivo.<a class="elsevierStyleCrossRef" href="#bib0055">11</a> In this method, a fixed bolus of regular insulin (0.1IU/kg bw) is given iv after an 8–10h fast. Blood samples are collected at 15 and 5min before and 3, 6, 9, 12, 15, 20 and 30min after insulin injection, and the plasma glucose decrement is then measured. Glucose is injected at 30min to stop the fall in plasma glucose.<a class="elsevierStyleCrossRefs" href="#bib0060">12,13</a> The faster the decline in glucose concentration, the more insulin sensitive the subject is. The slope of the linear decline in plasma glucose (KITT) can be calculated by dividing 0.693 by the plasma glucose half-time (50% from baseline):<elsevierMultimedia ident="eq0005"></elsevierMultimedia>where t1/2 represents the half-life of plasma glucose decrease, and is calculated from the slope of least square analysis of the plasma glucose concentrations from 3 to 15min after iv insulin injection, when the plasma glucose concentration declined linearly. Normal KITT is >2.0%/min and values <1.5%/min are considered abnormal. This method gives an indirect estimate of overall insulin sensitivity.The advantages of the ITT include its simplicity, rapidity and the use of a bolus injection of insulin. The bolus injection of insulin mimics the physiological pulsatile release of insulin.<a class="elsevierStyleCrossRef" href="#bib0030">6</a> Furthermore, because glucose tolerance after a meal is dependent on insulin sensitivity, measuring insulin sensitivity in the prandial state is physiologically relevant.Some of the drawbacks of this method include the supraphysiological insulin dose used, and also the fact that the test does not differentiate peripheral vs hepatic insulin resistance.<a class="elsevierStyleCrossRef" href="#bib0070">14</a> Another major limitation of this test is the risk of hypoglycemia. Hypoglycemia triggers hormonal responses, which may interfere with insulin sensitivity and in turn slows the disappearance rate of glucose from plasma.<a class="elsevierStyleCrossRef" href="#bib0075">15</a> In this view, the fall in plasma glucose concentration would be a function of the interplay between insulin, on the one hand, and glucagon, catecholamines, growth hormone and cortisol, on the other. Given that, the counterregulatory response occurs only 15–20min after insulin injection. The glucose fall occurring in the first 15min after iv insulin administration is probably a function of insulin-stimulated glucose uptake by tissues as well as insulin ability to suppress glucose output by the liver.<a class="elsevierStyleCrossRef" href="#bib0080">16</a>A lower insulin dose method of 0.05YIU/kg bw, or shortening the test to 15min was suggested as an attempt to decrease the risk of hypoglycemia.<a class="elsevierStyleCrossRefs" href="#bib0070">14,17</a> The shorter version<a class="elsevierStyleCrossRefs" href="#bib0060">12,16</a> derived from the notion that the counterregulatory hormone response occurs only after 20min of the insulin infusion.<a class="elsevierStyleCrossRef" href="#bib0090">18</a>The ITT has been shown to correlate with the HIEC in several studies.<a class="elsevierStyleCrossRefs" href="#bib0060">12,16</a> However, arterialization of blood is essential in the ITT, as data from standard venous blood measurements showed no significant relationship with HIEC-derived glucose disposal.<a class="elsevierStyleCrossRef" href="#bib0080">16</a>In conclusion, the ITT should be used with great caution in insulin sensitive individuals because of the increased risk of hypoglycemia, even when the smaller dose version of the test is used. The shorter ITT is a valid test in large-scale studies, especially when the site of resistance is not of importance.Insulin Suppression TestThe insulin-suppression test (IST), another method that directly measures metabolic insulin sensitivity/resistance, was introduced by Shen et al. in 1970 and subsequently modified by Harano et al.<a class="elsevierStyleCrossRefs" href="#bib0095">19,20</a> After an overnight fast, somatostatin (250μg/h) or the somatostatin analog octreotide (25μg bolus, followed by 0.5μg/min)<a class="elsevierStyleCrossRef" href="#bib0105">21</a> is intravenously infused, to suppress endogenous secretion of insulin and glucagon. Simultaneously, insulin (25mU/m2/min) and glucose (240mg/m2/min) are intravenously infused over 3h. Blood samples for glucose and insulin determinations are taken every 30min for 2.5h, and then at 10min intervals from 150 to 180min of the IST. The constant infusions of insulin and glucose determine steady-state plasma insulin (SSPI) and glucose (SSPG) concentrations. The steady-state period is assumed to be from 150 to 180min after initiation of the IST. SSPI concentrations are generally similar among subjects. Therefore, the SSPG concentration will be higher in insulin resistant subjects and lower in insulin sensitive subjects, i.e., SSPG values are inversely related to insulin sensitivity. The IST provides a direct measure (through SSPG) of the ability of exogenous insulin to mediate disposal of an iv glucose load, under steady-state conditions, where endogenous insulin secretion is suppressed.<a class="elsevierStyleCrossRef" href="#bib0110">22</a>The SSPG is a highly reproducible direct measure of metabolic actions of insulin, that is, less labor intensive and less technically demanding than HIEC. Indeed, since there are no variable infusions with the IST, steady-state conditions are more easily achieved with the IST than with HIEC. In research settings, the IST can be used for larger populations that may pose difficulties for application of HIEC. ELIMINAR esta frase.Many of the limitations of the IST are similar to those described for HIEC (with the exception that the IST is less technically demanding). Thus, it is impractical to apply the IST in large epidemiological studies or in the clinical care setting. SSPG under ideal conditions determines primarily skeletal muscle insulin sensitivity, and is not designed to reflect hepatic insulin sensitivity.<a class="elsevierStyleCrossRef" href="#bib0110">22</a>Continuous infusion of glucose with model assessmentThe continuous infusion of glucose with model assessment (CIGMA) is a procedure that assesses insulin sensitivity through the evaluation of the near steady-state glucose and insulin concentrations after a continuous infusion of glucose, with model assessment.<a class="elsevierStyleCrossRef" href="#bib0115">23</a> This method mimics postprandial glucose and insulin concentrations. CIGMA not only provides information about glucose tolerance and insulin sensitivity, but also about β-cell function. Using a mathematic model of glucose homeostasis, glucose and insulin values are compared with known physiologic data of glucose, and insulin kinetics in response to glucose infusion, which are derived from healthy lean subjects with no family history of diabetes.<a class="elsevierStyleCrossRef" href="#bib0115">23</a>The glucose and insulin values used for CIGMA are obtained during the last 15min of the 60min continuous glucose infusion (5mg glucose/kg bw/min). Samples are collected at 5min intervals and the average is then compared with predicted values from the computer model. The median value for normal subjects is 1.35, and for diabetic patients with mild hyperglycemia is 4.0.<a class="elsevierStyleCrossRef" href="#bib0115">23</a>There are two main advantages of CIGMA over Homeostasis Model Assessment (HOMA). First, the insulin values that are measured in CIGMA are much higher than those in HOMA owing to the glucose stimulus and second, higher insulin concentration in CIGMA stimulates peripheral glucose uptake producing a steady-state glucose concentration, which is a better reflection of the peripheral insulin sensitivity.<a class="elsevierStyleCrossRef" href="#bib0090">18</a>Although CIGMA is more practical, cheaper and less invasive than the frequently sampled intravenous glucose tolerance test (FSIVGTT) and HIEC procedure, the model incorrectly assumes that levels of insulin resistance at the liver and peripheral tissues are equal. Furthermore, in insulin-deficient subjects, where the insulin response is insufficient to stimulate glucose uptake, the interpretation of CIGMA is difficult.Minimal model analysis of frequently sampled intravenous glucose tolerance testThe minimal model, developed by Bergman, Cobelli and colleagues in 1979, provides an indirect measure of metabolic insulin sensitivity/resistance based on glucose and insulin data obtained during a frequently sampled intravenous glucose tolerance test (FSIVGTT).<a class="elsevierStyleCrossRef" href="#bib0120">24</a> After an overnight fast, an intravenous bolus of glucose (0.3g/kg bw) is infused over 2min starting at time 0.Currently, a modified FSIVGTT is used, where exogenous insulin (4mU/kg/min) is also infused over 5min beginning 20min after the iv glucose bolus.<a class="elsevierStyleCrossRefs" href="#bib0125">25,26</a> Some studies use tolbutamide (a potassium channel blocker) instead of insulin in the modified FSIVGTT, to stimulate endogenous insulin secretion.<a class="elsevierStyleCrossRefs" href="#bib0135">27,28</a>Blood samples are taken for plasma glucose and insulin measurements at different time points, before and 180min after glucose infusion. The data obtained are then subjected to minimal model analysis using the computer program MINMOD (minimal model approach – MINMOD), to generate an index of insulin sensitivity (SI).The MINMOD is defined by two coupled differential equations with four model parameters (<a class="elsevierStyleCrossRef" href="#fig0005">Fig. 1</a>). The first equation describes plasma glucose dynamics in a single compartment. The second equation describes insulin dynamics in a “remote compartment”. The structure of the MINMOD allows it to uniquely identify model parameters, which determine a best fit to glucose disappearance during the modified FSIVGTT. SI is calculated from two of these model parameters, and is defined as fractional glucose disappearance per insulin concentration unit.<a class="elsevierStyleCrossRef" href="#bib0145">29</a><elsevierMultimedia ident="fig0005"></elsevierMultimedia>In addition to SI, other minimal model parameters may be used to estimate a “glucose effectiveness” index (SG). SG is defined as the ability of glucose per se to promote its own disposal and inhibit hepatic glucose production (HGP) in the absence of an incremental insulin effect (i.e., when insulin is at basal levels).<elsevierMultimedia ident="eq0010"></elsevierMultimedia><elsevierMultimedia ident="eq0015"></elsevierMultimedia>Minimal model analysis of the modified FSIVGTT is easier than HIEC method because it is slightly less labor intensive, steady-state conditions are not required, and there are no iv infusions that require constant adjustment. Unlike HIEC or IST, information about insulin sensitivity, glucose effectiveness, and β-cell function can be derived from a single dynamic test. The minimal model generates excellent predictions of glucose disappearance during the FSIVGTT.In research settings, where assessing insulin sensitivity along with glucose effectiveness and β-cell function is of interest, minimal model analysis of the insulin-modified FSIVGTT may be appropriate. The minimal model approach is simpler than direct methods for determining insulin sensitivity. Nevertheless, it still involves iv infusions with multiple blood sampling over a 3h period, that is, nearly as labor intensive as the HIEC or IST. In addition, many limitations of minimal model analysis stem from the fact that the model oversimplifies the physiology of glucose homeostasis.<a class="elsevierStyleCrossRef" href="#bib0145">29</a>Another oversimplification of the minimal model involves lumping together effects of insulin to promote peripheral glucose utilization and suppress HGP. As insulin sensitivity/resistance varies, the relative contribution of HGP to SI may vary significantly. Since the minimal model relies on a dynamic test to evaluate insulin sensitivity, estimates of SI are much less reliable in individuals with impaired insulin secretion and/or significant insulin resistance (when compared with healthy subjects). Under these conditions, the minimal model may overestimate SG to accurately predict the disappearance of glucose during the FSIVGTT. Indeed, estimates of SG are spuriously affected by differences in insulin secretory capacity.<a class="elsevierStyleCrossRefs" href="#bib0130">26,30</a> Moreover, for similar reasons, minimal model analysis often generates senseless negative values for SI in a substantial proportion of subjects with diabetes, who have minimal insulin secretory capacity and significant insulin resistance.<a class="elsevierStyleCrossRefs" href="#bib0010">2,30</a> These nonsystematic errors inherent in the minimal model approach are highlighted by calibration model analysis, demonstrating that some simple surrogate indexes of insulin sensitivity have better absolute accuracy for predicting SIClamp than the minimal model-derived SI.<a class="elsevierStyleCrossRef" href="#bib0155">31</a>Oral Glucose Tolerance TestThe Oral Glucose Tolerance Test (OGTT) is a simple test, widely used in clinical practice to diagnose glucose intolerance and type 2 diabetes.<a class="elsevierStyleCrossRefs" href="#bib0090">18,32,33</a> After an overnight fast, blood samples for determinations of glucose and insulin concentrations are taken at 0, 30, 60, and 120min following a standard oral glucose load (75g).<a class="elsevierStyleCrossRef" href="#bib0165">33</a> A diagnosis of diabetes is conferred if an individual has a plasma glucose level ≥200mg/dl (11Ymmol/l) as measured 2h after the ingestion of a 75g glucose load. If an individual has a value in the range of 140–199mg/dl (7.7–11Ymmol/l) 2h post-glucose load, it is designated as having impaired glucose tolerance.<a class="elsevierStyleCrossRef" href="#bib0165">33</a> Oral glucose tolerance reflects the efficiency with which the body handles glucose after an oral glucose load.The OGTT mimics the glucose and insulin dynamics of physiological conditions more closely than conditions of the HIEC, IST or frequently sample intravenous glucose tolerance test (FSIVGTT).<a class="elsevierStyleCrossRef" href="#bib0170">34</a> However, it is important to recognize that glucose tolerance and insulin sensitivity are not equivalent concepts. In addition to metabolic actions of insulin, insulin secretion, incretin effects, and other factors contribute importantly to glucose tolerance. Thus, the OGTT, by itself, provides useful information about glucose tolerance but not insulin sensitivity/resistance per se.<a class="elsevierStyleCrossRefs" href="#bib0175">35,36</a> During the OGTT, the use of a glucose tracer and both insulin and C-peptide plasma measurements at specific time points, allows the calculation of glucose clearance.The OGTT is technically quite simple to perform and certainly lower in cost than HIEC or FSIVGTT. These considerations have made the OGTT the glucose challenge test of choice in clinical situations.<a class="elsevierStyleCrossRef" href="#bib0185">37</a> However, there are some problems with the OGTT that make it less desirable for use in research situations. First, there is variability in the rate of gastric emptying and glucose absorption from the gastrointestinal tract, causing some imprecision from the start. This variability can partially account for poorly reproducible results even within the same individual.<a class="elsevierStyleCrossRef" href="#bib0190">38</a> Second, glucose measurements in the standard OGTT do not give adequate information regarding the dynamics of glucose and insulin action.<a class="elsevierStyleCrossRef" href="#bib0165">33</a>The OGTT is a relatively crude measure of glucose tolerance. It does not measure the components of insulin sensitivity and insulin secretion. In light of this limitation, attempts have been made to obtain indices from OGTT data that might better reflect β-cell function and insulin sensitivity.<a class="elsevierStyleCrossRefs" href="#bib0195">39,40</a>Meal Tolerance TestIn an attempt to study the ability to regulate blood glucose in a more physiological situation than the OGTT, some authors measure the glycemic profile in response to the ingestion of a mixed meal containing carbohydrates, fat and proteins; the Meal Tolerance Test (MTT).The experimental procedure for the MTT is similar to the OGTT, that is, after an overnight fast (10–12h), a mixed meal (liquid or solid) is given and the glycemic profile is measured throughout 2h; usually the insulin profile is also determined during the same period of time.<a class="elsevierStyleCrossRefs" href="#bib0170">34,36</a>The MTT is a “physiologic” variant of OGTT<a class="elsevierStyleCrossRef" href="#bib0205">41</a> offering several advantages: (a) lack of artifactual postload hypoglycemia, thus making this test suitable for the study of postprandial hypoglycemia, a situation which is frequently due to high values of insulin sensitivity, but also to hyperinsulinism in a context of insulin resistance<a class="elsevierStyleCrossRef" href="#bib0210">42</a>; (b) use of a physiologic stimulus triggering a cephalic phase proportional to palatability scores<a class="elsevierStyleCrossRef" href="#bib0215">43</a>; (c) possibility to measure insulin sensitivity with a modified algorithm based on the minimal model<a class="elsevierStyleCrossRef" href="#bib0180">36</a> as well as glucose effectiveness and insulin secretion; (d) potential for evaluating the physiologic effects of incretins.<a class="elsevierStyleCrossRef" href="#bib0220">44</a>The MTT can represent a simple procedure, less unpleasant for the patient than the standard OGTT, and providing both a physiologic picture of glucoregulation, and a sophisticated and precise analysis of this glucoregulation, in terms of insulin sensitivity, glucose effectiveness, and insulin secretion.<a class="elsevierStyleCrossRef" href="#bib0205">41</a>The β-cell response is stronger after a mixed meal than after an OGTT with equal carbohydrate quantity, both for classical and model-based parameters. The higher response was mostly explained by higher β-cell sensitivity during the meal, which may lead to lower glucose excursions.<a class="elsevierStyleCrossRef" href="#bib0225">45</a>Several factors may contribute to differences in insulin secretion following an MTT compared with the OGTT. The MTT has a lower glycemic index than the OGTT, which may lead to lower glucose excursions.<a class="elsevierStyleCrossRef" href="#bib0230">46</a> Moreover, slower gastric emptying following the MTT due to larger volume,<a class="elsevierStyleCrossRef" href="#bib0235">47</a> solid character,<a class="elsevierStyleCrossRef" href="#bib0240">48</a> and fat content<a class="elsevierStyleCrossRef" href="#bib0245">49</a> will lead to a slower entry of nutrients into the circulation.The MTT might be considered as an additional tool for the assessment of metabolic abnormalities, in glucose-intolerant and insulin-resistant states.<a class="elsevierStyleCrossRef" href="#bib0170">34</a>Thus, the MTT is a more physiological test than the OGTT, in regard to human diet, and is potentially able to give useful information concerning islet β-cell function in the different categories of glucose intolerance,<a class="elsevierStyleCrossRef" href="#bib0250">50</a> but not insulin sensitivity/resistance per se.<a class="elsevierStyleCrossRef" href="#bib0180">36</a>As any other method that measures glucose tolerance, the MTT does not assess insulin sensitivity directly and may not be repeated in the same subject or animal on the same day.Rapid Insulin Sensitivity TestA new method for insulin sensitivity quantification, called the Rapid Insulin Sensitivity Test (RIST), was described and evaluated for use in rats,<a class="elsevierStyleCrossRefs" href="#bib0255">51,52</a> cats<a class="elsevierStyleCrossRefs" href="#bib0265">53,54</a> mice<a class="elsevierStyleCrossRef" href="#bib0275">55</a> and humans.<a class="elsevierStyleCrossRef" href="#bib0280">56</a> The standard dynamic profile for the RIST in fed and fasted humans as well as the RIST insulin sensitivity index is shown in <a class="elsevierStyleCrossRef" href="#fig0010">Fig. 2</a>.<elsevierMultimedia ident="fig0010"></elsevierMultimedia>The RIST is an euglycemic test and is carried out after establishing the glycemic baseline, which is done by taking arterialized venous blood samples at 5min intervals until three consecutive measurements are stable. An insulin infusion is commenced (50YmIU/kg administered over 5min) and, after 1min, glucose samples are taken at 2min intervals, and glucose is infused intravenously at a variable rate to maintain euglycemia. The test is completed when no more glucose is required. At the standard test dose of insulin of 50YmIU/kg, the RIST in the fasted state is complete within approximately 40min. The RIST index, the insulin sensitivity parameter, is simply the amount of glucose that had to be administered in order to maintain euglycemia after the bolus administration of insulin.<a class="elsevierStyleCrossRef" href="#bib0260">52</a>The majority of the insulin sensitivity tests are done in the fasted state, when insulin sensitivity would be logically anticipated to be at its lowest level. Studies performed by Patarrão et al. and Lautt et al. indicated that the fasted state results in a very low insulin responsiveness. It is reasonable that insulin sensitivity should be under a regulatory mechanism such that in the fasted state insulin effect would be minimized, and inappropriate release of insulin would not, therefore, lead to life-threatening hypoglycemia. The RIST can be carried out in the fed state.<a class="elsevierStyleCrossRefs" href="#bib0045">9,56</a> Furthermore, the RIST allows insulin sensitivity assessment before and after a meal, making it possible to test both meal and drug effects on insulin sensitivity.<a class="elsevierStyleCrossRefs" href="#bib0280">56,57</a>The RIST is extremely sensitive and can be shown to generate dose-response relationships to insulin, which makes the RIST the most advantageous method in the determination of small differences in insulin sensitivity. This method is able to be carried out more than one time in the same subject with high reproducibility, and is sufficiently versatile to permit paired experimental designs, in the same subjects and on the same day. Both the accuracy and precision of the test can be assessed from determination of the deviation from the ideal euglycemic target.<a class="elsevierStyleCrossRef" href="#bib0260">52</a>Insulin release normally occurs in a pulsatile manner, and hormones released in a pulsatile manner are best studied by pulsatile administration.<a class="elsevierStyleCrossRef" href="#bib0290">58</a> Based on this assumption, the intravenous insulin bolus administered at the beginning of the RIST mimics the physiological insulin action. It also avoids the vagal withdrawal and sympathetic activation induced by sustained hyperinsulinemia, during the HIEC<a class="elsevierStyleCrossRefs" href="#bib0275">55,59</a> and the hypoglycemia caused by the acute ITT.<a class="elsevierStyleCrossRef" href="#bib0295">59</a> It does not alter levels of counter-regulatory hormones, such as catecholamines, somatostatin or glucagon.<a class="elsevierStyleCrossRef" href="#bib0270">54</a> Moreover, both insulinemia and glycemia return to basal levels after each RIST.One methodological issue relates to the basal glucose concentration determined before and after the RIST. Previous studies demonstrate clearly that there is no mean change in basal blood glucose levels used as the euglycemic target when, for example, compared before and after denervation of the hepatic plexus in rats<a class="elsevierStyleCrossRef" href="#bib0300">60</a> or atropine.<a class="elsevierStyleCrossRef" href="#bib0305">61</a> In addition, we have also determined that there is no correlation between the magnitude of the RIST index and basal glucose levels when compared using a large number of data points.<a class="elsevierStyleCrossRef" href="#bib0260">52</a> Of more concern is the importance that glucose uptake or output should not change during the RIST. Whatever stimulus is used, including either ablation or stimulation protocols, the stimulus is administered prior to conducting the RIST, and a new stable glycemic baseline must be demonstrated. In addition, at the conclusion of the RIST index, the re-established baseline must not be significantly altered. In the event that such alteration occurs, it suggests that glucose output either increased or decreased during the test. This is usually obvious by comparing the shape of normal RIST curves with that obtained in the presence of the altered baseline. In such situations, the data must be excluded, and the RIST repeated.None of the available methods available to estimate insulin sensitivity/resistance proved to be a reliable way to assess insulin sensitivity/resistance since most of them have non-physiological continuous infusion of insulin and/or glucose, which interfere with peripheral insulin sensitivity/resistance; take a long time to be performed; could not avoid counter-regulatory responses to the hypoglycemia that follows an insulin bolus; could not allow the assessment of insulin sensitivity in different conditions in the same subject, and in the same day; and they only evaluate insulin sensitivity/resistance in the fasted state. Based on all of these drawbacks, it was necessary to develop another method for assessing insulin sensitivity/resistance.To summarize, the RIST is a quick method to evaluate insulin sensitivity, reproducible in the same subject and on the same day, utilizes a bolus of insulin to mimic pulsatile insulin release, and can be performed in the fed or fasting state. In addition, since the RIST is an euglycemic test, avoids hypoglycemia and prevents the activation of counter-regulatory hormones. The RIST provides a new powerful tool to dissect insulin action in the fasted and fed state, and may provide a means to detect the pre-diabetic state, where early insulin resistance can be detected well before the impairment of the direct effect of insulin at a time when lifestyle interventions can be readily tested.Simple surrogate indexes for insulin sensitivity/resistanceHomeostasis Model AssessmentThe Homeostasis Model Assessment (HOMA), developed in 1985, is a model of interactions between glucose and insulin dynamics, that is then used to predict fasting steady-state glucose and insulin concentrations, for a wide range of possible combinations of insulin resistance and β-cell function.<a class="elsevierStyleCrossRef" href="#bib0310">62</a> The model assumes a feedback loop between the liver and β-cell<a class="elsevierStyleCrossRefs" href="#bib0310">62,63</a>; and glucose concentrations are regulated by insulin-dependent hepatic glucose production, while insulin levels depend on the pancreatic β-cell response to glucose concentrations. Thus, a diminished response to glucose-stimulated insulin secretion reflects deficient β-cell function. Likewise, insulin resistance is reflected by diminished suppressive effect of insulin on hepatic glucose production.HOMA model describes this glucose-insulin homeostasis by a set of empirically derived non-linear equations. The model predicts fasting steady-state levels of plasma glucose and insulin for any given combination of pancreatic β-cell function (HOMA%B) and insulin sensitivity (HOMA%S).In practical terms, most studies using HOMA employ an approximation described by a simple equation to determine a surrogate index of insulin resistance. This is defined by the product of the fasting glucose and fasting insulin, divided by a constant. The formula for the HOMA model is:<elsevierMultimedia ident="eq0020"></elsevierMultimedia>The denominator of 22.5 is a normalizing factor, i.e., the product of normal fasting plasma insulin of 5μIU/ml and normal fasting plasma glucose of 4.5Ymmol/l obtained from an “ideal and normal” individual.<a class="elsevierStyleCrossRef" href="#bib0310">62</a> Therefore, for an individual with normal insulin sensitivity, HOMA=1. It is important to note that, over wide ranges of insulin sensitivity/resistance, log (HOMA) transforms the skewed distribution of fasting insulin values to determine a much stronger linear correlation with HIEC estimates of insulin sensitivity.<a class="elsevierStyleCrossRef" href="#bib0010">2</a>HOMA or log (HOMA) is extensively used in large epidemiological studies, prospective clinical trials, and research studies. In research settings where assessing insulin sensitivity/resistance is of secondary interest or feasibility issues preclude the use of direct measures by HIEC, it may be appropriate to use log (HOMA).<a class="elsevierStyleCrossRef" href="#bib0315">63</a>Quantitative insulin sensitivity check indexQuantitative insulin sensitivity check index (QUICKI) is an empirically derived mathematical transformation that uses fasting blood glucose and plasma insulin concentrations. It provides a reliable, reproducible, and accurate index of insulin sensitivity with excellent positive predictive power.<a class="elsevierStyleCrossRefs" href="#bib0010">2,64</a> Since fasting insulin levels have a non-normal skewed distribution, log transformation improves its linear correlation with reference standard glucose clamp (SIClamp). However, as with 1/(fasting insulin) and the glucose/insulin ratio, this correlation is not maintained in diabetic subjects with fasting hyperglycemia and impaired β-cell function that is insufficient to maintain euglycemia. To accommodate these clinically important circumstances where fasting glucose is inappropriately high, insulin is inappropriately low, application of logarithm to both fasting glucose, and fasting insulin provides a reasonable correction such that the linear correlation with SIClamp is maintained, in both diabetic and non-diabetic subjects. The reciprocal of this sum results in further transformation of the data generating an insulin sensitivity index that has a positive correlation with SIClamp. Thus, QUICKI is defined by the following formula:<elsevierMultimedia ident="eq0025"></elsevierMultimedia>QUICKI is among the most thoroughly evaluated and validated surrogate index for insulin sensitivity. As a simple, useful, inexpensive, and minimally invasive surrogate for HIEC-derived measures of insulin sensitivity, QUICKI is appropriate and effective for use in large epidemiological or clinical research studies, to follow changes after therapeutic interventions, and for use in studies where evaluation of insulin sensitivity is not of primary interest.<a class="elsevierStyleCrossRefs" href="#bib0010">2,65</a>QUICKI and HOMA were derived in a completely different conceptual fashion. Nevertheless, these two surrogate indexes are mathematically related, i.e., QUICKI is proportional to 1/log (HOMA).The major advantage of both the QUICKI and HOMA models is that they both require only one blood draw from a fasting patient. They thus do not require extensive technical expertise, and constitute a much lower cost per subject when compared with the HIEC or the FSIVGTT, making the QUICKI and HOMA models much more practical for use in large-scale epidemiologic studies, and for clinical situations.<a class="elsevierStyleCrossRef" href="#bib0315">63</a>However, the major disadvantage is that both of these methods fail to provide information about the stimulated glucose and insulin systems. Essentially, they provide information only about what is occurring with homeostatic mechanisms in the fasting state, largely reflecting insulin's effect on hepatic glucose production and not on peripheral glucose uptake, which is the more relevant aspect concerning insulin action/resistance.Insulin sensitivity indexesCederholm and Wibell indexThe insulin sensitivity index proposed by Cederholm and Wibell represents mainly peripheral insulin sensitivity and muscular glucose uptake, due to the dominant role of peripheral tissues in glucose disposal after an oral glucose load.<a class="elsevierStyleCrossRef" href="#bib0200">40</a>The formula for the Cederholm index is:<elsevierMultimedia ident="eq0030"></elsevierMultimedia>where 75,000 – oral glucose load in an OGTT in mg, G0 – fasting plasma glucose concentration (mmol/l), G120 – plasma glucose concentration in the 120th min of OGTT (mmol/l), 1.15 – factor transforming whole venous blood glucose to plasma values (not necessary, if glucose concentration is estimated in plasma), 180 – conversion factor to transform plasma glucose concentration from mmol/l into mg/dl, 0.19 – glucose space in liter per kg of body weight, m – body weight (kg), 120 – duration of OGTT (min), Imean – mean plasma insulin concentration during OGTT (mIU/l) and Gmean – mean plasma glucose concentration during OGTT (mmol/l).Values found in normal non-obese individuals were reported to be about 79±14mgl2/mmol/mIU/min, lower in obese individuals, in subjects with impaired glucose tolerance and in patients with type 2 diabetes.<a class="elsevierStyleCrossRef" href="#bib0200">40</a>Gutt et al. indexThe ISI0,120 was adapted from the Cederholm insulin sensitivity index, by omitting the constant terms, and using the plasma glucose and insulin concentration from fasting (0min) and 120min samples from the OGTT.<a class="elsevierStyleCrossRef" href="#bib0330">66</a>The ISI0,120 index is defined as:<elsevierMultimedia ident="eq0035"></elsevierMultimedia>where 75,000 – oral glucose load in an OGTT in mg, G0 – fasting plasma glucose concentration (mg/dl), G120 – plasma glucose concentration in the 120th min of OGTT (mg/dl), 0.19 – glucose space in l/kg of body weight, m – body weight (kg), 120 – duration of OGTT (min), Imean – mean plasma insulin concentration during OGTT (mIU/l) and Gmean – mean plasma glucose concentration during OGTT (mmol/l).The reference range for lean controls was 89±39, for obese 58±23 and for diabetic patients 23±19mgl2/mmol/mIU/min.<a class="elsevierStyleCrossRef" href="#bib0090">18</a>Avignon et al. indexAvignon<a class="elsevierStyleCrossRef" href="#bib0335">67</a> proposed 3 insulin sensitivity indices: Sib (derived from fasting plasma insulin and glucose concentrations), Si2h (derived from plasma insulin and glucose concentrations in the 120th min of OGTT) and SiM (derived by averaging Sib and Si2h after balancing Sib by a coefficient of 0.137 to give the same weight to both indices):<elsevierMultimedia ident="eq0040"></elsevierMultimedia>where I and G represent the plasma concentrations of insulin (mIU/l) and glucose (mmol/l), respectively and, VD is the glucose distribution volume calculated using a monocompartmental model: VD=150ml/kg of body weight.<a class="elsevierStyleCrossRef" href="#bib0140">28</a>Matsuda et al. indexOriginally proposed by Matsuda and DeFronzo,<a class="elsevierStyleCrossRef" href="#bib0195">39</a> insulin sensitivity index-Matsuda (ISI(Matsuda)) is an whole body insulin sensitivity index that reflects a composite estimate of hepatic and muscle insulin sensitivity. This index is calculated from plasma glucose (mg/dl) and insulin (mIU/l) concentrations in fasting state and during OGTT.The formula for the Matsuda index is:<elsevierMultimedia ident="eq0045"></elsevierMultimedia>where 10,000 – simplifying constant to get numbers from 0 to 12, √ – correction of the nonlinear values distribution, G0 – fasting plasma glucose concentration (mg/dl), I0 – fasting plasma insulin concentration (mIU/l), Gmean – mean plasma glucose concentration during OGTT (mg/dl), from 0 to 120min and Imean – mean plasma insulin concentration during OGTT (mIU/l), from 0 to 120min.The insulin secretion/insulin resistance (disposition) index calculated as the product of insulin secretion measured with (ΔI0–30/ΔG0–30 or ΔI0–120/ΔG0–120) and ISI(Matsuda) (or modified ISI(Matsuda) using plasma glucose and insulin concentrations at 30min during the OGTT), had excellent power to predict onset of type 2 diabetes.<a class="elsevierStyleCrossRef" href="#bib0340">68</a>Belfiore et al. indexThe condition for calculation of the Belfiore formula is the definition of the normal value for basal glucose and insulin concentrations, and for mean normal value for glucose and insulin areas during OGTT.<a class="elsevierStyleCrossRef" href="#bib0090">18</a> The main point of the Belfiore formula is the comparison of insulin and glucose values measured (fasting, 0–1–2h areas or 0–2h areas) with the defined normal reference values.The ISIBelfiore index is defined as:<elsevierMultimedia ident="eq0050"></elsevierMultimedia>where Gs, GN – plasma glucose concentrations expressed as fasting values or as areas obtained during a standard OGTT at 0 and 2h (0–2h areas are equal to GS,N=G0+G120) or at 0, 1 and 2h (0–1–2h areas equal to GS,N=½G0+G60+G120, Is, IN – plasma insulin concentrations expressed as fasting values or as areas obtained during a standard OGTT at 0 and 2h (0–2h areas are equal to IS,N=I0+I120) or at 0, 1 and 2h (0–1–2h areas equal to IS,N=½I0+I60+I120. The subscripts S and N refer to “subjects” and “normal reference values”, respectively.Insulin sensitivity calculated using these formulas can achieve only values between 0 and 2. In subjects with normal insulin sensitivity is it around 1; in overweight subjects, in subjects with impaired glucose tolerance, and with type 2 diabetes this value is below 1.<a class="elsevierStyleCrossRefs" href="#bib0345">69,70</a>Stumvoll et al. indexStumvoll proposed a series of indices calculated from plasma glucose (mmol/l) and insulin (pmol/l concentrations during OGTT).<a class="elsevierStyleCrossRef" href="#bib0350">70</a> The equations were generated using the multiple linear regression analysis and adapted to the availabilities of sampling times during OGTT, and of demographic parameters (BMI, age).An example equation could be the index of insulin sensitivity calculated from data obtained in 0, 60 and 120min of OGTT either with or without demographic data:<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005">ISIStumvoll=0.222−0.00333×BMI−0.0000779×I120−0.000422×age</li><li class="elsevierStyleListItem" id="lsti0010">ISIStumvoll=0.156−0.0000459×I120−0.000321×I0−0.00541×G120</li></ul>McAuley et al. indexThe authors proposed a formula for predicting insulin resistance in normoglycemic individuals.<a class="elsevierStyleCrossRef" href="#bib0355">71</a> Regression analysis was used to estimate the cut-off points and the importance of various data for insulin resistance (fasting concentrations of insulin, triglycerides, aspartate aminotransferase, BMI, waist circumference). A bootstrap procedure was used to find an index most strongly correlating with insulin sensitivity index, corrected for fat-free mass obtained by HIEC MffmI.<a class="elsevierStyleCrossRef" href="#bib0005">1</a>An insulin sensitivity index obtained from HIEC of ≤6.3 (expressed as glucose disposal rate in mg/kg/min divided by average plasma insulin concentration in mIU/l) was seen as a cut-off for individuals with insulin resistance. The combination of fasting insulin (mIU/l) and triglycerides (TAG, mmol/l) showed the best prediction of insulin resistance as follows:<elsevierMultimedia ident="eq0055"></elsevierMultimedia>where I0 – fasting plasma insulin concentration (mIU/l) and TAG0 – fasting plasma triglycerides concentration (mmol/l).Oral Glucose Insulin SensitivityThe Oral Glucose Insulin Sensitivity (OGIS) is a method for the assessment of insulin sensitivity from the OGTT. OGIS provides an index that correlates to the index of insulin sensitivity obtained from the HIEC.This method calculates insulin sensitivity with a model-derived equation of the form:<elsevierMultimedia ident="eq0060"></elsevierMultimedia>where G and I are glucose and insulin concentrations (subscripts represent time instant) and DO is the oral glucose dose (g/m2 body surface area).The function f is complex, but can be easily programmed on a spreadsheet (see <a id="intr0005" class="elsevierStyleInterRef" href="http://www.isib.cnr.it/bioing/ogis/home.html">http://www.isib.cnr.it/bioing/ogis/home.html</a>, where a web-based calculator is also available). The expression of f contains some parameters, chosen to maximize the agreement with the HIEC. Glucose and insulin can be given in either common or international units (with appropriate parameters, see table 2 in<a class="elsevierStyleCrossRef" href="#bib0360">72</a>).OGIS is a predictor of the HIEC insulin sensitivity, expressed as glucose clearance M/G, normalized to body surface area. The units of OGIS are thus ml/min/m2 of body surface area. OGIS has been validated against an 120mU/min/m2 insulin infusion HIEC (by direct comparison of the glucose clearance values), instead of the more standard 40mU/min/m2 used in the previous methods. Formulas for a 3h and 2h OGTT are also available.<a class="elsevierStyleCrossRef" href="#bib0360">72</a>OGIS exploits the known quantitative relationships between the observed data and the HIEC insulin sensitivity to attempt a genuine insulin sensitivity prediction. However, this advantage is limited by the necessity to use empirical assumptions, and to calculate parameters from regression.<a class="elsevierStyleCrossRef" href="#bib0360">72</a>Rapid Insulin Sensitivity Test indexThe RIST index is the parameter used to evaluate insulin sensitivity that represents the total amount of glucose infused during the Rapid Insulin Sensitivity Test (RIST), in order to maintain euglycemia after the exogenous bolus administration of insulin. It corresponds to the area under the curve (AUC) of total glucose infused (mg glucose/kg bw) throughout the test<a class="elsevierStyleCrossRef" href="#bib0260">52</a>:<elsevierMultimedia ident="eq0065"></elsevierMultimedia>ConclusionsThis paper has examined a wide variety of methods currently available for estimating insulin sensitivity/resistance and also introduces a new method – the RIST. The methods range from complex, time-consuming, labor-intensive, invasive procedures to simple tests involving a single fasting blood sample. It is important to understand the concepts underlying each method so that relative merits and limitations are appropriately matched to proposed applications. Developing valid, reliable, cost-effective methods of assessing insulin sensitivity is a major scientific challenge. Dynamic tests are useful if information about both insulin secretion and insulin action are needed. As with all measurement techniques, correct interpretation of data from different methods for measuring insulin sensitivity requires a complete understanding of the technique.FundingThis study was supported by Fundação para a Ciência e Tecnologia (FCT) grants FCT/POCI/SAU-OBS/56716/2004 and PIC/IC/82956/2007 and by the Portuguese Diabetes Society (SPD).Conflicts of interestThe authors declare no conflicts of interest." "textoCompletoSecciones" => array:1 [ "secciones" => array:12 [ 0 => array:2 [ "identificador" => "xres355297" "titulo" => "Abstract" ] 1 => array:2 [ "identificador" => "xpalclavsec336593" "titulo" => "Keywords" ] 2 => array:2 [ "identificador" => "xres355296" "titulo" => "Resumo" ] 3 => array:2 [ "identificador" => "xpalclavsec336592" "titulo" => "Palavras-chave" ] 4 => array:2 [ "identificador" => "sec0005" "titulo" => "Introduction" ] 5 => array:3 [ "identificador" => "sec0010" "titulo" => "Methods of insulin sensitivity/resistance assessment" "secciones" => array:8 [ 0 => array:2 [ "identificador" => "sec0015" "titulo" => "Hyperinsulinemic Euglycemic Glucose Clamp" ] 1 => array:2 [ "identificador" => "sec0020" "titulo" => "Insulin Tolerance Test" ] 2 => array:2 [ "identificador" => "sec0025" "titulo" => "Insulin Suppression Test" ] 3 => array:2 [ "identificador" => "sec0030" "titulo" => "Continuous infusion of glucose with model assessment" ] 4 => array:2 [ "identificador" => "sec0035" "titulo" => "Minimal model analysis of frequently sampled intravenous glucose tolerance test" ] 5 => array:2 [ "identificador" => "sec0040" "titulo" => "Oral Glucose Tolerance Test" ] 6 => array:2 [ "identificador" => "sec0045" "titulo" => "Meal Tolerance Test" ] 7 => array:2 [ "identificador" => "sec0050" "titulo" => "Rapid Insulin Sensitivity Test" ] ] ] 6 => array:3 [ "identificador" => "sec0055" "titulo" => "Simple surrogate indexes for insulin sensitivity/resistance" "secciones" => array:3 [ 0 => array:2 [ "identificador" => "sec0060" "titulo" => "Homeostasis Model Assessment" ] 1 => array:2 [ "identificador" => "sec0065" "titulo" => "Quantitative insulin sensitivity check index" ] 2 => array:3 [ "identificador" => "sec0070" "titulo" => "Insulin sensitivity indexes" "secciones" => array:9 [ 0 => array:2 [ "identificador" => "sec0075" "titulo" => "Cederholm and Wibell index" ] 1 => array:2 [ "identificador" => "sec0080" "titulo" => "Gutt et al. index" ] 2 => array:2 [ "identificador" => "sec0085" "titulo" => "Avignon et al. index" ] 3 => array:2 [ "identificador" => "sec0090" "titulo" => "Matsuda et al. index" ] 4 => array:2 [ "identificador" => "sec0095" "titulo" => "Belfiore et al. index" ] 5 => array:2 [ "identificador" => "sec0100" "titulo" => "Stumvoll et al. index" ] 6 => array:2 [ "identificador" => "sec0105" "titulo" => "McAuley et al. index" ] 7 => array:2 [ "identificador" => "sec0110" "titulo" => "Oral Glucose Insulin Sensitivity" ] 8 => array:2 [ "identificador" => "sec0115" "titulo" => "Rapid Insulin Sensitivity Test index" ] ] ] ] ] 7 => array:2 [ "identificador" => "sec0120" "titulo" => "Conclusions" ] 8 => array:2 [ "identificador" => "sec0125" "titulo" => "Funding" ] 9 => array:2 [ "identificador" => "sec0130" "titulo" => "Conflicts of interest" ] 10 => array:2 [ "identificador" => "xack87666" "titulo" => "Acknowledgements" ] 11 => array:1 [ "titulo" => "References" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "fechaRecibido" => "2012-09-05" "fechaAceptado" => "2013-10-22" "PalabrasClave" => array:2 [ "en" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Keywords" "identificador" => "xpalclavsec336593" "palabras" => array:6 [ 0 => "Hyperinsulinemic Euglycemic Glucose Clamp" 1 => "Oral Glucose Tolerance Test" 2 => "Meal Tolerance Test" 3 => "Rapid Insulin Sensitivity Test" 4 => "Homeostasis Model Assessment" 5 => "Oral Glucose Insulin Sensitivity" ] ] ] "pt" => array:1 [ 0 => array:4 [ "clase" => "keyword" "titulo" => "Palavras-chave" "identificador" => "xpalclavsec336592" "palabras" => array:6 [ 0 => "Clamp de glucose hiperinsulinémico e euglicémico" 1 => "Teste oral de tolerância à glucose" 2 => "Teste de tolerância à refeição" 3 => "Teste rápido de sensibilidade à insulina" 4 => "Avaliação do modelo de homeostase" 5 => "Glucose oral e sensibilidade à insulina" ] ] ] ] "tieneResumen" => true "resumen" => array:2 [ "en" => array:2 [ "titulo" => "Abstract" "resumen" => "Insulin resistance contributes to the pathophysiology of diabetes and is a hallmark of obesity, metabolic syndrome, and many cardiovascular diseases. Therefore, quantifying insulin sensitivity/resistance in humans and animal models is of great importance.Various methods are used to assess insulin sensitivity both in individuals and in study populations. Validity, reproducibility, cost, and degree of subject burden are important factors for both clinicians and researchers to consider when weighing the merits of a particular method. Some methods rely on steady-state analysis of glucose and insulin, whereas others rely on dynamic testing. Each of these methods has distinct advantages and limitations. Thus, optimal choice and employment of a specific method depend on the nature of the studies being performed. Established direct methods for measuring insulin sensitivity in vivo are relatively complex. Finally, simple surrogate indexes for insulin sensitivity/resistance are available that are derived from blood insulin and glucose concentrations under fasting conditions (steady state) or in the postprandial state (dynamic). This article highlight merits, limitations, and appropriate use of current in vivo measures of insulin sensitivity/resistance and presents the advantages and disadvantages of each." ] "pt" => array:2 [ "titulo" => "Resumo" "resumen" => "A resistência à insulina contribui para a fisiopatologia da diabetes e é uma característica marcante da obesidade, da síndrome metabólica, e de doenças cardiovasculares. Assim, quantificar a sensibilidade à insulina vs resistência à insulina em humanos e em modelos animais é de grande importância.Existem vários métodos para avaliar a sensibilidade à insulina, tanto em indivíduos, como em populações de estudo. A validade, reprodutibilidade, custo e envolvimento dos indivíduos são fatores importantes a considerar para os clínicos e investigadores aquando da escolha de um determinado método de avaliação da sensibilidade e/ou resistência à insulina. Alguns métodos dependem da quantificação dos níveis de glucose e de insulina no estado estacionário, embora outros métodos possam ser utilizados no estado dinâmico. Cada um destes métodos tem vantagens e limitações distintas. Assim, a escolha e a aplicabilidade correta de um método específico depende da natureza dos estudos a serem realizados. O desenho de métodos diretos para medir a sensibilidade à insulina in vivo é relativamente complexo. Existem alguns índices simples para avaliar a sensibilidade e/ou resistência à insulina, que resultam da avaliação das concentrações de insulina e glucose em jejum (estado estacionário) ou no estado pós-prandial (estado dinâmico). Este artigo destaca as limitações e a utilização adequada dos atuais métodos de avaliação de sensibilidade e/ou resistência à insulina e apresenta as vantagens e desvantagens de cada um dos métodos." ] ] "multimedia" => array:15 [ 0 => array:8 [ "identificador" => "fig0005" "etiqueta" => "Fig. 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "fuente" => "Adapted from Ref. <a class="elsevierStyleCrossRef" href="#bib0145">29</a>." "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 649 "Ancho" => 1587 "Tamanyo" => 69743 ] ] "descripcion" => array:1 [ "en" => "Schematic equations and parameters for the minimal model of glucose metabolism. Differential equations describing glucose dynamics [G(t)] in a monocompartmental “glucose space” and insulin dynamics in a “remote compartment” [X(t)] are shown at the top. Glucose leaves or enters its space at a rate proportional to the difference between plasma glucose level, G(t) and the basal fasting level, Gb. In addition, glucose also disappears from its compartment at a rate proportional to insulin levels in the “remote” compartment [X(t)]. In this model, t – time; G(t) – plasma glucose at time t; I(t) – plasma insulin concentration at time t; X(t) – insulin concentration in “remote” compartment at time t; Gb – basal plasma glucose concentration; Ib – basal plasma insulin concentration; G(0) – G0 (assuming instantaneous mixing of the iv glucose load); p1, p2, p3 and G0 – unknown parameters in the model that are uniquely identifiable from FSIVGTT; glucose effectiveness (SG) – p1 and insulin sensitivity – p3/p2." ] ] 1 => array:7 [ "identificador" => "fig0010" "etiqueta" => "Fig. 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 789 "Ancho" => 2143 "Tamanyo" => 97102 ] ] "descripcion" => array:1 [ "en" => "(A) Mean profile using the dynamic analysis of the pattern of glucose infusion during the Rapid Insulin Sensitivity Test (RIST). The mean RIST curves were obtained by averaging glucose infusion rates at 0.1-min intervals throughout the test (Postprandial RIST (bold line) and the RIST obtained after 24h-fast (simple line)). (B) Calculation of the area under the curve during the 24 h-fast and postprandial RIST, that corresponds to the total amount of glucose infused to maintain euglycemia over the test period, which is terminated when no further glucose infusion is required (RIST index).<a class="elsevierStyleCrossRef" href="#bib0280">56</a>" ] ] 2 => array:5 [ "identificador" => "eq0005" "tipo" => "MULTIMEDIAFORMULA" "mostrarFloat" => false "mostrarDisplay" => true "Formula" => array:5 [ "Matematica" => "KITT=0.693t1/2×100" "Fichero" => "si2.jpeg" "Tamanyo" => 1578 "Alto" => 36 "Ancho" => 134 ] ] 3 => array:6 [ "identificador" => "eq0010" "etiqueta" => "(1)" "tipo" => "MULTIMEDIAFORMULA" "mostrarFloat" => false "mostrarDisplay" => true "Formula" => array:5 [ "Matematica" => "dG(t)dt=−[p1+X(t)]G(t)+p1Gb" "Fichero" => "si3.jpeg" "Tamanyo" => 2380 "Alto" => 32 "Ancho" => 218 ] ] 4 => array:6 [ "identificador" => "eq0015" "etiqueta" => "(2)" "tipo" => "MULTIMEDIAFORMULA" "mostrarFloat" => false "mostrarDisplay" => true "Formula" => array:5 [ "Matematica" => "dX(t)dt=−p2X(t)+p3[I(t)−ib]" "Fichero" => "si4.jpeg" "Tamanyo" => 2208 "Alto" => 32 "Ancho" => 207 ] ] 5 => array:5 [ "identificador" => "eq0020" "tipo" => "MULTIMEDIAFORMULA" "mostrarFloat" => false "mostrarDisplay" => true "Formula" => array:5 [ "Matematica" => "HOMA=Fasting Insulin (μIU/ml)×Fasting Glucose (mmol/l)22.5" "Fichero" => "si5.jpeg" "Tamanyo" => 4865 "Alto" => 32 "Ancho" => 424 ] ] 6 => array:5 [ "identificador" => "eq0025" "tipo" => "MULTIMEDIAFORMULA" "mostrarFloat" => false "mostrarDisplay" => true "Formula" => array:5 [ "Matematica" => "QUICKI=1log(fasting insulin, μIU/ml)+log (fasting glucose, mg/dl)" "Fichero" => "si6.jpeg" "Tamanyo" => 4798 "Alto" => 60 "Ancho" => 428 ] ] 7 => array:5 [ "identificador" => "eq0030" "tipo" => "MULTIMEDIAFORMULA" "mostrarFloat" => false "mostrarDisplay" => true "Formula" => array:5 [ "Matematica" => "ISICederholm=75000+(G0−G120)×1.15×180×0.19×m120×Gmean×log(Imean)" "Fichero" => "si7.jpeg" "Tamanyo" => 5037 "Alto" => 35 "Ancho" => 401 ] ] 8 => array:5 [ "identificador" => "eq0035" "tipo" => "MULTIMEDIAFORMULA" "mostrarFloat" => false "mostrarDisplay" => true "Formula" => array:5 [ "Matematica" => "ISI0,120=75,000+(G0−G120)×0.19×m120×Gmean×log(Imean)" "Fichero" => "si8.jpeg" "Tamanyo" => 4189 "Alto" => 35 "Ancho" => 292 ] ] 9 => array:5 [ "identificador" => "eq0040" "tipo" => "MULTIMEDIAFORMULA" "mostrarFloat" => false "mostrarDisplay" => true "Formula" => array:5 [ "Matematica" => "Sib=108I0×G0×VD Si2h=108I120×G120×VD SiM=(0.137×Sib)+Si2h2" "Fichero" => "si9.jpeg" "Tamanyo" => 5516 "Alto" => 81 "Ancho" => 303 ] ] 10 => array:5 [ "identificador" => "eq0045" "tipo" => "MULTIMEDIAFORMULA" "mostrarFloat" => false "mostrarDisplay" => true "Formula" => array:5 [ "Matematica" => "ISI(Matsuda)=10,000G0×I0×Gmean×Imean" "Fichero" => "si10.jpeg" "Tamanyo" => 3050 "Alto" => 39 "Ancho" => 254 ] ] 11 => array:5 [ "identificador" => "eq0050" "tipo" => "MULTIMEDIAFORMULA" "mostrarFloat" => false "mostrarDisplay" => true "Formula" => array:5 [ "Matematica" => "ISIBelfiore=2(GS/GN)×(IS/IN)+1" "Fichero" => "si11.jpeg" "Tamanyo" => 2237 "Alto" => 35 "Ancho" => 216 ] ] 12 => array:5 [ "identificador" => "eq0055" "tipo" => "MULTIMEDIAFORMULA" "mostrarFloat" => false "mostrarDisplay" => true "Formula" => array:5 [ "Matematica" => "MffmI=e2.63−0.28 ln (I0)−0.31 ln (TAG0)" "Fichero" => "si13.jpeg" "Tamanyo" => 2514 "Alto" => 40 "Ancho" => 245 ] ] 13 => array:5 [ "identificador" => "eq0060" "tipo" => "MULTIMEDIAFORMULA" "mostrarFloat" => false "mostrarDisplay" => true "Formula" => array:5 [ "Matematica" => "OGIS=f(G0, G90, G120, I0, I90, I120, DO)" "Fichero" => "si14.jpeg" "Tamanyo" => 2406 "Alto" => 15 "Ancho" => 276 ] ] 14 => array:5 [ "identificador" => "eq0065" "tipo" => "MULTIMEDIAFORMULA" "mostrarFloat" => false "mostrarDisplay" => true "Formula" => array:5 [ "Matematica" => "RIST Index=AUC of Glucose" "Fichero" => "si15.jpeg" "Tamanyo" => 1917 "Alto" => 12 "Ancho" => 196 ] ] ] "bibliografia" => array:2 [ "titulo" => "References" "seccion" => array:1 [ 0 => array:2 [ "identificador" => "bibs0005" "bibliografiaReferencia" => array:72 [ 0 => array:3 [ "identificador" => "bib0005" "etiqueta" => "1" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Glucose clamp technique: a method for quantifying insulin secretion and resistance" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "R.A. DeFronzo" 1 => "J.D. Tobin" 2 => "R. Andres" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Am J Physiol" "fecha" => "1979" "volumen" => "237" "paginaInicial" => "E214" "paginaFinal" => "E223" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/382871" "web" => "Medline" ] ] ] ] ] ] ] ] 1 => array:3 [ "identificador" => "bib0010" "etiqueta" => "2" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "A. Katz" 1 => "S.S. Nambi" 2 => "K. Mather" 3 => "A.D. Baron" 4 => "D.A. Follmann" 5 => "G. Sullivan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jcem.85.7.6661" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2000" "volumen" => "85" "paginaInicial" => "2402" "paginaFinal" => "2410" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10902785" "web" => "Medline" ] ] ] ] ] ] ] ] 2 => array:3 [ "identificador" => "bib0015" "etiqueta" => "3" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Quantitation of basal endogenous glucose production in Type II diabetes: importance of the volume of distribution" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J. Radziuk" 1 => "S. Pye" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1007/s00125-002-0841-6" "Revista" => array:6 [ "tituloSerie" => "Diabetologia" "fecha" => "2002" "volumen" => "45" "paginaInicial" => "1053" "paginaFinal" => "1084" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12189437" "web" => "Medline" ] ] ] ] ] ] ] ] 3 => array:3 [ "identificador" => "bib0020" "etiqueta" => "4" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Estimation of endogenous glucose production during hyperinsulinemic-euglycemic glucose clamps. Comparison of unlabeled and labeled exogenous glucose infusates" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "D.T. Finegood" 1 => "R.N. Bergman" 2 => "M. Vranic" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Diabetes" "fecha" => "1987" "volumen" => "36" "paginaInicial" => "914" "paginaFinal" => "924" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3297886" "web" => "Medline" ] ] ] ] ] ] ] ] 4 => array:3 [ "identificador" => "bib0025" "etiqueta" => "5" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Underestimation of glucose turnover measured with [6-3H]- and [6,6-2H]- but not [6-14C]glucose during hyperinsulinemia in humans" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "M.M. McMahon" 1 => "W.F. Schwenk" 2 => "M.W. Haymond" 3 => "R.A. Rizza" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Diabetes" "fecha" => "1989" "volumen" => "38" "paginaInicial" => "97" "paginaFinal" => "107" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2642865" "web" => "Medline" ] ] ] ] ] ] ] ] 5 => array:3 [ "identificador" => "bib0030" "etiqueta" => "6" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effects of glucose ingestion versus infusion on pulsatile insulin secretion. The incretin effect is achieved by amplification of insulin secretory burst mass" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "N. Porksen" 1 => "S. Munn" 2 => "J. Steers" 3 => "J.D. Veldhuis" 4 => "P.C. Butler" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Diabetes" "fecha" => "1996" "volumen" => "45" "paginaInicial" => "1317" "paginaFinal" => "1323" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8826965" "web" => "Medline" ] ] ] ] ] ] ] ] 6 => array:3 [ "identificador" => "bib0035" "etiqueta" => "7" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Pulsatile, synchronous basal insulin and glucagon secretion in man" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "D.A. Lang" 1 => "D.R. Matthews" 2 => "M. Burnett" 3 => "G.M. Ward" 4 => "R.C. Turner" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Diabetes" "fecha" => "1982" "volumen" => "31" "paginaInicial" => "22" "paginaFinal" => "26" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/6759209" "web" => "Medline" ] ] ] ] ] ] ] ] 7 => array:3 [ "identificador" => "bib0040" "etiqueta" => "8" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rapid oscillations in plasma insulin, glucagon, and glucose in obese and normal weight humans" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "B.C. Hansen" 1 => "K.C. Jen" 2 => "S. Belbez Pek" 3 => "R.A. Wolfe" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jcem-54-4-785" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "1982" "volumen" => "54" "paginaInicial" => "785" "paginaFinal" => "792" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7037815" "web" => "Medline" ] ] ] ] ] ] ] ] 8 => array:3 [ "identificador" => "bib0045" "etiqueta" => "9" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hepatic parasympathetic (HISS) control of insulin sensitivity determined by feeding and fasting" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "W.W. Lautt" 1 => "M.P. Macedo" 2 => "P. Sadri" 3 => "S. Takayama" 4 => "F. Duarte Ramos" 5 => "D.J. Legare" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Am J Physiol Gastrointest Liver Physiol" "fecha" => "2001" "volumen" => "281" "paginaInicial" => "G29" "paginaFinal" => "G36" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11408252" "web" => "Medline" ] ] ] ] ] ] ] ] 9 => array:3 [ "identificador" => "bib0050" "etiqueta" => "10" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparison of insulin sensitivity, clearance, and secretion estimates using euglycemic and hyperglycemic clamps in children" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "G.I. Uwaifo" 1 => "S.J. Parikh" 2 => "M. Keil" 3 => "J. Elberg" 4 => "J. Chin" 5 => "J.A. Yanovski" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jcem.87.6.8578" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2002" "volumen" => "87" "paginaInicial" => "2899" "paginaFinal" => "2905" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12050270" "web" => "Medline" ] ] ] ] ] ] ] ] 10 => array:3 [ "identificador" => "bib0055" "etiqueta" => "11" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical investigation into the effect of the intravenous injection of insulin" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "A. Horgaard" 1 => "T.H. Thayssen" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Acta Med Scand" "fecha" => "1929" "volumen" => "72" "paginaInicial" => "92" "paginaFinal" => "95" ] ] ] ] ] ] 11 => array:3 [ "identificador" => "bib0060" "etiqueta" => "12" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Estimates of in vivo insulin action in man: comparison of insulin tolerance tests with euglycemic and hyperglycemic glucose clamp studies" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E. Bonora" 1 => "P. Moghetti" 2 => "C. Zancanaro" 3 => "M. Cigolini" 4 => "M. Querena" 5 => "V. Cacciatori" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jcem-68-2-374" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "1989" "volumen" => "68" "paginaInicial" => "374" "paginaFinal" => "378" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2645308" "web" => "Medline" ] ] ] ] ] ] ] ] 12 => array:3 [ "identificador" => "bib0065" "etiqueta" => "13" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The short insulin tolerance test: feasibility study using venous sampling" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "R.P. Young" 1 => "J.A. Critchley" 2 => "P.J. Anderson" 3 => "M.S. Lau" 4 => "K.K. Lee" 5 => "J.C. Chan" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/(SICI)1096-9136(199605)13:5<429::AID-DIA98>3.0.CO;2-K" "Revista" => array:6 [ "tituloSerie" => "Diabet Med" "fecha" => "1996" "volumen" => "13" "paginaInicial" => "429" "paginaFinal" => "433" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8737024" "web" => "Medline" ] ] ] ] ] ] ] ] 13 => array:3 [ "identificador" => "bib0070" "etiqueta" => "14" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Reproducibility of the short insulin tolerance test" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "S. Hirst" 1 => "D.I. Phillips" 2 => "S.K. Vines" 3 => "P.M. Clark" 4 => "C.N. Hales" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Diabet Med" "fecha" => "1993" "volumen" => "10" "paginaInicial" => "839" "paginaFinal" => "842" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8281729" "web" => "Medline" ] ] ] ] ] ] ] ] 14 => array:3 [ "identificador" => "bib0075" "etiqueta" => "15" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Insulin resistance in noninsulin-dependent diabetes mellitus. Does it exist and can it be measured?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "G.M. Reaven" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Am J Med" "fecha" => "1983" "volumen" => "74" "paginaInicial" => "3" "paginaFinal" => "17" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/6344631" "web" => "Medline" ] ] ] ] ] ] ] ] 15 => array:3 [ "identificador" => "bib0080" "etiqueta" => "16" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The short insulin tolerance test for determination of insulin sensitivity: a comparison with the euglycaemic clamp" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "A. Akinmokun" 1 => "P.L. Selby" 2 => "K. Ramaiya" 3 => "K.G. Alberti" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Diabet Med" "fecha" => "1992" "volumen" => "9" "paginaInicial" => "432" "paginaFinal" => "437" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1611830" "web" => "Medline" ] ] ] ] ] ] ] ] 16 => array:3 [ "identificador" => "bib0085" "etiqueta" => "17" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Is the short insulin tolerance test safe and reproducible?" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ 0 => "C.C. Chen" 1 => "T.Y. Wang" 2 => "S.Y. Hsu" 3 => "R.H. Chen" 4 => "C.T. Chang" 5 => "S.J. Chen" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1002/(SICI)1096-9136(1998110)15:11<924::AID-DIA699>3.0.CO;2-H" "Revista" => array:6 [ "tituloSerie" => "Diabet Med" "fecha" => "1998" "volumen" => "15" "paginaInicial" => "924" "paginaFinal" => "927" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9827846" "web" => "Medline" ] ] ] ] ] ] ] ] 17 => array:3 [ "identificador" => "bib0090" "etiqueta" => "18" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evaluation of insulin sensitivity in clinical practice and in research settings" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "L.U. Monzillo" 1 => "O. Hamdy" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Nutr Rev" "fecha" => "2003" "volumen" => "61" "paginaInicial" => "397" "paginaFinal" => "412" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14968910" "web" => "Medline" ] ] ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bib0095" "etiqueta" => "19" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparison of impedance to insulin-mediated glucose uptake in normal subjects and in subjects with latent diabetes" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "S.W. Shen" 1 => "G.M. Reaven" 2 => "J.W. Farquhar" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1172/JCI106433" "Revista" => array:6 [ "tituloSerie" => "J Clin Invest" "fecha" => "1970" "volumen" => "49" "paginaInicial" => "2151" "paginaFinal" => "2160" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/5480843" "web" => "Medline" ] ] ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bib0100" "etiqueta" => "20" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Glucose, insulin, and somatostatin infusion for the determination of insulin sensitivity in vivo" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "Y. Harano" 1 => "H. Hidaka" 2 => "K. Takatsuki" 3 => "S. Ohgaku" 4 => "M. Haneda" 5 => "S. Motoi" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Metabolism" "fecha" => "1978" "volumen" => "27" "numero" => "Suppl. 1" "paginaInicial" => "1449" "paginaFinal" => "1452" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/683015" "web" => "Medline" ] ] ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bib0105" "etiqueta" => "21" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evaluation of octreotide to assess insulin-mediated glucose disposal by the insulin suppression test" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "D. Pei" 1 => "C.N. Jones" 2 => "R. Bhargava" 3 => "Y.D. Chen" 4 => "G.M. Reaven" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Diabetologia" "fecha" => "1994" "volumen" => "37" "paginaInicial" => "843" "paginaFinal" => "845" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7988789" "web" => "Medline" ] ] ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bib0110" "etiqueta" => "22" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Assessment of insulin resistance with the insulin suppression test and the euglycemic clamp" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "M.S. Greenfield" 1 => "L. Doberne" 2 => "F. Kraemer" 3 => "T. Tobey" 4 => "G. Reaven" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Diabetes" "fecha" => "1981" "volumen" => "30" "paginaInicial" => "387" "paginaFinal" => "392" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7014307" "web" => "Medline" ] ] ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bib0115" "etiqueta" => "23" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Continuous infusion of glucose with model assessment: measurement of insulin resistance and beta-cell function in man" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.P. Hosker" 1 => "D.R. Matthews" 2 => "A.S. Rudenski" 3 => "M.A. Burnett" 4 => "P. Darling" 5 => "E.G. Bown" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Diabetologia" "fecha" => "1985" "volumen" => "28" "paginaInicial" => "401" "paginaFinal" => "411" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3899824" "web" => "Medline" ] ] ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bib0120" "etiqueta" => "24" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Quantitative estimation of insulin sensitivity" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "R.N. Bergman" 1 => "Y.Z. Ider" 2 => "C.R. Bowden" 3 => "C. Cobelli" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Am J Physiol" "fecha" => "1979" "volumen" => "236" "paginaInicial" => "E667" "paginaFinal" => "E677" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/443421" "web" => "Medline" ] ] ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bib0125" "etiqueta" => "25" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A modified protocol for estimation of insulin sensitivity with the minimal model of glucose kinetics in patients with insulin-dependent diabetes" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "D.T. Finegood" 1 => "I.M. Hramiak" 2 => "J. Dupre" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jcem-70-6-1538" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "1990" "volumen" => "70" "paginaInicial" => "1538" "paginaFinal" => "1549" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2189884" "web" => "Medline" ] ] ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bib0130" "etiqueta" => "26" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Direct comparison of standard and insulin modified protocols for minimal model estimation of insulin sensitivity in normal subjects" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "M.J. Quon" 1 => "C. Cochran" 2 => "S.I. Taylor" 3 => "R.C. Eastman" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Diabetes Res" "fecha" => "1994" "volumen" => "25" "paginaInicial" => "139" "paginaFinal" => "149" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7648784" "web" => "Medline" ] ] ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bib0135" "etiqueta" => "27" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Differences between the tolbutamide-boosted and the insulin-modified minimal model protocols" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "M.F. Saad" 1 => "G.M. Steil" 2 => "W.W. Kades" 3 => "M.F. Ayad" 4 => "W.A. Elsewafy" 5 => "R. Boyadjian" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Diabetes" "fecha" => "1997" "volumen" => "46" "paginaInicial" => "1167" "paginaFinal" => "1171" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9200652" "web" => "Medline" ] ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bib0140" "etiqueta" => "28" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Equivalence of the insulin sensitivity index in man derived by the minimal model method and the euglycemic glucose clamp" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "R.N. Bergman" 1 => "R. Prager" 2 => "A. Volund" 3 => "J.M. Olefsky" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1172/JCI112886" "Revista" => array:6 [ "tituloSerie" => "J Clin Invest" "fecha" => "1987" "volumen" => "79" "paginaInicial" => "790" "paginaFinal" => "800" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3546379" "web" => "Medline" ] ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bib0145" "etiqueta" => "29" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Minimal model: perspective from 2005" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "R.N. Bergman" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1159/000089312" "Revista" => array:7 [ "tituloSerie" => "Horm Res" "fecha" => "2005" "volumen" => "64" "numero" => "Suppl. 3" "paginaInicial" => "8" "paginaFinal" => "15" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16439839" "web" => "Medline" ] ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bib0150" "etiqueta" => "30" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Reduced glucose effectiveness associated with reduced insulin release: an artifact of the minimal-model method" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "D.T. Finegood" 1 => "D. Tzur" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Am J Physiol Endocrinol Metab" "fecha" => "1996" "volumen" => "271" "paginaInicial" => "E485" "paginaFinal" => "E495" ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bib0155" "etiqueta" => "31" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Assessing the predictive accuracy of QUICKI as a surrogate index for insulin sensitivity using a calibration model" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "H. Chen" 1 => "G. Sullivan" 2 => "M.J. Quon" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Diabetes" "fecha" => "2005" "volumen" => "54" "paginaInicial" => "1914" "paginaFinal" => "1925" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15983190" "web" => "Medline" ] ] ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bib0160" "etiqueta" => "32" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Dilution of the 75-g oral glucose tolerance test increases postprandial glycemia: implications for diagnostic criteria" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "J.L. Sievenpiper" 1 => "D.J.A. Jenkins" 2 => "R.G. Josse" 3 => "V. Vuksan" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "CMAJ" "fecha" => "2000" "volumen" => "162" "paginaInicial" => "993" "paginaFinal" => "996" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10763397" "web" => "Medline" ] ] ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bib0165" "etiqueta" => "33" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diagnosis and classification of diabetes mellitus" "autores" => array:1 [ 0 => array:2 [ "colaboracion" => "American Diabetes Association" "etal" => false ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2337/dc10-S062" "Revista" => array:7 [ "tituloSerie" => "Diabetes Care" "fecha" => "2010" "volumen" => "33" "numero" => "Suppl. 1" "paginaInicial" => "S62" "paginaFinal" => "S69" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20042775" "web" => "Medline" ] ] ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bib0170" "etiqueta" => "34" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Metabolic responses in a model of insulin resistance: comparison between oral glucose and meal tolerance tests" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "N. Berthiaume" 1 => "B.A. Zinker" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Metabolism" "fecha" => "2002" "volumen" => "51" "paginaInicial" => "595" "paginaFinal" => "598" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11979391" "web" => "Medline" ] ] ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bib0175" "etiqueta" => "35" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evaluation of insulin sensitivity and {beta}-cell function indexes obtained from minimal model analysis of a meal tolerance test" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "G.M. Steil" 1 => "Hwu C-m" 2 => "R. Janowski" 3 => "F. Hariri" 4 => "S. Jinagouda" 5 => "C. Darwin" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Diabetes" "fecha" => "2004" "volumen" => "53" "paginaInicial" => "1201" "paginaFinal" => "1207" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15111487" "web" => "Medline" ] ] ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bib0180" "etiqueta" => "36" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Insulin sensitivity from meal tolerance tests in normal subjects: a minimal model index" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "A. Caumo" 1 => "R.N. Bergman" 2 => "C. Cobelli" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jcem.85.11.6982" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2000" "volumen" => "85" "paginaInicial" => "4396" "paginaFinal" => "4402" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11095485" "web" => "Medline" ] ] ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bib0185" "etiqueta" => "37" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diagnosis and classification of diabetes mellitus" "autores" => array:1 [ 0 => array:2 [ "colaboracion" => "American Diabetes Association" "etal" => false ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2337/dc07-S042" "Revista" => array:7 [ "tituloSerie" => "Diabetes Care" "fecha" => "2007" "volumen" => "30" "numero" => "Suppl. 1" "paginaInicial" => "S42" "paginaFinal" => "S47" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17192378" "web" => "Medline" ] ] ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bib0190" "etiqueta" => "38" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Standards of medical care in diabetes" "autores" => array:1 [ 0 => array:2 [ "colaboracion" => "American Diabetes Association" "etal" => false ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.2337/dc10-S011" "Revista" => array:7 [ "tituloSerie" => "Diabetes Care" "fecha" => "2010" "volumen" => "33" "numero" => "Suppl. 1" "paginaInicial" => "S11" "paginaFinal" => "S61" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20042772" "web" => "Medline" ] ] ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bib0195" "etiqueta" => "39" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "M. Matsuda" 1 => "R. DeFronzo" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Diabetes Care" "fecha" => "1999" "volumen" => "22" "paginaInicial" => "1462" "paginaFinal" => "1470" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10480510" "web" => "Medline" ] ] ] ] ] ] ] ] 39 => array:3 [ "identificador" => "bib0200" "etiqueta" => "40" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Insulin release and peripheral sensitivity at the oral glucose tolerance test" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "J. Cederholm" 1 => "L. Wibell" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Diabetes Res Clin Pract" "fecha" => "1990" "volumen" => "10" "paginaInicial" => "167" "paginaFinal" => "175" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2261853" "web" => "Medline" ] ] ] ] ] ] ] ] 40 => array:3 [ "identificador" => "bib0205" "etiqueta" => "41" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The breakfast tolerance test: a return to physiology" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "P.J. Lefebvre" 1 => "A.S. Luyckx" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Diabetes Metab" "fecha" => "1976" "volumen" => "2" "paginaInicial" => "15" "paginaFinal" => "19" ] ] ] ] ] ] 41 => array:3 [ "identificador" => "bib0210" "etiqueta" => "42" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Postprandial reactive hypoglycemia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "J.F. Brun" 1 => "C. Fedou" 2 => "J. Mercier" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Diabetes Metab" "fecha" => "2000" "volumen" => "26" "paginaInicial" => "337" "paginaFinal" => "351" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11119013" "web" => "Medline" ] ] ] ] ] ] ] ] 42 => array:3 [ "identificador" => "bib0215" "etiqueta" => "43" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Serum leptin is associated with the perception of palatability during a standardized high-carbohydrate breakfast test" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "E. Raynaud" 1 => "J.F. Brun" 2 => "A. Perez-Martin" 3 => "C. Sagnes" 4 => "A.M. Boularan" 5 => "C. Fedou" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Clin Sci (Lond)" "fecha" => "1999" "volumen" => "96" "paginaInicial" => "343" "paginaFinal" => "348" ] ] ] ] ] ] 43 => array:3 [ "identificador" => "bib0220" "etiqueta" => "44" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effects of meal size and composition on incretin, [alpha]-cell, and [beta]-cell responses" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.M. Rijkelijkhuizen" 1 => "K. McQuarrie" 2 => "C.J. Girman" 3 => "P.P. Stein" 4 => "A. Mari" 5 => "J.J. Holst" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.metabol.2009.07.039" "Revista" => array:6 [ "tituloSerie" => "Metabolism" "fecha" => "2010" "volumen" => "59" "paginaInicial" => "502" "paginaFinal" => "511" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19846181" "web" => "Medline" ] ] ] ] ] ] ] ] 44 => array:3 [ "identificador" => "bib0225" "etiqueta" => "45" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Classical and model-based estimates of beta-cell function during a mixed meal vs. an OGTT in a population-based cohort" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "J.M. Rijkelijkhuizen" 1 => "C.J. Girman" 2 => "A. Mari" 3 => "M. Alssema" 4 => "T. Rhodes" 5 => "G. Nijpels" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1016/j.diabres.2008.11.017" "Revista" => array:6 [ "tituloSerie" => "Diabetes Res Clin Pract" "fecha" => "2009" "volumen" => "83" "paginaInicial" => "280" "paginaFinal" => "288" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19097663" "web" => "Medline" ] ] ] ] ] ] ] ] 45 => array:3 [ "identificador" => "bib0230" "etiqueta" => "46" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Food glycemic index, as given in glycemic index tables, is a significant determinant of glycemic responses elicited by composite breakfast meals" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "T.M. Wolever" 1 => "M. Yang" 2 => "X.Y. Zeng" 3 => "F. Atkinson" 4 => "J.C. Brand-Miller" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Am J Clin Nutr" "fecha" => "2006" "volumen" => "83" "paginaInicial" => "1306" "paginaFinal" => "1312" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16762941" "web" => "Medline" ] ] ] ] ] ] ] ] 46 => array:3 [ "identificador" => "bib0235" "etiqueta" => "47" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Effects of meal volume and posture on gastric emptying of solids and appetite" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ 0 => "S. Doran" 1 => "K.L. Jones" 2 => "J.M. Andrews" 3 => "M. Horowitz" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Am J Physiol" "fecha" => "1998" "volumen" => "275" "numero" => "Pt 2" "paginaInicial" => "R1712" "paginaFinal" => "R1718" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9791094" "web" => "Medline" ] ] ] ] ] ] ] ] 47 => array:3 [ "identificador" => "bib0240" "etiqueta" => "48" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparison of gastric emptying of a solid and a liquid nutritional rehabilitation food" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "L. Achour" 1 => "S. Meance" 2 => "A. Briend" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1038/sj.ejcn.1601221" "Revista" => array:6 [ "tituloSerie" => "Eur J Clin Nutr" "fecha" => "2001" "volumen" => "55" "paginaInicial" => "769" "paginaFinal" => "772" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11528491" "web" => "Medline" ] ] ] ] ] ] ] ] 48 => array:3 [ "identificador" => "bib0245" "etiqueta" => "49" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The effect of incorporating fat into different components of a meal on gastric emptying and postprandial blood glucose and insulin responses" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "K.M. Cunningham" 1 => "N.W. Read" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Br J Nutr" "fecha" => "1989" "volumen" => "61" "paginaInicial" => "285" "paginaFinal" => "290" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2650735" "web" => "Medline" ] ] ] ] ] ] ] ] 49 => array:3 [ "identificador" => "bib0250" "etiqueta" => "50" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparison of the metabolic effects of mixed meal and standard oral glucose tolerance test on glucose, insulin and C-peptide response in healthy, impaired glucose tolerance, mild and severe non-insulin-dependent diabetic subjects" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "S. Marena" 1 => "G. Montegrosso" 2 => "F. De Michieli" 3 => "E. Pisu" 4 => "G. Pagano" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Acta Diabetol" "fecha" => "1992" "volumen" => "29" "paginaInicial" => "29" "paginaFinal" => "33" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1520903" "web" => "Medline" ] ] ] ] ] ] ] ] 50 => array:3 [ "identificador" => "bib0255" "etiqueta" => "51" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Insulin resistance caused by hepatic cholinergic interruption and reversed by acetylcholine administration" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "H. Xie" 1 => "W.W. Lautt" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Am J Physiol" "fecha" => "1996" "volumen" => "271" "numero" => "Pt. 1" "paginaInicial" => "E587" "paginaFinal" => "E592" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8843755" "web" => "Medline" ] ] ] ] ] ] ] ] 51 => array:3 [ "identificador" => "bib0260" "etiqueta" => "52" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Rapid insulin sensitivity test (RIST)" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "W.W. Lautt" 1 => "X. Wang" 2 => "P. Sadri" 3 => "D.J. Legare" 4 => "M.P. Macedo" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Can J Physiol Pharmacol" "fecha" => "1998" "volumen" => "76" "paginaInicial" => "1080" "paginaFinal" => "1086" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10326829" "web" => "Medline" ] ] ] ] ] ] ] ] 52 => array:3 [ "identificador" => "bib0265" "etiqueta" => "53" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Insulin sensitivity tested with a modified euglycemic technique in cats and rats" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "H. Xie" 1 => "L. Zhu" 2 => "Y.L. Zhang" 3 => "D.J. Legare" 4 => "W.W. Lautt" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Pharmacol Toxicol Methods" "fecha" => "1996" "volumen" => "35" "paginaInicial" => "77" "paginaFinal" => "82" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8729433" "web" => "Medline" ] ] ] ] ] ] ] ] 53 => array:3 [ "identificador" => "bib0270" "etiqueta" => "54" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Induction of insulin resistance by cholinergic blockade with atropine in the cat" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "H. Xie" 1 => "W.W. Lautt" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Auton Pharmacol" "fecha" => "1995" "volumen" => "15" "paginaInicial" => "361" "paginaFinal" => "369" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8744976" "web" => "Medline" ] ] ] ] ] ] ] ] 54 => array:3 [ "identificador" => "bib0275" "etiqueta" => "55" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A rapid insulin sensitivity test (RIST) in the anesthetized mice" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "M.G. Latour" 1 => "C.C. Chan" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Diabetes" "fecha" => "2002" "volumen" => "51" "numero" => "Suppl. 2" "paginaInicial" => "A422" ] ] ] ] ] ] 55 => array:3 [ "identificador" => "bib0280" "etiqueta" => "56" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Meal-induced insulin sensitization and its parasympathetic regulation in humans" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "R.S. Patarrão" 1 => "W.W. Lautt" 2 => "R.A. Afonso" 3 => "R.T. Ribeiro" 4 => "M.P. Guarino" 5 => "A.B. Fernandes" ] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1139/Y08-080" "Revista" => array:6 [ "tituloSerie" => "Can J Physiol Pharmacol" "fecha" => "2008" "volumen" => "86" "paginaInicial" => "880" "paginaFinal" => "888" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19088809" "web" => "Medline" ] ] ] ] ] ] ] ] 56 => array:3 [ "identificador" => "bib0285" "etiqueta" => "57" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Meal-induced insulin sensitization in conscious and anaesthetized rat models comparing liquid mixed meal with glucose and sucrose" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ 0 => "P. Sadri" 1 => "M.A. Reid" 2 => "R.A. Afonso" 3 => "J. Schafer" 4 => "D.J. Legare" 5 => "M.P. Macedo" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Br J Nutr" "fecha" => "2006" "volumen" => "95" "paginaInicial" => "288" "paginaFinal" => "295" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16469144" "web" => "Medline" ] ] ] ] ] ] ] ] 57 => array:3 [ "identificador" => "bib0290" "etiqueta" => "58" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Insulin sensitivity in skeletal muscle regulated by a hepatic hormone" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "W.W. Lautt" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "HISS Can J Appl Physiol" "fecha" => "2005" "volumen" => "30" "paginaInicial" => "304" "paginaFinal" => "312" ] ] ] ] ] ] 58 => array:3 [ "identificador" => "bib0295" "etiqueta" => "59" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Comparison of the rapid insulin sensitivity test (RIST), the insulin tolerance test (ITT), and the hyperinsulinemic euglycemic clamp (HIEC) to measure insulin action in rats" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ 0 => "M.A. Reid" 1 => "M.G. Latour" 2 => "D.J. Legare" 3 => "N. Rong" 4 => "W.W. Lautt" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Can J Physiol Pharmacol" "fecha" => "2002" "volumen" => "80" "paginaInicial" => "811" "paginaFinal" => "818" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12269792" "web" => "Medline" ] ] ] ] ] ] ] ] 59 => array:3 [ "identificador" => "bib0300" "etiqueta" => "60" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The hepatic vagus nerve in the control of insulin sensitivity in the rat" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "M.G. Latour" 1 => "W.W. Lautt" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Auton Neurosci" "fecha" => "2002" "volumen" => "95" "paginaInicial" => "125" "paginaFinal" => "130" "link" => array:1 [ 0 => array:2 [ "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11871777" "web" => "Medline" ] ] ] ] ] ] ] ] 60 => array:3 [ "identificador" => "bib0305" "etiqueta" => "61" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Insulin resistance of skeletal muscle produced by hepatic parasympathetic interruption" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "H. Xie" …1 ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Am J Physiol" "fecha" => "1996" "volumen" => "270" "numero" => "Pt 1" "paginaInicial" => "E858" "paginaFinal" => "E863" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 61 => array:3 [ "identificador" => "bib0310" "etiqueta" => "62" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Diabetologia" "fecha" => "1985" "volumen" => "28" "paginaInicial" => "412" "paginaFinal" => "419" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 62 => array:3 [ "identificador" => "bib0315" "etiqueta" => "63" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Use and abuse of HOMA modeling" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Diabetes Care" "fecha" => "2004" "volumen" => "27" "paginaInicial" => "1487" "paginaFinal" => "1495" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 63 => array:3 [ "identificador" => "bib0320" "etiqueta" => "64" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Repeatability characteristics of simple indices of insulin resistance: implications for research applications" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1210/jcem.86.11.7880" "Revista" => array:6 [ "tituloSerie" => "J Clin Endocrinol Metab" "fecha" => "2001" "volumen" => "86" "paginaInicial" => "5457" "paginaFinal" => "5464" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 64 => array:3 [ "identificador" => "bib0325" "etiqueta" => "65" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Evaluation of the quantitative insulin sensitivity check index as an estimate of insulin sensitivity in humans" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ …2] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Metabolism" "fecha" => "2002" "volumen" => "51" "paginaInicial" => "235" "paginaFinal" => "237" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 65 => array:3 [ "identificador" => "bib0330" "etiqueta" => "66" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Validation of the insulin sensitivity index (ISI(0,120)): comparison with other measures" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Diabetes Res Clin Pract" "fecha" => "2000" "volumen" => "47" "paginaInicial" => "177" "paginaFinal" => "184" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 66 => array:3 [ "identificador" => "bib0335" "etiqueta" => "67" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Non-steady state: error analysis of Steele's model and developments for glucose kinetics" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ …3] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:7 [ "tituloSerie" => "Am J Physiol" "fecha" => "1987" "volumen" => "252" "numero" => "Pt 1" "paginaInicial" => "E679" "paginaFinal" => "E689" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 67 => array:3 [ "identificador" => "bib0340" "etiqueta" => "68" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Insulin sensitivity of blood glucose versus insulin sensitivity of blood free fatty acids in normal, obese, and obese-diabetic subjects" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:2 [ "doi" => "10.1053/meta.2001.22518" "Revista" => array:6 [ "tituloSerie" => "Metabolism" "fecha" => "2001" "volumen" => "50" "paginaInicial" => "573" "paginaFinal" => "582" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 68 => array:3 [ "identificador" => "bib0345" "etiqueta" => "69" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Diabetes Care" "fecha" => "2000" "volumen" => "23" "paginaInicial" => "295" "paginaFinal" => "301" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 69 => array:3 [ "identificador" => "bib0350" "etiqueta" => "70" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Oral glucose tolerance test indexes for insulin sensitivity and secretion based on various availabilities of sampling times" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:4 [ …4] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Diabetes Care" "fecha" => "2001" "volumen" => "24" "paginaInicial" => "796" "paginaFinal" => "797" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 70 => array:3 [ "identificador" => "bib0355" "etiqueta" => "71" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Diagnosing insulin resistance in the general population" "autores" => array:1 [ 0 => array:2 [ "etal" => true "autores" => array:6 [ …6] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Diabetes Care" "fecha" => "2001" "volumen" => "24" "paginaInicial" => "460" "paginaFinal" => "464" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] 71 => array:3 [ "identificador" => "bib0360" "etiqueta" => "72" "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "A model-based method for assessing insulin sensitivity from the oral glucose tolerance test" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:5 [ …5] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Diabetes Care" "fecha" => "2001" "volumen" => "24" "paginaInicial" => "539" "paginaFinal" => "548" "link" => array:1 [ 0 => array:2 [ …2] ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:4 [ "identificador" => "xack87666" "titulo" => "Acknowledgements" "texto" => "We thank Fernandes AB, Afonso RA, Ribeiro RT and Inês S. Lima for helpful scientific discussions." "vista" => "all" ] ] ] "idiomaDefecto" => "en" "url" => "/16463439/0000000900000001/v1_201407280026/S1646343913000734/v1_201407280026/en/main.assets" "Apartado" => array:4 [ "identificador" => "19187" "tipo" => "SECCION" "en" => array:2 [ "titulo" => "Revisão" "idiomaDefecto" => true ] "idiomaDefecto" => "en" ] "PDF" => "https://static.elsevier.es/multimedia/16463439/0000000900000001/v1_201407280026/S1646343913000734/v1_201407280026/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1646343913000734?idApp=UINPBA00004N"]

Statistics

Revisão

Assessment of methods and indexes of insulin sensitivity

Métodos de avaliação e índices de sensibilidade à insulina

Rita S. Patarrãoa,

Corresponding author

rita.patarrao@fcm.unl.pt

Corresponding author.

, Wilford Wayne Lauttb, Maria Paula Macedoc,d

a CEDOC, Área de Ensino e Investigação de Medicina Celular e Molecular, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal

b Department of Pharmacology and Therapeutics, Faculty of Medicine, University of Manitoba, Winnipeg, Manitoba R3E OW3, Canada

c CEDOC, Departamento de Fisiologia, Faculdade de Ciências Médicas, Universidade Nova de Lisboa, 1169-056 Lisboa, Portugal

d APDP-ERC Portuguese Diabetes Association Education and Research Center, Rua do Salitre, 118-120, 1250-203 Lisbon, Portugal

Read

36882

Times
was read the article

5083

Total PDF

31799

Total HTML

Share statistics

 array:24 [
  "pii" => "S1646343913000734"
  "issn" => "16463439"
  "doi" => "10.1016/j.rpedm.2013.10.004"
  "estado" => "S300"
  "fechaPublicacion" => "2014-01-01"
  "aid" => "25"
  "copyright" => "Sociedade Portuguesa de Endocrinologia&#44; Diabetes e Metabolismo"
  "copyrightAnyo" => "2012"
  "documento" => "article"
  "crossmark" => 0
  "licencia" => "http://creativecommons.org/licenses/by-nc-nd/3.0/"
  "subdocumento" => "ssu"
  "cita" => "Rev Port Endocrinol Diabetes Metab. 2014;9:65-73"
  "abierto" => array:3 [
    "ES" => true
    "ES2" => true
    "LATM" => true
  ]
  "gratuito" => true
  "lecturas" => array:2 [
    "total" => 16662
    "formatos" => array:3 [
      "EPUB" => 129
      "HTML" => 14012
      "PDF" => 2521
    ]
  ]
  "itemSiguiente" => array:19 [
    "pii" => "S164634391400008X"
    "issn" => "16463439"
    "doi" => "10.1016/j.rpedm.2014.03.001"
    "estado" => "S300"
    "fechaPublicacion" => "2014-01-01"
    "aid" => "33"
    "copyright" => "Sociedade Portuguesa de Endocrinologia&#44; Diabetes e Metabolismo"
    "documento" => "article"
    "crossmark" => 0
    "licencia" => "http://creativecommons.org/licenses/by-nc-nd/3.0/"
    "subdocumento" => "ssu"
    "cita" => "Rev Port Endocrinol Diabetes Metab. 2014;9:74-8"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:2 [
      "total" => 5122
      "formatos" => array:3 [
        "EPUB" => 124
        "HTML" => 4199
        "PDF" => 799
      ]
    ]
    "pt" => array:12 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Revis&#227;o</span>"
      "titulo" => "Sobrecarga de ferro e diabetes <span class="elsevierStyleItalic">mellitus</span>"
      "tienePdf" => "pt"
      "tieneTextoCompleto" => "pt"
      "tieneResumen" => array:2 [
        0 => "pt"
        1 => "en"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "74"
          "paginaFinal" => "78"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "en" => array:1 [
          "titulo" => "Iron overload and diabetes <span class="elsevierStyleItalic">mellitus</span>"
        ]
      ]
      "contieneResumen" => array:2 [
        "pt" => true
        "en" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "pt" => true
      ]
      "contienePdf" => array:1 [
        "pt" => true
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Sofia Gouveia, Cristina Ribeiro, Francisco Carrilho"
          "autores" => array:3 [
            0 => array:2 [
              "nombre" => "Sofia"
              "apellidos" => "Gouveia"
            ]
            1 => array:2 [
              "nombre" => "Cristina"
              "apellidos" => "Ribeiro"
            ]
            2 => array:2 [
              "nombre" => "Francisco"
              "apellidos" => "Carrilho"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "pt"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S164634391400008X?idApp=UINPBA00004N"
    "url" => "/16463439/0000000900000001/v1_201407280026/S164634391400008X/v1_201407280026/pt/main.assets"
  ]
  "itemAnterior" => array:19 [
    "pii" => "S1646343914000029"
    "issn" => "16463439"
    "doi" => "10.1016/j.rpedm.2013.12.001"
    "estado" => "S300"
    "fechaPublicacion" => "2014-01-01"
    "aid" => "27"
    "copyright" => "Sociedade Portuguesa de Endocrinologia&#44; Diabetes e Metabolismo"
    "documento" => "article"
    "crossmark" => 0
    "licencia" => "http://creativecommons.org/licenses/by-nc-nd/3.0/"
    "subdocumento" => "ssu"
    "cita" => "Rev Port Endocrinol Diabetes Metab. 2014;9:59-64"
    "abierto" => array:3 [
      "ES" => true
      "ES2" => true
      "LATM" => true
    ]
    "gratuito" => true
    "lecturas" => array:2 [
      "total" => 31669
      "formatos" => array:3 [
        "EPUB" => 146
        "HTML" => 30097
        "PDF" => 1426
      ]
    ]
    "pt" => array:13 [
      "idiomaDefecto" => true
      "cabecera" => "<span class="elsevierStyleTextfn">Revis&#227;o</span>"
      "titulo" => "Hiperplasia cong&#233;nita da suprarrenal n&#227;o cl&#225;ssica &#8211; aspetos relevantes para a pr&#225;tica cl&#237;nica"
      "tienePdf" => "pt"
      "tieneTextoCompleto" => "pt"
      "tieneResumen" => array:2 [
        0 => "pt"
        1 => "en"
      ]
      "paginas" => array:1 [
        0 => array:2 [
          "paginaInicial" => "59"
          "paginaFinal" => "64"
        ]
      ]
      "titulosAlternativos" => array:1 [
        "en" => array:1 [
          "titulo" => "Nonclassical congenital adrenal hyperplasia &#8211; relevant aspects for clinical practice"
        ]
      ]
      "contieneResumen" => array:2 [
        "pt" => true
        "en" => true
      ]
      "contieneTextoCompleto" => array:1 [
        "pt" => true
      ]
      "contienePdf" => array:1 [
        "pt" => true
      ]
      "resumenGrafico" => array:2 [
        "original" => 0
        "multimedia" => array:7 [
          "identificador" => "fig0010"
          "etiqueta" => "Figura 2"
          "tipo" => "MULTIMEDIAFIGURA"
          "mostrarFloat" => true
          "mostrarDisplay" => false
          "figura" => array:1 [
            0 => array:4 [
              "imagen" => "gr2.jpeg"
              "Alto" => 445
              "Ancho" => 1672
              "Tamanyo" => 62912
            ]
          ]
          "descripcion" => array:1 [
            "pt" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">Valores de refer&#234;ncia para diagn&#243;stico de hiperplasia cong&#233;nita suprarrenal atrav&#233;s da prova de estimula&#231;&#227;o com ACTH&#46;</p>"
          ]
        ]
      ]
      "autores" => array:1 [
        0 => array:2 [
          "autoresLista" => "Teresa Azevedo, Teresa Martins, Manuel Carlos Lemos, Fernando Rodrigues"
          "autores" => array:4 [
            0 => array:2 [
              "nombre" => "Teresa"
              "apellidos" => "Azevedo"
            ]
            1 => array:2 [
              "nombre" => "Teresa"
              "apellidos" => "Martins"
            ]
            2 => array:2 [
              "nombre" => "Manuel Carlos"
              "apellidos" => "Lemos"
            ]
            3 => array:2 [
              "nombre" => "Fernando"
              "apellidos" => "Rodrigues"
            ]
          ]
        ]
      ]
    ]
    "idiomaDefecto" => "pt"
    "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1646343914000029?idApp=UINPBA00004N"
    "url" => "/16463439/0000000900000001/v1_201407280026/S1646343914000029/v1_201407280026/pt/main.assets"
  ]
  "en" => array:20 [
    "idiomaDefecto" => true
    "cabecera" => "<span class="elsevierStyleTextfn">Revis&#227;o</span>"
    "titulo" => "Assessment of methods and indexes of insulin sensitivity"
    "tieneTextoCompleto" => true
    "paginas" => array:1 [
      0 => array:2 [
        "paginaInicial" => "65"
        "paginaFinal" => "73"
      ]
    ]
    "autores" => array:1 [
      0 => array:4 [
        "autoresLista" => "Rita S&#46; Patarr&#227;o, Wilford Wayne Lautt, Maria Paula Macedo"
        "autores" => array:3 [
          0 => array:4 [
            "nombre" => "Rita S&#46;"
            "apellidos" => "Patarr&#227;o"
            "email" => array:1 [
              0 => "rita&#46;patarrao&#64;fcm&#46;unl&#46;pt"
            ]
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">a</span>"
                "identificador" => "aff0005"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">&#42;</span>"
                "identificador" => "cor0005"
              ]
            ]
          ]
          1 => array:3 [
            "nombre" => "Wilford"
            "apellidos" => "Wayne Lautt"
            "referencia" => array:1 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">b</span>"
                "identificador" => "aff0010"
              ]
            ]
          ]
          2 => array:3 [
            "nombre" => "Maria"
            "apellidos" => "Paula Macedo"
            "referencia" => array:2 [
              0 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">c</span>"
                "identificador" => "aff0015"
              ]
              1 => array:2 [
                "etiqueta" => "<span class="elsevierStyleSup">d</span>"
                "identificador" => "aff0020"
              ]
            ]
          ]
        ]
        "afiliaciones" => array:4 [
          0 => array:3 [
            "entidad" => "CEDOC&#44; &#193;rea de Ensino e Investiga&#231;&#227;o de Medicina Celular e Molecular&#44; Faculdade de Ci&#234;ncias M&#233;dicas&#44; Universidade Nova de Lisboa&#44; 1169-056 Lisboa&#44; Portugal"
            "etiqueta" => "a"
            "identificador" => "aff0005"
          ]
          1 => array:3 [
            "entidad" => "Department of Pharmacology and Therapeutics&#44; Faculty of Medicine&#44; University of Manitoba&#44; Winnipeg&#44; Manitoba R3E OW3&#44; Canada"
            "etiqueta" => "b"
            "identificador" => "aff0010"
          ]
          2 => array:3 [
            "entidad" => "CEDOC&#44; Departamento de Fisiologia&#44; Faculdade de Ci&#234;ncias M&#233;dicas&#44; Universidade Nova de Lisboa&#44; 1169-056 Lisboa&#44; Portugal"
            "etiqueta" => "c"
            "identificador" => "aff0015"
          ]
          3 => array:3 [
            "entidad" => "APDP-ERC Portuguese Diabetes Association Education and Research Center&#44; Rua do Salitre&#44; 118-120&#44; 1250-203 Lisbon&#44; Portugal"
            "etiqueta" => "d"
            "identificador" => "aff0020"
          ]
        ]
        "correspondencia" => array:1 [
          0 => array:3 [
            "identificador" => "cor0005"
            "etiqueta" => "&#8270;"
            "correspondencia" => "Corresponding author&#46;"
          ]
        ]
      ]
    ]
    "titulosAlternativos" => array:1 [
      "pt" => array:1 [
        "titulo" => "M&#233;todos de avalia&#231;&#227;o e &#237;ndices de sensibilidade &#224; insulina"
      ]
    ]
    "resumenGrafico" => array:2 [
      "original" => 0
      "multimedia" => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Fig&#46; 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 789
            "Ancho" => 2143
            "Tamanyo" => 97102
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; Mean profile using the dynamic analysis of the pattern of glucose infusion during the Rapid Insulin Sensitivity Test &#40;RIST&#41;&#46; The mean RIST curves were obtained by averaging glucose infusion rates at 0&#46;1-min intervals throughout the test &#40;Postprandial RIST &#40;bold line&#41; and the RIST obtained after 24<span class="elsevierStyleHsp" style=""></span>h-fast &#40;simple line&#41;&#41;&#46; &#40;B&#41; Calculation of the area under the curve during the 24 h-fast and postprandial RIST&#44; that corresponds to the total amount of glucose infused to maintain euglycemia over the test period&#44; which is terminated when no further glucose infusion is required &#40;RIST index&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a></p>"
        ]
      ]
    ]
    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Measurements of insulin sensitivity provide clinicians and researchers with excellent instruments to objectively evaluate the efficiency of both current and potentially useful interventional tools&#46;</p><p id="par0010" class="elsevierStylePara elsevierViewall">It is of great importance to develop tools for quantifying insulin sensitivity&#47;resistance in humans&#44; which may be used to appropriately investigate the epidemiology&#44; pathophysiologic mechanisms&#44; outcomes of therapeutic interventions&#44; and clinical course of patients with insulin resistance&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Methods of insulin sensitivity&#47;resistance assessment</span><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">Hyperinsulinemic Euglycemic Glucose Clamp</span><p id="par0015" class="elsevierStylePara elsevierViewall">The Hyperinsulinemic Euglycemic Clamp &#40;HIEC&#41;&#44; originally developed by DeFronzo&#44; is widely accepted as the &#8220;gold standard&#8221; for directly determining metabolic insulin sensitivity in humans&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a> After an overnight fast&#44; insulin is infused intravenously at a constant rate that may range from 5 to 120<span class="elsevierStyleHsp" style=""></span>mU&#47;m<span class="elsevierStyleSup">2</span>&#47;min &#40;dose per body surface area per minute&#44; during 180<span class="elsevierStyleHsp" style=""></span>min&#41;&#46; This constant insulin infusion results in a new steady-state insulin level that is above the fasting level &#40;hyperinsulinemic&#41;&#46; Consequently&#44; glucose disposal in skeletal muscle and adipose tissue is increased while hepatic glucose production &#40;HGP&#41; is suppressed&#46; Under these conditions&#44; a glucose analyzer is used to frequently monitor blood glucose levels at 5&#8211;10<span class="elsevierStyleHsp" style=""></span>min intervals&#44; while 20&#37; dextrose is given intravenously at a variable rate in order to &#8220;clamp&#8221; blood glucose concentrations in the normal range &#40;euglycemic&#41;&#46; After several hours of constant insulin infusion&#44; steady-state conditions are typically achieved for plasma insulin&#44; blood glucose&#44; and the glucose infusion rate &#40;GIR&#41;&#46; Assuming that the hyperinsulinemic state is sufficient to completely suppress HGP&#44; and since there is no net change in blood glucose concentrations under steady-state clamp conditions&#44; the GIR must be equal to the glucose disposal rate &#40;<span class="elsevierStyleItalic">M</span>&#41;&#46; Thus&#44; whole body glucose disposal at a given level of hyperinsulinemia can be directly determined&#46; <span class="elsevierStyleItalic">M</span> is typically normalized to body weight or fat-free mass to generate an estimate of insulin sensitivity&#46; Alternatively&#44; an insulin sensitivity index &#40;<span class="elsevierStyleItalic">SI</span>&#41; derived from clamp data can be defined as SIClamp&#61;MG&#215;&#916;I&#44; where <span class="elsevierStyleItalic">M</span> is normalized for <span class="elsevierStyleItalic">G</span> &#40;steady-state blood glucose concentration&#41; and &#916;<span class="elsevierStyleItalic">I</span> &#40;difference between fasting and steady-state plasma insulin concentrations&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0020" class="elsevierStylePara elsevierViewall">The validity of glucose clamp measurements of insulin sensitivity depends on achieving steady-state conditions&#46; &#8220;Steady-state&#8221; is often defined as a period greater than 30<span class="elsevierStyleHsp" style=""></span>min &#40;at least 1<span class="elsevierStyleHsp" style=""></span>h after initiation of insulin infusion&#41; during which the coefficients of variation for blood glucose&#44; plasma insulin&#44; and GIR are less than 5&#37;&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a> It is possible to use a radiolabeled glucose tracer under clamp conditions to estimate hepatic glucose production&#44; so that appropriate corrections can be made to <span class="elsevierStyleItalic">M</span> in the event HGP is not completely suppressed&#46;<a class="elsevierStyleCrossRefs" href="#bib0015"><span class="elsevierStyleSup">3&#8211;5</span></a> An alternative approach is to use an insulin infusion rate sufficiently high to completely suppress HGP according to the insulin sensitivity&#47;resistance of the population to be studied&#46;</p><p id="par0025" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">M</span> is routinely obtained at only a single insulin infusion rate&#44; and therefore comparisons between <span class="elsevierStyleItalic">M</span> or <span class="elsevierStyleItalic">SI</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">Clamp</span></span> among different subjects is valid only if the same insulin infusion rate is used for all subjects&#46;</p><p id="par0030" class="elsevierStylePara elsevierViewall">The principal advantage of the glucose clamp in humans is that it directly measures whole body glucose disposal at a given level of insulinemia under steady-state conditions&#46; Conceptually&#44; the approach is straightforward but there is a limited number of assumptions that are clearly defined&#46; In research settings where assessing insulin sensitivity&#47;resistance is of primary interest and feasibility is not an issue&#44; it is appropriate to use the glucose clamp technique&#46;</p><p id="par0035" class="elsevierStylePara elsevierViewall">The main limitations of the HIEC approach are that it is time-consuming&#44; labor intensive&#44; expensive&#44; and requires an experienced operator to manage technical difficulties&#46; Another limitation is that the clamp utilizes steady-state insulin levels that may be supraphysiological&#46; This results in a reversal of the normal portal to peripheral insulin gradient&#46; Thus&#44; the glucose clamp may not accurately reflect insulin action and glucose dynamics under physiological conditions that a dynamic test&#44; such as&#44; an oral meal or oral glucose load may determine&#46; Further&#44; in the HIEC insulin sensitivity is measured only under a steady-state condition&#44; and therefore&#44; the test does not realistically portray dynamic conditions such as those occurring after normal meals&#46; Because HIEC is dependent on steady-state conditions&#44; insulin infusion is continuous for &#8776;3<span class="elsevierStyleHsp" style=""></span>h&#44; and the subjects are in the fasted state&#46; The results of the HIEC may be limited by these restraints&#44; because insulin release is pulsatile&#44;<a class="elsevierStyleCrossRefs" href="#bib0030"><span class="elsevierStyleSup">6&#8211;8</span></a> and insulin action is sensitized in the postprandial state&#46;<a class="elsevierStyleCrossRef" href="#bib0045"><span class="elsevierStyleSup">9</span></a> Nevertheless&#44; it should be remembered that the HIEC measures insulin-stimulated glucose disposal only at insulin levels in the upper physiological range&#59; information on the effects of insulin on glucose uptake and production in the basal condition&#44; which is physiologically very important&#44; is not provided &#40;unless tracers are used&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0050"><span class="elsevierStyleSup">10</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">Insulin Tolerance Test</span><p id="par0040" class="elsevierStylePara elsevierViewall">The Insulin Tolerance Test &#40;ITT&#41; was one of the first methods developed to assess insulin sensitivity <span class="elsevierStyleItalic">in vivo</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0055"><span class="elsevierStyleSup">11</span></a> In this method&#44; a fixed bolus of regular insulin &#40;0&#46;1<span class="elsevierStyleHsp" style=""></span>IU&#47;kg bw&#41; is given iv after an 8&#8211;10<span class="elsevierStyleHsp" style=""></span>h fast&#46; Blood samples are collected at 15 and 5<span class="elsevierStyleHsp" style=""></span>min before and 3&#44; 6&#44; 9&#44; 12&#44; 15&#44; 20 and 30<span class="elsevierStyleHsp" style=""></span>min after insulin injection&#44; and the plasma glucose decrement is then measured&#46; Glucose is injected at 30<span class="elsevierStyleHsp" style=""></span>min to stop the fall in plasma glucose&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;13</span></a> The faster the decline in glucose concentration&#44; the more insulin sensitive the subject is&#46; The slope of the linear decline in plasma glucose &#40;<span class="elsevierStyleItalic">K</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">ITT</span></span>&#41; can be calculated by dividing 0&#46;693 by the plasma glucose half-time &#40;50&#37; from baseline&#41;&#58;<elsevierMultimedia ident="eq0005"></elsevierMultimedia>where <span class="elsevierStyleItalic">t</span><span class="elsevierStyleInf">1&#47;2</span> represents the half-life of plasma glucose decrease&#44; and is calculated from the slope of least square analysis of the plasma glucose concentrations from 3 to 15<span class="elsevierStyleHsp" style=""></span>min after iv insulin injection&#44; when the plasma glucose concentration declined linearly&#46; Normal <span class="elsevierStyleItalic">K</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">ITT</span></span> is &#62;2&#46;0&#37;&#47;min and values &#60;1&#46;5&#37;&#47;min are considered abnormal&#46; This method gives an indirect estimate of overall insulin sensitivity&#46;</p><p id="par0045" class="elsevierStylePara elsevierViewall">The advantages of the ITT include its simplicity&#44; rapidity and the use of a bolus injection of insulin&#46; The bolus injection of insulin mimics the physiological pulsatile release of insulin&#46;<a class="elsevierStyleCrossRef" href="#bib0030"><span class="elsevierStyleSup">6</span></a> Furthermore&#44; because glucose tolerance after a meal is dependent on insulin sensitivity&#44; measuring insulin sensitivity in the prandial state is physiologically relevant&#46;</p><p id="par0050" class="elsevierStylePara elsevierViewall">Some of the drawbacks of this method include the supraphysiological insulin dose used&#44; and also the fact that the test does not differentiate peripheral <span class="elsevierStyleItalic">vs</span> hepatic insulin resistance&#46;<a class="elsevierStyleCrossRef" href="#bib0070"><span class="elsevierStyleSup">14</span></a> Another major limitation of this test is the risk of hypoglycemia&#46; Hypoglycemia triggers hormonal responses&#44; which may interfere with insulin sensitivity and in turn slows the disappearance rate of glucose from plasma&#46;<a class="elsevierStyleCrossRef" href="#bib0075"><span class="elsevierStyleSup">15</span></a> In this view&#44; the fall in plasma glucose concentration would be a function of the interplay between insulin&#44; on the one hand&#44; and glucagon&#44; catecholamines&#44; growth hormone and cortisol&#44; on the other&#46; Given that&#44; the counterregulatory response occurs only 15&#8211;20<span class="elsevierStyleHsp" style=""></span>min after insulin injection&#46; The glucose fall occurring in the first 15<span class="elsevierStyleHsp" style=""></span>min after iv insulin administration is probably a function of insulin-stimulated glucose uptake by tissues as well as insulin ability to suppress glucose output by the liver&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">A lower insulin dose method of 0&#46;05<span class="elsevierStyleMonospace">Y</span>IU&#47;kg bw&#44; or shortening the test to 15<span class="elsevierStyleHsp" style=""></span>min was suggested as an attempt to decrease the risk of hypoglycemia&#46;<a class="elsevierStyleCrossRefs" href="#bib0070"><span class="elsevierStyleSup">14&#44;17</span></a> The shorter version<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;16</span></a> derived from the notion that the counterregulatory hormone response occurs only after 20<span class="elsevierStyleHsp" style=""></span>min of the insulin infusion&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">The ITT has been shown to correlate with the HIEC in several studies&#46;<a class="elsevierStyleCrossRefs" href="#bib0060"><span class="elsevierStyleSup">12&#44;16</span></a> However&#44; arterialization of blood is essential in the ITT&#44; as data from standard venous blood measurements showed no significant relationship with HIEC-derived glucose disposal&#46;<a class="elsevierStyleCrossRef" href="#bib0080"><span class="elsevierStyleSup">16</span></a></p><p id="par0065" class="elsevierStylePara elsevierViewall">In conclusion&#44; the ITT should be used with great caution in insulin sensitive individuals because of the increased risk of hypoglycemia&#44; even when the smaller dose version of the test is used&#46; The shorter ITT is a valid test in large-scale studies&#44; especially when the site of resistance is not of importance&#46;</p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">Insulin Suppression Test</span><p id="par0070" class="elsevierStylePara elsevierViewall">The insulin-suppression test &#40;IST&#41;&#44; another method that directly measures metabolic insulin sensitivity&#47;resistance&#44; was introduced by Shen et al&#46; in 1970 and subsequently modified by Harano et al&#46;<a class="elsevierStyleCrossRefs" href="#bib0095"><span class="elsevierStyleSup">19&#44;20</span></a> After an overnight fast&#44; somatostatin &#40;250<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;h&#41; or the somatostatin analog octreotide &#40;25<span class="elsevierStyleHsp" style=""></span>&#956;g bolus&#44; followed by 0&#46;5<span class="elsevierStyleHsp" style=""></span>&#956;g&#47;min&#41;<a class="elsevierStyleCrossRef" href="#bib0105"><span class="elsevierStyleSup">21</span></a> is intravenously infused&#44; to suppress endogenous secretion of insulin and glucagon&#46; Simultaneously&#44; insulin &#40;25<span class="elsevierStyleHsp" style=""></span>mU&#47;m<span class="elsevierStyleSup">2</span>&#47;min&#41; and glucose &#40;240<span class="elsevierStyleHsp" style=""></span>mg&#47;m<span class="elsevierStyleSup">2</span>&#47;min&#41; are intravenously infused over 3<span class="elsevierStyleHsp" style=""></span>h&#46; Blood samples for glucose and insulin determinations are taken every 30<span class="elsevierStyleHsp" style=""></span>min for 2&#46;5<span class="elsevierStyleHsp" style=""></span>h&#44; and then at 10<span class="elsevierStyleHsp" style=""></span>min intervals from 150 to 180<span class="elsevierStyleHsp" style=""></span>min of the IST&#46; The constant infusions of insulin and glucose determine steady-state plasma insulin &#40;SSPI&#41; and glucose &#40;SSPG&#41; concentrations&#46; The steady-state period is assumed to be from 150 to 180<span class="elsevierStyleHsp" style=""></span>min after initiation of the IST&#46; SSPI concentrations are generally similar among subjects&#46; Therefore&#44; the SSPG concentration will be higher in insulin resistant subjects and lower in insulin sensitive subjects&#44; <span class="elsevierStyleItalic">i&#46;e&#46;</span>&#44; SSPG values are inversely related to insulin sensitivity&#46; The IST provides a direct measure &#40;through SSPG&#41; of the ability of exogenous insulin to mediate disposal of an iv glucose load&#44; under steady-state conditions&#44; where endogenous insulin secretion is suppressed&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">The SSPG is a highly reproducible direct measure of metabolic actions of insulin&#44; that is&#44; less labor intensive and less technically demanding than HIEC&#46; Indeed&#44; since there are no variable infusions with the IST&#44; steady-state conditions are more easily achieved with the IST than with HIEC&#46; In research settings&#44; the IST can be used for larger populations that may pose difficulties for application of HIEC&#46; ELIMINAR esta frase&#46;</p><p id="par0080" class="elsevierStylePara elsevierViewall">Many of the limitations of the IST are similar to those described for HIEC &#40;with the exception that the IST is less technically demanding&#41;&#46; Thus&#44; it is impractical to apply the IST in large epidemiological studies or in the clinical care setting&#46; SSPG under ideal conditions determines primarily skeletal muscle insulin sensitivity&#44; and is not designed to reflect hepatic insulin sensitivity&#46;<a class="elsevierStyleCrossRef" href="#bib0110"><span class="elsevierStyleSup">22</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">Continuous infusion of glucose with model assessment</span><p id="par0085" class="elsevierStylePara elsevierViewall">The continuous infusion of glucose with model assessment &#40;CIGMA&#41; is a procedure that assesses insulin sensitivity through the evaluation of the near steady-state glucose and insulin concentrations after a continuous infusion of glucose&#44; with model assessment&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a> This method mimics postprandial glucose and insulin concentrations&#46; CIGMA not only provides information about glucose tolerance and insulin sensitivity&#44; but also about &#946;-cell function&#46; Using a mathematic model of glucose homeostasis&#44; glucose and insulin values are compared with known physiologic data of glucose&#44; and insulin kinetics in response to glucose infusion&#44; which are derived from healthy lean subjects with no family history of diabetes&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p><p id="par0090" class="elsevierStylePara elsevierViewall">The glucose and insulin values used for CIGMA are obtained during the last 15<span class="elsevierStyleHsp" style=""></span>min of the 60<span class="elsevierStyleHsp" style=""></span>min continuous glucose infusion &#40;5<span class="elsevierStyleHsp" style=""></span>mg glucose&#47;kg bw&#47;min&#41;&#46; Samples are collected at 5<span class="elsevierStyleHsp" style=""></span>min intervals and the average is then compared with predicted values from the computer model&#46; The median value for normal subjects is 1&#46;35&#44; and for diabetic patients with mild hyperglycemia is 4&#46;0&#46;<a class="elsevierStyleCrossRef" href="#bib0115"><span class="elsevierStyleSup">23</span></a></p><p id="par0095" class="elsevierStylePara elsevierViewall">There are two main advantages of CIGMA over Homeostasis Model Assessment &#40;HOMA&#41;&#46; First&#44; the insulin values that are measured in CIGMA are much higher than those in HOMA owing to the glucose stimulus and second&#44; higher insulin concentration in CIGMA stimulates peripheral glucose uptake producing a steady-state glucose concentration&#44; which is a better reflection of the peripheral insulin sensitivity&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Although CIGMA is more practical&#44; cheaper and less invasive than the frequently sampled intravenous glucose tolerance test &#40;FSIVGTT&#41; and HIEC procedure&#44; the model incorrectly assumes that levels of insulin resistance at the liver and peripheral tissues are equal&#46; Furthermore&#44; in insulin-deficient subjects&#44; where the insulin response is insufficient to stimulate glucose uptake&#44; the interpretation of CIGMA is difficult&#46;</p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">Minimal model analysis of frequently sampled intravenous glucose tolerance test</span><p id="par0105" class="elsevierStylePara elsevierViewall">The minimal model&#44; developed by Bergman&#44; Cobelli and colleagues in 1979&#44; provides an indirect measure of metabolic insulin sensitivity&#47;resistance based on glucose and insulin data obtained during a frequently sampled intravenous glucose tolerance test &#40;FSIVGTT&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0120"><span class="elsevierStyleSup">24</span></a> After an overnight fast&#44; an intravenous bolus of glucose &#40;0&#46;3<span class="elsevierStyleHsp" style=""></span>g&#47;kg bw&#41; is infused over 2<span class="elsevierStyleHsp" style=""></span>min starting at time 0&#46;</p><p id="par0110" class="elsevierStylePara elsevierViewall">Currently&#44; a modified FSIVGTT is used&#44; where exogenous insulin &#40;4<span class="elsevierStyleHsp" style=""></span>mU&#47;kg&#47;min&#41; is also infused over 5<span class="elsevierStyleHsp" style=""></span>min beginning 20<span class="elsevierStyleHsp" style=""></span>min after the iv glucose bolus&#46;<a class="elsevierStyleCrossRefs" href="#bib0125"><span class="elsevierStyleSup">25&#44;26</span></a> Some studies use tolbutamide &#40;a potassium channel blocker&#41; instead of insulin in the modified FSIVGTT&#44; to stimulate endogenous insulin secretion&#46;<a class="elsevierStyleCrossRefs" href="#bib0135"><span class="elsevierStyleSup">27&#44;28</span></a></p><p id="par0115" class="elsevierStylePara elsevierViewall">Blood samples are taken for plasma glucose and insulin measurements at different time points&#44; before and 180<span class="elsevierStyleHsp" style=""></span>min after glucose infusion&#46; The data obtained are then subjected to minimal model analysis using the computer program MINMOD &#40;minimal model approach &#8211; MINMOD&#41;&#44; to generate an index of insulin sensitivity &#40;<span class="elsevierStyleItalic">S</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">I</span></span>&#41;&#46;</p><p id="par0120" class="elsevierStylePara elsevierViewall">The MINMOD is defined by two coupled differential equations with four model parameters &#40;<a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; The first equation describes plasma glucose dynamics in a single compartment&#46; The second equation describes insulin dynamics in a &#8220;remote compartment&#8221;&#46; The structure of the MINMOD allows it to uniquely identify model parameters&#44; which determine a best fit to glucose disappearance during the modified FSIVGTT&#46; <span class="elsevierStyleItalic">S</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">I</span></span> is calculated from two of these model parameters&#44; and is defined as fractional glucose disappearance <span class="elsevierStyleItalic">per</span> insulin concentration unit&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p><elsevierMultimedia ident="fig0005"></elsevierMultimedia><p id="par0125" class="elsevierStylePara elsevierViewall">In addition to <span class="elsevierStyleItalic">S</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">I</span></span>&#44; other minimal model parameters may be used to estimate a &#8220;glucose effectiveness&#8221; index &#40;<span class="elsevierStyleItalic">S</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">G</span></span>&#41;&#46; <span class="elsevierStyleItalic">S</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">G</span></span> is defined as the ability of glucose <span class="elsevierStyleItalic">per se</span> to promote its own disposal and inhibit hepatic glucose production &#40;HGP&#41; in the absence of an incremental insulin effect &#40;<span class="elsevierStyleItalic">i&#46;e&#46;</span>&#44; when insulin is at basal levels&#41;&#46;<elsevierMultimedia ident="eq0010"></elsevierMultimedia><elsevierMultimedia ident="eq0015"></elsevierMultimedia></p><p id="par0130" class="elsevierStylePara elsevierViewall">Minimal model analysis of the modified FSIVGTT is easier than HIEC method because it is slightly less labor intensive&#44; steady-state conditions are not required&#44; and there are no iv infusions that require constant adjustment&#46; Unlike HIEC or IST&#44; information about insulin sensitivity&#44; glucose effectiveness&#44; and &#946;-cell function can be derived from a single dynamic test&#46; The minimal model generates excellent predictions of glucose disappearance during the FSIVGTT&#46;</p><p id="par0135" class="elsevierStylePara elsevierViewall">In research settings&#44; where assessing insulin sensitivity along with glucose effectiveness and &#946;-cell function is of interest&#44; minimal model analysis of the insulin-modified FSIVGTT may be appropriate&#46; The minimal model approach is simpler than direct methods for determining insulin sensitivity&#46; Nevertheless&#44; it still involves iv infusions with multiple blood sampling over a 3<span class="elsevierStyleHsp" style=""></span>h period&#44; that is&#44; nearly as labor intensive as the HIEC or IST&#46; In addition&#44; many limitations of minimal model analysis stem from the fact that the model oversimplifies the physiology of glucose homeostasis&#46;<a class="elsevierStyleCrossRef" href="#bib0145"><span class="elsevierStyleSup">29</span></a></p><p id="par0140" class="elsevierStylePara elsevierViewall">Another oversimplification of the minimal model involves lumping together effects of insulin to promote peripheral glucose utilization and suppress HGP&#46; As insulin sensitivity&#47;resistance varies&#44; the relative contribution of HGP to S<span class="elsevierStyleInf">I</span> may vary significantly&#46; Since the minimal model relies on a dynamic test to evaluate insulin sensitivity&#44; estimates of <span class="elsevierStyleItalic">S</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">I</span></span> are much less reliable in individuals with impaired insulin secretion and&#47;or significant insulin resistance &#40;when compared with healthy subjects&#41;&#46; Under these conditions&#44; the minimal model may overestimate <span class="elsevierStyleItalic">S</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">G</span></span> to accurately predict the disappearance of glucose during the FSIVGTT&#46; Indeed&#44; estimates of <span class="elsevierStyleItalic">S</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">G</span></span> are spuriously affected by differences in insulin secretory capacity&#46;<a class="elsevierStyleCrossRefs" href="#bib0130"><span class="elsevierStyleSup">26&#44;30</span></a> Moreover&#44; for similar reasons&#44; minimal model analysis often generates senseless negative values for <span class="elsevierStyleItalic">S</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">I</span></span> in a substantial proportion of subjects with diabetes&#44; who have minimal insulin secretory capacity and significant insulin resistance&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;30</span></a> These nonsystematic errors inherent in the minimal model approach are highlighted by calibration model analysis&#44; demonstrating that some simple surrogate indexes of insulin sensitivity have better absolute accuracy for predicting <span class="elsevierStyleItalic">SI</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">Clamp</span></span> than the minimal model-derived <span class="elsevierStyleItalic">S</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">I</span></span>&#46;<a class="elsevierStyleCrossRef" href="#bib0155"><span class="elsevierStyleSup">31</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">Oral Glucose Tolerance Test</span><p id="par0145" class="elsevierStylePara elsevierViewall">The Oral Glucose Tolerance Test &#40;OGTT&#41; is a simple test&#44; widely used in clinical practice to diagnose glucose intolerance and type 2 diabetes&#46;<a class="elsevierStyleCrossRefs" href="#bib0090"><span class="elsevierStyleSup">18&#44;32&#44;33</span></a> After an overnight fast&#44; blood samples for determinations of glucose and insulin concentrations are taken at 0&#44; 30&#44; 60&#44; and 120<span class="elsevierStyleHsp" style=""></span>min following a standard oral glucose load &#40;75<span class="elsevierStyleHsp" style=""></span>g&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> A diagnosis of diabetes is conferred if an individual has a plasma glucose level &#8805;200<span class="elsevierStyleHsp" style=""></span>mg&#47;dl &#40;11<span class="elsevierStyleMonospace">Y</span>mmol&#47;l&#41; as measured 2<span class="elsevierStyleHsp" style=""></span>h after the ingestion of a 75<span class="elsevierStyleHsp" style=""></span>g glucose load&#46; If an individual has a value in the range of 140&#8211;199<span class="elsevierStyleHsp" style=""></span>mg&#47;dl &#40;7&#46;7&#8211;11<span class="elsevierStyleMonospace">Y</span>mmol&#47;l&#41; 2<span class="elsevierStyleHsp" style=""></span>h post-glucose load&#44; it is designated as having impaired glucose tolerance&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a> Oral glucose tolerance reflects the efficiency with which the body handles glucose after an oral glucose load&#46;</p><p id="par0150" class="elsevierStylePara elsevierViewall">The OGTT mimics the glucose and insulin dynamics of physiological conditions more closely than conditions of the HIEC&#44; IST or frequently sample intravenous glucose tolerance test &#40;FSIVGTT&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a> However&#44; it is important to recognize that glucose tolerance and insulin sensitivity are not equivalent concepts&#46; In addition to metabolic actions of insulin&#44; insulin secretion&#44; incretin effects&#44; and other factors contribute importantly to glucose tolerance&#46; Thus&#44; the OGTT&#44; by itself&#44; provides useful information about glucose tolerance but not insulin sensitivity&#47;resistance <span class="elsevierStyleItalic">per se</span>&#46;<a class="elsevierStyleCrossRefs" href="#bib0175"><span class="elsevierStyleSup">35&#44;36</span></a> During the OGTT&#44; the use of a glucose tracer and both insulin and C-peptide plasma measurements at specific time points&#44; allows the calculation of glucose clearance&#46;</p><p id="par0155" class="elsevierStylePara elsevierViewall">The OGTT is technically quite simple to perform and certainly lower in cost than HIEC or FSIVGTT&#46; These considerations have made the OGTT the glucose challenge test of choice in clinical situations&#46;<a class="elsevierStyleCrossRef" href="#bib0185"><span class="elsevierStyleSup">37</span></a> However&#44; there are some problems with the OGTT that make it less desirable for use in research situations&#46; First&#44; there is variability in the rate of gastric emptying and glucose absorption from the gastrointestinal tract&#44; causing some imprecision from the start&#46; This variability can partially account for poorly reproducible results even within the same individual&#46;<a class="elsevierStyleCrossRef" href="#bib0190"><span class="elsevierStyleSup">38</span></a> Second&#44; glucose measurements in the standard OGTT do not give adequate information regarding the dynamics of glucose and insulin action&#46;<a class="elsevierStyleCrossRef" href="#bib0165"><span class="elsevierStyleSup">33</span></a></p><p id="par0160" class="elsevierStylePara elsevierViewall">The OGTT is a relatively crude measure of glucose tolerance&#46; It does not measure the components of insulin sensitivity and insulin secretion&#46; In light of this limitation&#44; attempts have been made to obtain indices from OGTT data that might better reflect &#946;-cell function and insulin sensitivity&#46;<a class="elsevierStyleCrossRefs" href="#bib0195"><span class="elsevierStyleSup">39&#44;40</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">Meal Tolerance Test</span><p id="par0165" class="elsevierStylePara elsevierViewall">In an attempt to study the ability to regulate blood glucose in a more physiological situation than the OGTT&#44; some authors measure the glycemic profile in response to the ingestion of a mixed meal containing carbohydrates&#44; fat and proteins&#59; the Meal Tolerance Test &#40;MTT&#41;&#46;</p><p id="par0170" class="elsevierStylePara elsevierViewall">The experimental procedure for the MTT is similar to the OGTT&#44; that is&#44; after an overnight fast &#40;10&#8211;12<span class="elsevierStyleHsp" style=""></span>h&#41;&#44; a mixed meal &#40;liquid or solid&#41; is given and the glycemic profile is measured throughout 2<span class="elsevierStyleHsp" style=""></span>h&#59; usually the insulin profile is also determined during the same period of time&#46;<a class="elsevierStyleCrossRefs" href="#bib0170"><span class="elsevierStyleSup">34&#44;36</span></a></p><p id="par0175" class="elsevierStylePara elsevierViewall">The MTT is a &#8220;physiologic&#8221; variant of OGTT<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a> offering several advantages&#58; &#40;a&#41; lack of artifactual postload hypoglycemia&#44; thus making this test suitable for the study of postprandial hypoglycemia&#44; a situation which is frequently due to high values of insulin sensitivity&#44; but also to hyperinsulinism in a context of insulin resistance<a class="elsevierStyleCrossRef" href="#bib0210"><span class="elsevierStyleSup">42</span></a>&#59; &#40;b&#41; use of a physiologic stimulus triggering a cephalic phase proportional to palatability scores<a class="elsevierStyleCrossRef" href="#bib0215"><span class="elsevierStyleSup">43</span></a>&#59; &#40;c&#41; possibility to measure insulin sensitivity with a modified algorithm based on the minimal model<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a> as well as glucose effectiveness and insulin secretion&#59; &#40;d&#41; potential for evaluating the physiologic effects of incretins&#46;<a class="elsevierStyleCrossRef" href="#bib0220"><span class="elsevierStyleSup">44</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">The MTT can represent a simple procedure&#44; less unpleasant for the patient than the standard OGTT&#44; and providing both a physiologic picture of glucoregulation&#44; and a sophisticated and precise analysis of this glucoregulation&#44; in terms of insulin sensitivity&#44; glucose effectiveness&#44; and insulin secretion&#46;<a class="elsevierStyleCrossRef" href="#bib0205"><span class="elsevierStyleSup">41</span></a></p><p id="par0185" class="elsevierStylePara elsevierViewall">The &#946;-cell response is stronger after a mixed meal than after an OGTT with equal carbohydrate quantity&#44; both for classical and model-based parameters&#46; The higher response was mostly explained by higher &#946;-cell sensitivity during the meal&#44; which may lead to lower glucose excursions&#46;<a class="elsevierStyleCrossRef" href="#bib0225"><span class="elsevierStyleSup">45</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">Several factors may contribute to differences in insulin secretion following an MTT compared with the OGTT&#46; The MTT has a lower glycemic index than the OGTT&#44; which may lead to lower glucose excursions&#46;<a class="elsevierStyleCrossRef" href="#bib0230"><span class="elsevierStyleSup">46</span></a> Moreover&#44; slower gastric emptying following the MTT due to larger volume&#44;<a class="elsevierStyleCrossRef" href="#bib0235"><span class="elsevierStyleSup">47</span></a> solid character&#44;<a class="elsevierStyleCrossRef" href="#bib0240"><span class="elsevierStyleSup">48</span></a> and fat content<a class="elsevierStyleCrossRef" href="#bib0245"><span class="elsevierStyleSup">49</span></a> will lead to a slower entry of nutrients into the circulation&#46;</p><p id="par0195" class="elsevierStylePara elsevierViewall">The MTT might be considered as an additional tool for the assessment of metabolic abnormalities&#44; in glucose-intolerant and insulin-resistant states&#46;<a class="elsevierStyleCrossRef" href="#bib0170"><span class="elsevierStyleSup">34</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">Thus&#44; the MTT is a more physiological test than the OGTT&#44; in regard to human diet&#44; and is potentially able to give useful information concerning islet &#946;-cell function in the different categories of glucose intolerance&#44;<a class="elsevierStyleCrossRef" href="#bib0250"><span class="elsevierStyleSup">50</span></a> but not insulin sensitivity&#47;resistance <span class="elsevierStyleItalic">per se</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0180"><span class="elsevierStyleSup">36</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">As any other method that measures glucose tolerance&#44; the MTT does not assess insulin sensitivity directly and may not be repeated in the same subject or animal on the same day&#46;</p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">Rapid Insulin Sensitivity Test</span><p id="par0210" class="elsevierStylePara elsevierViewall">A new method for insulin sensitivity quantification&#44; called the Rapid Insulin Sensitivity Test &#40;RIST&#41;&#44; was described and evaluated for use in rats&#44;<a class="elsevierStyleCrossRefs" href="#bib0255"><span class="elsevierStyleSup">51&#44;52</span></a> cats<a class="elsevierStyleCrossRefs" href="#bib0265"><span class="elsevierStyleSup">53&#44;54</span></a> mice<a class="elsevierStyleCrossRef" href="#bib0275"><span class="elsevierStyleSup">55</span></a> and humans&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a> The standard dynamic profile for the RIST in fed and fasted humans as well as the RIST insulin sensitivity index is shown in <a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#46;</p><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0215" class="elsevierStylePara elsevierViewall">The RIST is an euglycemic test and is carried out after establishing the glycemic baseline&#44; which is done by taking arterialized venous blood samples at 5<span class="elsevierStyleHsp" style=""></span>min intervals until three consecutive measurements are stable&#46; An insulin infusion is commenced &#40;50<span class="elsevierStyleMonospace">Y</span>mIU&#47;kg administered over 5<span class="elsevierStyleHsp" style=""></span>min&#41; and&#44; after 1<span class="elsevierStyleHsp" style=""></span>min&#44; glucose samples are taken at 2<span class="elsevierStyleHsp" style=""></span>min intervals&#44; and glucose is infused intravenously at a variable rate to maintain euglycemia&#46; The test is completed when no more glucose is required&#46; At the standard test dose of insulin of 50<span class="elsevierStyleMonospace">Y</span>mIU&#47;kg&#44; the RIST in the fasted state is complete within approximately 40<span class="elsevierStyleHsp" style=""></span>min&#46; The RIST index&#44; the insulin sensitivity parameter&#44; is simply the amount of glucose that had to be administered in order to maintain euglycemia after the bolus administration of insulin&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a></p><p id="par0220" class="elsevierStylePara elsevierViewall">The majority of the insulin sensitivity tests are done in the fasted state&#44; when insulin sensitivity would be logically anticipated to be at its lowest level&#46; Studies performed by Patarr&#227;o et al&#46; and Lautt et al&#46; indicated that the fasted state results in a very low insulin responsiveness&#46; It is reasonable that insulin sensitivity should be under a regulatory mechanism such that in the fasted state insulin effect would be minimized&#44; and inappropriate release of insulin would not&#44; therefore&#44; lead to life-threatening hypoglycemia&#46; The RIST can be carried out in the fed state&#46;<a class="elsevierStyleCrossRefs" href="#bib0045"><span class="elsevierStyleSup">9&#44;56</span></a> Furthermore&#44; the RIST allows insulin sensitivity assessment before and after a meal&#44; making it possible to test both meal and drug effects on insulin sensitivity&#46;<a class="elsevierStyleCrossRefs" href="#bib0280"><span class="elsevierStyleSup">56&#44;57</span></a></p><p id="par0225" class="elsevierStylePara elsevierViewall">The RIST is extremely sensitive and can be shown to generate dose-response relationships to insulin&#44; which makes the RIST the most advantageous method in the determination of small differences in insulin sensitivity&#46; This method is able to be carried out more than one time in the same subject with high reproducibility&#44; and is sufficiently versatile to permit paired experimental designs&#44; in the same subjects and on the same day&#46; Both the accuracy and precision of the test can be assessed from determination of the deviation from the ideal euglycemic target&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a></p><p id="par0230" class="elsevierStylePara elsevierViewall">Insulin release normally occurs in a pulsatile manner&#44; and hormones released in a pulsatile manner are best studied by pulsatile administration&#46;<a class="elsevierStyleCrossRef" href="#bib0290"><span class="elsevierStyleSup">58</span></a> Based on this assumption&#44; the intravenous insulin bolus administered at the beginning of the RIST mimics the physiological insulin action&#46; It also avoids the vagal withdrawal and sympathetic activation induced by sustained hyperinsulinemia&#44; during the HIEC<a class="elsevierStyleCrossRefs" href="#bib0275"><span class="elsevierStyleSup">55&#44;59</span></a> and the hypoglycemia caused by the acute ITT&#46;<a class="elsevierStyleCrossRef" href="#bib0295"><span class="elsevierStyleSup">59</span></a> It does not alter levels of counter-regulatory hormones&#44; such as catecholamines&#44; somatostatin or glucagon&#46;<a class="elsevierStyleCrossRef" href="#bib0270"><span class="elsevierStyleSup">54</span></a> Moreover&#44; both insulinemia and glycemia return to basal levels after each RIST&#46;</p><p id="par0235" class="elsevierStylePara elsevierViewall">One methodological issue relates to the basal glucose concentration determined before and after the RIST&#46; Previous studies demonstrate clearly that there is no mean change in basal blood glucose levels used as the euglycemic target when&#44; for example&#44; compared before and after denervation of the hepatic plexus in rats<a class="elsevierStyleCrossRef" href="#bib0300"><span class="elsevierStyleSup">60</span></a> or atropine&#46;<a class="elsevierStyleCrossRef" href="#bib0305"><span class="elsevierStyleSup">61</span></a> In addition&#44; we have also determined that there is no correlation between the magnitude of the RIST index and basal glucose levels when compared using a large number of data points&#46;<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a> Of more concern is the importance that glucose uptake or output should not change during the RIST&#46; Whatever stimulus is used&#44; including either ablation or stimulation protocols&#44; the stimulus is administered prior to conducting the RIST&#44; and a new stable glycemic baseline must be demonstrated&#46; In addition&#44; at the conclusion of the RIST index&#44; the re-established baseline must not be significantly altered&#46; In the event that such alteration occurs&#44; it suggests that glucose output either increased or decreased during the test&#46; This is usually obvious by comparing the shape of normal RIST curves with that obtained in the presence of the altered baseline&#46; In such situations&#44; the data must be excluded&#44; and the RIST repeated&#46;</p><p id="par0240" class="elsevierStylePara elsevierViewall">None of the available methods available to estimate insulin sensitivity&#47;resistance proved to be a reliable way to assess insulin sensitivity&#47;resistance since most of them have non-physiological continuous infusion of insulin and&#47;or glucose&#44; which interfere with peripheral insulin sensitivity&#47;resistance&#59; take a long time to be performed&#59; could not avoid counter-regulatory responses to the hypoglycemia that follows an insulin bolus&#59; could not allow the assessment of insulin sensitivity in different conditions in the same subject&#44; and in the same day&#59; and they only evaluate insulin sensitivity&#47;resistance in the fasted state&#46; Based on all of these drawbacks&#44; it was necessary to develop another method for assessing insulin sensitivity&#47;resistance&#46;</p><p id="par0245" class="elsevierStylePara elsevierViewall">To summarize&#44; the RIST is a quick method to evaluate insulin sensitivity&#44; reproducible in the same subject and on the same day&#44; utilizes a bolus of insulin to mimic pulsatile insulin release&#44; and can be performed in the fed or fasting state&#46; In addition&#44; since the RIST is an euglycemic test&#44; avoids hypoglycemia and prevents the activation of counter-regulatory hormones&#46; The RIST provides a new powerful tool to dissect insulin action in the fasted and fed state&#44; and may provide a means to detect the pre-diabetic state&#44; where early insulin resistance can be detected well before the impairment of the direct effect of insulin at a time when lifestyle interventions can be readily tested&#46;</p></span></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">Simple surrogate indexes for insulin sensitivity&#47;resistance</span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">Homeostasis Model Assessment</span><p id="par0250" class="elsevierStylePara elsevierViewall">The Homeostasis Model Assessment &#40;HOMA&#41;&#44; developed in 1985&#44; is a model of interactions between glucose and insulin dynamics&#44; that is then used to predict fasting steady-state glucose and insulin concentrations&#44; for a wide range of possible combinations of insulin resistance and &#946;-cell function&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a> The model assumes a feedback loop between the liver and &#946;-cell<a class="elsevierStyleCrossRefs" href="#bib0310"><span class="elsevierStyleSup">62&#44;63</span></a>&#59; and glucose concentrations are regulated by insulin-dependent hepatic glucose production&#44; while insulin levels depend on the pancreatic &#946;-cell response to glucose concentrations&#46; Thus&#44; a diminished response to glucose-stimulated insulin secretion reflects deficient &#946;-cell function&#46; Likewise&#44; insulin resistance is reflected by diminished suppressive effect of insulin on hepatic glucose production&#46;</p><p id="par0255" class="elsevierStylePara elsevierViewall">HOMA model describes this glucose-insulin homeostasis by a set of empirically derived non-linear equations&#46; The model predicts fasting steady-state levels of plasma glucose and insulin for any given combination of pancreatic &#946;-cell function &#40;HOMA&#37;B&#41; and insulin sensitivity &#40;HOMA&#37;S&#41;&#46;</p><p id="par0260" class="elsevierStylePara elsevierViewall">In practical terms&#44; most studies using HOMA employ an approximation described by a simple equation to determine a surrogate index of insulin resistance&#46; This is defined by the product of the fasting glucose and fasting insulin&#44; divided by a constant&#46; The formula for the HOMA model is&#58;<elsevierMultimedia ident="eq0020"></elsevierMultimedia></p><p id="par0265" class="elsevierStylePara elsevierViewall">The denominator of 22&#46;5 is a normalizing factor&#44; <span class="elsevierStyleItalic">i&#46;e&#46;</span>&#44; the product of normal fasting plasma insulin of 5<span class="elsevierStyleHsp" style=""></span>&#956;IU&#47;ml and normal fasting plasma glucose of 4&#46;5<span class="elsevierStyleMonospace">Y</span>mmol&#47;l obtained from an &#8220;ideal and normal&#8221; individual&#46;<a class="elsevierStyleCrossRef" href="#bib0310"><span class="elsevierStyleSup">62</span></a> Therefore&#44; for an individual with normal insulin sensitivity&#44; HOMA<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>1&#46; It is important to note that&#44; over wide ranges of insulin sensitivity&#47;resistance&#44; log &#40;HOMA&#41; transforms the skewed distribution of fasting insulin values to determine a much stronger linear correlation with HIEC estimates of insulin sensitivity&#46;<a class="elsevierStyleCrossRef" href="#bib0010"><span class="elsevierStyleSup">2</span></a></p><p id="par0270" class="elsevierStylePara elsevierViewall">HOMA or log &#40;HOMA&#41; is extensively used in large epidemiological studies&#44; prospective clinical trials&#44; and research studies&#46; In research settings where assessing insulin sensitivity&#47;resistance is of secondary interest or feasibility issues preclude the use of direct measures by HIEC&#44; it may be appropriate to use log &#40;HOMA&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">Quantitative insulin sensitivity check index</span><p id="par0275" class="elsevierStylePara elsevierViewall">Quantitative insulin sensitivity check index &#40;QUICKI&#41; is an empirically derived mathematical transformation that uses fasting blood glucose and plasma insulin concentrations&#46; It provides a reliable&#44; reproducible&#44; and accurate index of insulin sensitivity with excellent positive predictive power&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;64</span></a> Since fasting insulin levels have a non-normal skewed distribution&#44; log transformation improves its linear correlation with reference standard glucose clamp &#40;<span class="elsevierStyleItalic">SI</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">Clamp</span></span>&#41;&#46; However&#44; as with 1&#47;&#40;fasting insulin&#41; and the glucose&#47;insulin ratio&#44; this correlation is not maintained in diabetic subjects with fasting hyperglycemia and impaired &#946;-cell function that is insufficient to maintain euglycemia&#46; To accommodate these clinically important circumstances where fasting glucose is inappropriately high&#44; insulin is inappropriately low&#44; application of logarithm to both fasting glucose&#44; and fasting insulin provides a reasonable correction such that the linear correlation with <span class="elsevierStyleItalic">SI</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">Clamp</span></span> is maintained&#44; in both diabetic and non-diabetic subjects&#46; The reciprocal of this sum results in further transformation of the data generating an insulin sensitivity index that has a positive correlation with <span class="elsevierStyleItalic">SI</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">Clamp</span></span>&#46; Thus&#44; QUICKI is defined by the following formula&#58;<elsevierMultimedia ident="eq0025"></elsevierMultimedia></p><p id="par0280" class="elsevierStylePara elsevierViewall">QUICKI is among the most thoroughly evaluated and validated surrogate index for insulin sensitivity&#46; As a simple&#44; useful&#44; inexpensive&#44; and minimally invasive surrogate for HIEC-derived measures of insulin sensitivity&#44; QUICKI is appropriate and effective for use in large epidemiological or clinical research studies&#44; to follow changes after therapeutic interventions&#44; and for use in studies where evaluation of insulin sensitivity is not of primary interest&#46;<a class="elsevierStyleCrossRefs" href="#bib0010"><span class="elsevierStyleSup">2&#44;65</span></a></p><p id="par0285" class="elsevierStylePara elsevierViewall">QUICKI and HOMA were derived in a completely different conceptual fashion&#46; Nevertheless&#44; these two surrogate indexes are mathematically related&#44; <span class="elsevierStyleItalic">i&#46;e&#46;</span>&#44; QUICKI is proportional to 1&#47;log &#40;HOMA&#41;&#46;</p><p id="par0290" class="elsevierStylePara elsevierViewall">The major advantage of both the QUICKI and HOMA models is that they both require only one blood draw from a fasting patient&#46; They thus do not require extensive technical expertise&#44; and constitute a much lower cost <span class="elsevierStyleItalic">per</span> subject when compared with the HIEC or the FSIVGTT&#44; making the QUICKI and HOMA models much more practical for use in large-scale epidemiologic studies&#44; and for clinical situations&#46;<a class="elsevierStyleCrossRef" href="#bib0315"><span class="elsevierStyleSup">63</span></a></p><p id="par0295" class="elsevierStylePara elsevierViewall">However&#44; the major disadvantage is that both of these methods fail to provide information about the stimulated glucose and insulin systems&#46; Essentially&#44; they provide information only about what is occurring with homeostatic mechanisms in the fasting state&#44; largely reflecting insulin&#39;s effect on hepatic glucose production and not on peripheral glucose uptake&#44; which is the more relevant aspect concerning insulin action&#47;resistance&#46;</p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">Insulin sensitivity indexes</span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">Cederholm and Wibell index</span><p id="par0300" class="elsevierStylePara elsevierViewall">The insulin sensitivity index proposed by Cederholm and Wibell represents mainly peripheral insulin sensitivity and muscular glucose uptake&#44; due to the dominant role of peripheral tissues in glucose disposal after an oral glucose load&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a></p><p id="par0305" class="elsevierStylePara elsevierViewall">The formula for the Cederholm index is&#58;<elsevierMultimedia ident="eq0030"></elsevierMultimedia>where 75&#44;000 &#8211; oral glucose load in an OGTT in mg&#44; <span class="elsevierStyleItalic">G</span><span class="elsevierStyleInf">0</span> &#8211; fasting plasma glucose concentration &#40;mmol&#47;l&#41;&#44; <span class="elsevierStyleItalic">G</span><span class="elsevierStyleInf">120</span> &#8211; plasma glucose concentration in the 120th min of OGTT &#40;mmol&#47;l&#41;&#44; 1&#46;15 &#8211; factor transforming whole venous blood glucose to plasma values &#40;not necessary&#44; if glucose concentration is estimated in plasma&#41;&#44; 180 &#8211; conversion factor to transform plasma glucose concentration from mmol&#47;l into mg&#47;dl&#44; 0&#46;19 &#8211; glucose space in liter per kg of body weight&#44; <span class="elsevierStyleItalic">m</span> &#8211; body weight &#40;kg&#41;&#44; 120 &#8211; duration of OGTT &#40;min&#41;&#44; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleInf">mean</span> &#8211; mean plasma insulin concentration during OGTT &#40;mIU&#47;l&#41; and <span class="elsevierStyleItalic">G</span><span class="elsevierStyleInf">mean</span> &#8211; mean plasma glucose concentration during OGTT &#40;mmol&#47;l&#41;&#46;</p><p id="par0310" class="elsevierStylePara elsevierViewall">Values found in normal non-obese individuals were reported to be about 79<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>14<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleHsp" style=""></span>l<span class="elsevierStyleSup">2</span>&#47;mmol&#47;mIU&#47;min&#44; lower in obese individuals&#44; in subjects with impaired glucose tolerance and in patients with type 2 diabetes&#46;<a class="elsevierStyleCrossRef" href="#bib0200"><span class="elsevierStyleSup">40</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">Gutt et al&#46; index</span><p id="par0315" class="elsevierStylePara elsevierViewall">The ISI<span class="elsevierStyleInf">0&#44;120</span> was adapted from the Cederholm insulin sensitivity index&#44; by omitting the constant terms&#44; and using the plasma glucose and insulin concentration from fasting &#40;0<span class="elsevierStyleHsp" style=""></span>min&#41; and 120<span class="elsevierStyleHsp" style=""></span>min samples from the OGTT&#46;<a class="elsevierStyleCrossRef" href="#bib0330"><span class="elsevierStyleSup">66</span></a></p><p id="par0320" class="elsevierStylePara elsevierViewall">The ISI<span class="elsevierStyleInf">0&#44;120</span> index is defined as&#58;<elsevierMultimedia ident="eq0035"></elsevierMultimedia>where 75&#44;000 &#8211; oral glucose load in an OGTT in mg&#44; <span class="elsevierStyleItalic">G</span><span class="elsevierStyleInf">0</span> &#8211; fasting plasma glucose concentration &#40;mg&#47;dl&#41;&#44; <span class="elsevierStyleItalic">G</span><span class="elsevierStyleInf">120</span> &#8211; plasma glucose concentration in the 120th min of OGTT &#40;mg&#47;dl&#41;&#44; 0&#46;19 &#8211; glucose space in l&#47;kg of body weight&#44; m &#8211; body weight &#40;kg&#41;&#44; 120 &#8211; duration of OGTT &#40;min&#41;&#44; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleInf">mean</span> &#8211; mean plasma insulin concentration during OGTT &#40;mIU&#47;l&#41; and <span class="elsevierStyleItalic">G</span><span class="elsevierStyleInf">mean</span> &#8211; mean plasma glucose concentration during OGTT &#40;mmol&#47;l&#41;&#46;</p><p id="par0325" class="elsevierStylePara elsevierViewall">The reference range for lean controls was 89<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>39&#44; for obese 58<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>23 and for diabetic patients 23<span class="elsevierStyleHsp" style=""></span>&#177;<span class="elsevierStyleHsp" style=""></span>19<span class="elsevierStyleHsp" style=""></span>mg<span class="elsevierStyleHsp" style=""></span>l<span class="elsevierStyleSup">2</span>&#47;mmol&#47;mIU&#47;min&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a></p></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Avignon et al&#46; index</span><p id="par0330" class="elsevierStylePara elsevierViewall">Avignon<a class="elsevierStyleCrossRef" href="#bib0335"><span class="elsevierStyleSup">67</span></a> proposed 3 insulin sensitivity indices&#58; Sib &#40;derived from fasting plasma insulin and glucose concentrations&#41;&#44; Si2h &#40;derived from plasma insulin and glucose concentrations in the 120th min of OGTT&#41; and SiM &#40;derived by averaging Sib and Si2h after balancing Sib by a coefficient of 0&#46;137 to give the same weight to both indices&#41;&#58;<elsevierMultimedia ident="eq0040"></elsevierMultimedia>where <span class="elsevierStyleItalic">I</span> and <span class="elsevierStyleItalic">G</span> represent the plasma concentrations of insulin &#40;mIU&#47;l&#41; and glucose &#40;mmol&#47;l&#41;&#44; respectively and&#44; VD is the glucose distribution volume calculated using a monocompartmental model&#58; VD<span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>150<span class="elsevierStyleHsp" style=""></span>ml&#47;kg of body weight&#46;<a class="elsevierStyleCrossRef" href="#bib0140"><span class="elsevierStyleSup">28</span></a></p></span><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Matsuda et al&#46; index</span><p id="par0335" class="elsevierStylePara elsevierViewall">Originally proposed by Matsuda and DeFronzo&#44;<a class="elsevierStyleCrossRef" href="#bib0195"><span class="elsevierStyleSup">39</span></a> insulin sensitivity index-Matsuda &#40;ISI<span class="elsevierStyleInf">&#40;Matsuda&#41;</span>&#41; is an whole body insulin sensitivity index that reflects a composite estimate of hepatic and muscle insulin sensitivity&#46; This index is calculated from plasma glucose &#40;mg&#47;dl&#41; and insulin &#40;mIU&#47;l&#41; concentrations in fasting state and during OGTT&#46;</p><p id="par0340" class="elsevierStylePara elsevierViewall">The formula for the Matsuda index is&#58;<elsevierMultimedia ident="eq0045"></elsevierMultimedia>where 10&#44;000 &#8211; simplifying constant to get numbers from 0 to 12&#44; &#8730; &#8211; correction of the nonlinear values distribution&#44; <span class="elsevierStyleItalic">G</span><span class="elsevierStyleInf">0</span> &#8211; fasting plasma glucose concentration &#40;mg&#47;dl&#41;&#44; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleInf">0</span> &#8211; fasting plasma insulin concentration &#40;mIU&#47;l&#41;&#44; <span class="elsevierStyleItalic">G</span><span class="elsevierStyleInf">mean</span> &#8211; mean plasma glucose concentration during OGTT &#40;mg&#47;dl&#41;&#44; from 0 to 120<span class="elsevierStyleHsp" style=""></span>min and <span class="elsevierStyleItalic">I</span><span class="elsevierStyleInf">mean</span> &#8211; mean plasma insulin concentration during OGTT &#40;mIU&#47;l&#41;&#44; from 0 to 120<span class="elsevierStyleHsp" style=""></span>min&#46;</p><p id="par0345" class="elsevierStylePara elsevierViewall">The insulin secretion&#47;insulin resistance &#40;disposition&#41; index calculated as the product of insulin secretion measured with &#40;&#916;<span class="elsevierStyleItalic">I</span><span class="elsevierStyleInf">0&#8211;30</span>&#47;&#916;<span class="elsevierStyleItalic">G</span><span class="elsevierStyleInf">0&#8211;30</span> or &#916;<span class="elsevierStyleItalic">I</span><span class="elsevierStyleInf">0&#8211;120</span>&#47;&#916;<span class="elsevierStyleItalic">G</span><span class="elsevierStyleInf">0&#8211;120</span>&#41; and ISI<span class="elsevierStyleInf">&#40;Matsuda&#41;</span> &#40;or modified ISI<span class="elsevierStyleInf">&#40;Matsuda&#41;</span> using plasma glucose and insulin concentrations at 30<span class="elsevierStyleHsp" style=""></span>min during the OGTT&#41;&#44; had excellent power to predict onset of type 2 diabetes&#46;<a class="elsevierStyleCrossRef" href="#bib0340"><span class="elsevierStyleSup">68</span></a></p></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Belfiore et al&#46; index</span><p id="par0350" class="elsevierStylePara elsevierViewall">The condition for calculation of the Belfiore formula is the definition of the normal value for basal glucose and insulin concentrations&#44; and for mean normal value for glucose and insulin areas during OGTT&#46;<a class="elsevierStyleCrossRef" href="#bib0090"><span class="elsevierStyleSup">18</span></a> The main point of the Belfiore formula is the comparison of insulin and glucose values measured &#40;fasting&#44; 0&#8211;1&#8211;2<span class="elsevierStyleHsp" style=""></span>h areas or 0&#8211;2<span class="elsevierStyleHsp" style=""></span>h areas&#41; with the defined normal reference values&#46;</p><p id="par0355" class="elsevierStylePara elsevierViewall">The ISI<span class="elsevierStyleInf">Belfiore</span> index is defined as&#58;<elsevierMultimedia ident="eq0050"></elsevierMultimedia>where <span class="elsevierStyleItalic">G</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">s</span></span>&#44; <span class="elsevierStyleItalic">G</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">N</span></span> &#8211; plasma glucose concentrations expressed as fasting values or as areas obtained during a standard OGTT at 0 and 2<span class="elsevierStyleHsp" style=""></span>h &#40;0&#8211;2<span class="elsevierStyleHsp" style=""></span>h areas are equal to <span class="elsevierStyleItalic">G</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">S</span>&#44;<span class="elsevierStyleItalic">N</span></span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">G</span><span class="elsevierStyleInf">0</span><span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">G</span><span class="elsevierStyleInf">120</span>&#41; or at 0&#44; 1 and 2<span class="elsevierStyleHsp" style=""></span>h &#40;0&#8211;1&#8211;2<span class="elsevierStyleHsp" style=""></span>h areas equal to <span class="elsevierStyleItalic">G</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">S</span>&#44;<span class="elsevierStyleItalic">N</span></span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#189;<span class="elsevierStyleItalic">G</span><span class="elsevierStyleInf">0</span><span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">G</span><span class="elsevierStyleInf">60</span><span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">G</span><span class="elsevierStyleInf">120</span>&#44; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">s</span></span>&#44; <span class="elsevierStyleItalic">I</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">N</span></span> &#8211; plasma insulin concentrations expressed as fasting values or as areas obtained during a standard OGTT at 0 and 2<span class="elsevierStyleHsp" style=""></span>h &#40;0&#8211;2<span class="elsevierStyleHsp" style=""></span>h areas are equal to <span class="elsevierStyleItalic">I</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">S</span>&#44;<span class="elsevierStyleItalic">N</span></span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">I</span><span class="elsevierStyleInf">0</span><span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">I</span><span class="elsevierStyleInf">120</span>&#41; or at 0&#44; 1 and 2<span class="elsevierStyleHsp" style=""></span>h &#40;0&#8211;1&#8211;2<span class="elsevierStyleHsp" style=""></span>h areas equal to <span class="elsevierStyleItalic">I</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">S</span>&#44;<span class="elsevierStyleItalic">N</span></span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>&#189;<span class="elsevierStyleItalic">I</span><span class="elsevierStyleInf">0</span><span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">I</span><span class="elsevierStyleInf">60</span><span class="elsevierStyleHsp" style=""></span>&#43;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">I</span><span class="elsevierStyleInf">120</span>&#46; The subscripts <span class="elsevierStyleItalic">S</span> and <span class="elsevierStyleItalic">N</span> refer to &#8220;subjects&#8221; and &#8220;normal reference values&#8221;&#44; respectively&#46;</p><p id="par0360" class="elsevierStylePara elsevierViewall">Insulin sensitivity calculated using these formulas can achieve only values between 0 and 2&#46; In subjects with normal insulin sensitivity is it around 1&#59; in overweight subjects&#44; in subjects with impaired glucose tolerance&#44; and with type 2 diabetes this value is below 1&#46;<a class="elsevierStyleCrossRefs" href="#bib0345"><span class="elsevierStyleSup">69&#44;70</span></a></p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Stumvoll et al&#46; index</span><p id="par0365" class="elsevierStylePara elsevierViewall">Stumvoll proposed a series of indices calculated from plasma glucose &#40;mmol&#47;l&#41; and insulin &#40;pmol&#47;l concentrations during OGTT&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0350"><span class="elsevierStyleSup">70</span></a> The equations were generated using the multiple linear regression analysis and adapted to the availabilities of sampling times during OGTT&#44; and of demographic parameters &#40;BMI&#44; age&#41;&#46;</p><p id="par0370" class="elsevierStylePara elsevierViewall">An example equation could be the index of insulin sensitivity calculated from data obtained in 0&#44; 60 and 120<span class="elsevierStyleHsp" style=""></span>min of OGTT either with or without demographic data&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><p id="par0375" class="elsevierStylePara elsevierViewall">ISI<span class="elsevierStyleInf">Stumvoll</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;222<span class="elsevierStyleHsp" style=""></span>&#8722;<span class="elsevierStyleHsp" style=""></span>0&#46;00333<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>BMI<span class="elsevierStyleHsp" style=""></span>&#8722;<span class="elsevierStyleHsp" style=""></span>0&#46;0000779<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">I</span><span class="elsevierStyleInf">120</span><span class="elsevierStyleHsp" style=""></span>&#8722;<span class="elsevierStyleHsp" style=""></span>0&#46;000422<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span>age</p></li><li class="elsevierStyleListItem" id="lsti0010"><p id="par0380" class="elsevierStylePara elsevierViewall">ISI<span class="elsevierStyleInf">Stumvoll</span><span class="elsevierStyleHsp" style=""></span>&#61;<span class="elsevierStyleHsp" style=""></span>0&#46;156<span class="elsevierStyleHsp" style=""></span>&#8722;<span class="elsevierStyleHsp" style=""></span>0&#46;0000459<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">I</span><span class="elsevierStyleInf">120</span><span class="elsevierStyleHsp" style=""></span>&#8722;<span class="elsevierStyleHsp" style=""></span>0&#46;000321<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">I</span><span class="elsevierStyleInf">0</span><span class="elsevierStyleHsp" style=""></span>&#8722;<span class="elsevierStyleHsp" style=""></span>0&#46;00541<span class="elsevierStyleHsp" style=""></span>&#215;<span class="elsevierStyleHsp" style=""></span><span class="elsevierStyleItalic">G</span><span class="elsevierStyleInf">120</span></p></li></ul></p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">McAuley et al&#46; index</span><p id="par0385" class="elsevierStylePara elsevierViewall">The authors proposed a formula for predicting insulin resistance in normoglycemic individuals&#46;<a class="elsevierStyleCrossRef" href="#bib0355"><span class="elsevierStyleSup">71</span></a> Regression analysis was used to estimate the cut-off points and the importance of various data for insulin resistance &#40;fasting concentrations of insulin&#44; triglycerides&#44; aspartate aminotransferase&#44; BMI&#44; waist circumference&#41;&#46; A bootstrap procedure was used to find an index most strongly correlating with insulin sensitivity index&#44; corrected for fat-free mass obtained by HIEC MffmI&#46;<a class="elsevierStyleCrossRef" href="#bib0005"><span class="elsevierStyleSup">1</span></a></p><p id="par0390" class="elsevierStylePara elsevierViewall">An insulin sensitivity index obtained from HIEC of &#8804;6&#46;3 &#40;expressed as glucose disposal rate in mg&#47;kg&#47;min divided by average plasma insulin concentration in mIU&#47;l&#41; was seen as a cut-off for individuals with insulin resistance&#46; The combination of fasting insulin &#40;mIU&#47;l&#41; and triglycerides &#40;TAG&#44; mmol&#47;l&#41; showed the best prediction of insulin resistance as follows&#58;<elsevierMultimedia ident="eq0055"></elsevierMultimedia>where <span class="elsevierStyleItalic">I</span><span class="elsevierStyleInf">0</span> &#8211; fasting plasma insulin concentration &#40;mIU&#47;l&#41; and TAG<span class="elsevierStyleInf">0</span> &#8211; fasting plasma triglycerides concentration &#40;mmol&#47;l&#41;&#46;</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Oral Glucose Insulin Sensitivity</span><p id="par0395" class="elsevierStylePara elsevierViewall">The Oral Glucose Insulin Sensitivity &#40;OGIS&#41; is a method for the assessment of insulin sensitivity from the OGTT&#46; OGIS provides an index that correlates to the index of insulin sensitivity obtained from the HIEC&#46;</p><p id="par0400" class="elsevierStylePara elsevierViewall">This method calculates insulin sensitivity with a model-derived equation of the form&#58;<elsevierMultimedia ident="eq0060"></elsevierMultimedia>where <span class="elsevierStyleItalic">G</span> and <span class="elsevierStyleItalic">I</span> are glucose and insulin concentrations &#40;subscripts represent time instant&#41; and <span class="elsevierStyleItalic">D</span><span class="elsevierStyleInf"><span class="elsevierStyleItalic">O</span></span> is the oral glucose dose &#40;g&#47;m<span class="elsevierStyleSup">2</span> body surface area&#41;&#46;</p><p id="par0405" class="elsevierStylePara elsevierViewall">The function <span class="elsevierStyleItalic">f</span> is complex&#44; but can be easily programmed on a spreadsheet &#40;see <a id="intr0005" class="elsevierStyleInterRef" href="http://www.isib.cnr.it/bioing/ogis/home.html">http&#58;&#47;&#47;www&#46;isib&#46;cnr&#46;it&#47;bioing&#47;ogis&#47;home&#46;html</a>&#44; where a web-based calculator is also available&#41;&#46; The expression of <span class="elsevierStyleItalic">f</span> contains some parameters&#44; chosen to maximize the agreement with the HIEC&#46; Glucose and insulin can be given in either common or international units &#40;with appropriate parameters&#44; see table 2 in<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">72</span></a>&#41;&#46;</p><p id="par0410" class="elsevierStylePara elsevierViewall">OGIS is a predictor of the HIEC insulin sensitivity&#44; expressed as glucose clearance M&#47;G&#44; normalized to body surface area&#46; The units of OGIS are thus ml&#47;min&#47;m<span class="elsevierStyleSup">2</span> of body surface area&#46; OGIS has been validated against an 120<span class="elsevierStyleHsp" style=""></span>mU&#47;min&#47;m<span class="elsevierStyleSup">2</span> insulin infusion HIEC &#40;by direct comparison of the glucose clearance values&#41;&#44; instead of the more standard 40<span class="elsevierStyleHsp" style=""></span>mU&#47;min&#47;m<span class="elsevierStyleSup">2</span> used in the previous methods&#46; Formulas for a 3<span class="elsevierStyleHsp" style=""></span>h and 2<span class="elsevierStyleHsp" style=""></span>h OGTT are also available&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">72</span></a></p><p id="par0415" class="elsevierStylePara elsevierViewall">OGIS exploits the known quantitative relationships between the observed data and the HIEC insulin sensitivity to attempt a genuine insulin sensitivity prediction&#46; However&#44; this advantage is limited by the necessity to use empirical assumptions&#44; and to calculate parameters from regression&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">72</span></a></p></span><span id="sec0115" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0135">Rapid Insulin Sensitivity Test index</span><p id="par0420" class="elsevierStylePara elsevierViewall">The RIST index is the parameter used to evaluate insulin sensitivity that represents the total amount of glucose infused during the Rapid Insulin Sensitivity Test &#40;RIST&#41;&#44; in order to maintain euglycemia after the exogenous bolus administration of insulin&#46; It corresponds to the area under the curve &#40;AUC&#41; of total glucose infused &#40;mg glucose&#47;kg bw&#41; throughout the test<a class="elsevierStyleCrossRef" href="#bib0260"><span class="elsevierStyleSup">52</span></a>&#58;<elsevierMultimedia ident="eq0065"></elsevierMultimedia></p></span></span></span><span id="sec0120" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0140">Conclusions</span><p id="par0425" class="elsevierStylePara elsevierViewall">This paper has examined a wide variety of methods currently available for estimating insulin sensitivity&#47;resistance and also introduces a new method &#8211; the RIST&#46; The methods range from complex&#44; time-consuming&#44; labor-intensive&#44; invasive procedures to simple tests involving a single fasting blood sample&#46; It is important to understand the concepts underlying each method so that relative merits and limitations are appropriately matched to proposed applications&#46; Developing valid&#44; reliable&#44; cost-effective methods of assessing insulin sensitivity is a major scientific challenge&#46; Dynamic tests are useful if information about both insulin secretion and insulin action are needed&#46; As with all measurement techniques&#44; correct interpretation of data from different methods for measuring insulin sensitivity requires a complete understanding of the technique&#46;</p></span><span id="sec0125" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0145">Funding</span><p id="par0430" class="elsevierStylePara elsevierViewall">This study was supported by <span class="elsevierStyleGrantSponsor" id="gs0005">Funda&#231;&#227;o para a Ci&#234;ncia e Tecnologia &#40;FCT&#41;</span> grants <span class="elsevierStyleGrantNumber" refid="gs0005">FCT&#47;POCI&#47;SAU-OBS&#47;56716&#47;2004</span> and <span class="elsevierStyleGrantNumber" refid="gs0005">PIC&#47;IC&#47;82956&#47;2007</span> and by the <span class="elsevierStyleGrantSponsor" id="gs0010">Portuguese Diabetes Society &#40;SPD&#41;</span>&#46;</p></span><span id="sec0130" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0150">Conflicts of interest</span><p id="par0435" class="elsevierStylePara elsevierViewall">The authors declare no conflicts of interest&#46;</p></span></span>"
    "textoCompletoSecciones" => array:1 [
      "secciones" => array:12 [
        0 => array:2 [
          "identificador" => "xres355297"
          "titulo" => "Abstract"
        ]
        1 => array:2 [
          "identificador" => "xpalclavsec336593"
          "titulo" => "Keywords"
        ]
        2 => array:2 [
          "identificador" => "xres355296"
          "titulo" => "Resumo"
        ]
        3 => array:2 [
          "identificador" => "xpalclavsec336592"
          "titulo" => "Palavras-chave"
        ]
        4 => array:2 [
          "identificador" => "sec0005"
          "titulo" => "Introduction"
        ]
        5 => array:3 [
          "identificador" => "sec0010"
          "titulo" => "Methods of insulin sensitivity&#47;resistance assessment"
          "secciones" => array:8 [
            0 => array:2 [
              "identificador" => "sec0015"
              "titulo" => "Hyperinsulinemic Euglycemic Glucose Clamp"
            ]
            1 => array:2 [
              "identificador" => "sec0020"
              "titulo" => "Insulin Tolerance Test"
            ]
            2 => array:2 [
              "identificador" => "sec0025"
              "titulo" => "Insulin Suppression Test"
            ]
            3 => array:2 [
              "identificador" => "sec0030"
              "titulo" => "Continuous infusion of glucose with model assessment"
            ]
            4 => array:2 [
              "identificador" => "sec0035"
              "titulo" => "Minimal model analysis of frequently sampled intravenous glucose tolerance test"
            ]
            5 => array:2 [
              "identificador" => "sec0040"
              "titulo" => "Oral Glucose Tolerance Test"
            ]
            6 => array:2 [
              "identificador" => "sec0045"
              "titulo" => "Meal Tolerance Test"
            ]
            7 => array:2 [
              "identificador" => "sec0050"
              "titulo" => "Rapid Insulin Sensitivity Test"
            ]
          ]
        ]
        6 => array:3 [
          "identificador" => "sec0055"
          "titulo" => "Simple surrogate indexes for insulin sensitivity&#47;resistance"
          "secciones" => array:3 [
            0 => array:2 [
              "identificador" => "sec0060"
              "titulo" => "Homeostasis Model Assessment"
            ]
            1 => array:2 [
              "identificador" => "sec0065"
              "titulo" => "Quantitative insulin sensitivity check index"
            ]
            2 => array:3 [
              "identificador" => "sec0070"
              "titulo" => "Insulin sensitivity indexes"
              "secciones" => array:9 [
                0 => array:2 [
                  "identificador" => "sec0075"
                  "titulo" => "Cederholm and Wibell index"
                ]
                1 => array:2 [
                  "identificador" => "sec0080"
                  "titulo" => "Gutt et al&#46; index"
                ]
                2 => array:2 [
                  "identificador" => "sec0085"
                  "titulo" => "Avignon et al&#46; index"
                ]
                3 => array:2 [
                  "identificador" => "sec0090"
                  "titulo" => "Matsuda et al&#46; index"
                ]
                4 => array:2 [
                  "identificador" => "sec0095"
                  "titulo" => "Belfiore et al&#46; index"
                ]
                5 => array:2 [
                  "identificador" => "sec0100"
                  "titulo" => "Stumvoll et al&#46; index"
                ]
                6 => array:2 [
                  "identificador" => "sec0105"
                  "titulo" => "McAuley et al&#46; index"
                ]
                7 => array:2 [
                  "identificador" => "sec0110"
                  "titulo" => "Oral Glucose Insulin Sensitivity"
                ]
                8 => array:2 [
                  "identificador" => "sec0115"
                  "titulo" => "Rapid Insulin Sensitivity Test index"
                ]
              ]
            ]
          ]
        ]
        7 => array:2 [
          "identificador" => "sec0120"
          "titulo" => "Conclusions"
        ]
        8 => array:2 [
          "identificador" => "sec0125"
          "titulo" => "Funding"
        ]
        9 => array:2 [
          "identificador" => "sec0130"
          "titulo" => "Conflicts of interest"
        ]
        10 => array:2 [
          "identificador" => "xack87666"
          "titulo" => "Acknowledgements"
        ]
        11 => array:1 [
          "titulo" => "References"
        ]
      ]
    ]
    "pdfFichero" => "main.pdf"
    "tienePdf" => true
    "fechaRecibido" => "2012-09-05"
    "fechaAceptado" => "2013-10-22"
    "PalabrasClave" => array:2 [
      "en" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Keywords"
          "identificador" => "xpalclavsec336593"
          "palabras" => array:6 [
            0 => "Hyperinsulinemic Euglycemic Glucose Clamp"
            1 => "Oral Glucose Tolerance Test"
            2 => "Meal Tolerance Test"
            3 => "Rapid Insulin Sensitivity Test"
            4 => "Homeostasis Model Assessment"
            5 => "Oral Glucose Insulin Sensitivity"
          ]
        ]
      ]
      "pt" => array:1 [
        0 => array:4 [
          "clase" => "keyword"
          "titulo" => "Palavras-chave"
          "identificador" => "xpalclavsec336592"
          "palabras" => array:6 [
            0 => "Clamp de glucose hiperinsulin&#233;mico e euglic&#233;mico"
            1 => "Teste oral de toler&#226;ncia &#224; glucose"
            2 => "Teste de toler&#226;ncia &#224; refei&#231;&#227;o"
            3 => "Teste r&#225;pido de sensibilidade &#224; insulina"
            4 => "Avalia&#231;&#227;o do modelo de homeostase"
            5 => "Glucose oral e sensibilidade &#224; insulina"
          ]
        ]
      ]
    ]
    "tieneResumen" => true
    "resumen" => array:2 [
      "en" => array:2 [
        "titulo" => "Abstract"
        "resumen" => "<p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Insulin resistance contributes to the pathophysiology of diabetes and is a hallmark of obesity&#44; metabolic syndrome&#44; and many cardiovascular diseases&#46; Therefore&#44; quantifying insulin sensitivity&#47;resistance in humans and animal models is of great importance&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Various methods are used to assess insulin sensitivity both in individuals and in study populations&#46; Validity&#44; reproducibility&#44; cost&#44; and degree of subject burden are important factors for both clinicians and researchers to consider when weighing the merits of a particular method&#46; Some methods rely on steady-state analysis of glucose and insulin&#44; whereas others rely on dynamic testing&#46; Each of these methods has distinct advantages and limitations&#46; Thus&#44; optimal choice and employment of a specific method depend on the nature of the studies being performed&#46; Established direct methods for measuring insulin sensitivity <span class="elsevierStyleItalic">in vivo</span> are relatively complex&#46; Finally&#44; simple surrogate indexes for insulin sensitivity&#47;resistance are available that are derived from blood insulin and glucose concentrations under fasting conditions &#40;steady state&#41; or in the postprandial state &#40;dynamic&#41;&#46; This article highlight merits&#44; limitations&#44; and appropriate use of current <span class="elsevierStyleItalic">in vivo</span> measures of insulin sensitivity&#47;resistance and presents the advantages and disadvantages of each&#46;</p>"
      ]
      "pt" => array:2 [
        "titulo" => "Resumo"
        "resumen" => "<p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">A resist&#234;ncia &#224; insulina contribui para a fisiopatologia da diabetes e &#233; uma caracter&#237;stica marcante da obesidade&#44; da s&#237;ndrome metab&#243;lica&#44; e de doen&#231;as cardiovasculares&#46; Assim&#44; quantificar a sensibilidade &#224; insulina <span class="elsevierStyleItalic">vs</span> resist&#234;ncia &#224; insulina em humanos e em modelos animais &#233; de grande import&#226;ncia&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Existem v&#225;rios m&#233;todos para avaliar a sensibilidade &#224; insulina&#44; tanto em indiv&#237;duos&#44; como em popula&#231;&#245;es de estudo&#46; A validade&#44; reprodutibilidade&#44; custo e envolvimento dos indiv&#237;duos s&#227;o fatores importantes a considerar para os cl&#237;nicos e investigadores aquando da escolha de um determinado m&#233;todo de avalia&#231;&#227;o da sensibilidade e&#47;ou resist&#234;ncia &#224; insulina&#46; Alguns m&#233;todos dependem da quantifica&#231;&#227;o dos n&#237;veis de glucose e de insulina no estado estacion&#225;rio&#44; embora outros m&#233;todos possam ser utilizados no estado din&#226;mico&#46; Cada um destes m&#233;todos tem vantagens e limita&#231;&#245;es distintas&#46; Assim&#44; a escolha e a aplicabilidade correta de um m&#233;todo espec&#237;fico depende da natureza dos estudos a serem realizados&#46; O desenho de m&#233;todos diretos para medir a sensibilidade &#224; insulina <span class="elsevierStyleItalic">in vivo</span> &#233; relativamente complexo&#46; Existem alguns &#237;ndices simples para avaliar a sensibilidade e&#47;ou resist&#234;ncia &#224; insulina&#44; que resultam da avalia&#231;&#227;o das concentra&#231;&#245;es de insulina e glucose em jejum &#40;estado estacion&#225;rio&#41; ou no estado p&#243;s-prandial &#40;estado din&#226;mico&#41;&#46; Este artigo destaca as limita&#231;&#245;es e a utiliza&#231;&#227;o adequada dos atuais m&#233;todos de avalia&#231;&#227;o de sensibilidade e&#47;ou resist&#234;ncia &#224; insulina e apresenta as vantagens e desvantagens de cada um dos m&#233;todos&#46;</p>"
      ]
    ]
    "multimedia" => array:15 [
      0 => array:8 [
        "identificador" => "fig0005"
        "etiqueta" => "Fig&#46; 1"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "fuente" => "Adapted from Ref&#46; <a class="elsevierStyleCrossRef" href="#bib0145">29</a>&#46;"
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 649
            "Ancho" => 1587
            "Tamanyo" => 69743
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Schematic equations and parameters for the minimal model of glucose metabolism&#46; Differential equations describing glucose dynamics &#91;<span class="elsevierStyleItalic">G</span>&#40;<span class="elsevierStyleItalic">t</span>&#41;&#93; in a monocompartmental &#8220;glucose space&#8221; and insulin dynamics in a &#8220;remote compartment&#8221; &#91;<span class="elsevierStyleItalic">X</span>&#40;<span class="elsevierStyleItalic">t</span>&#41;&#93; are shown at the top&#46; Glucose leaves or enters its space at a rate proportional to the difference between plasma glucose level&#44; <span class="elsevierStyleItalic">G</span>&#40;<span class="elsevierStyleItalic">t</span>&#41; and the basal fasting level&#44; <span class="elsevierStyleItalic">G<span class="elsevierStyleInf">b</span></span>&#46; In addition&#44; glucose also disappears from its compartment at a rate proportional to insulin levels in the &#8220;remote&#8221; compartment &#91;<span class="elsevierStyleItalic">X</span>&#40;<span class="elsevierStyleItalic">t</span>&#41;&#93;&#46; In this model&#44; <span class="elsevierStyleItalic">t</span> &#8211; time&#59; <span class="elsevierStyleItalic">G</span>&#40;<span class="elsevierStyleItalic">t</span>&#41; &#8211; plasma glucose at time <span class="elsevierStyleItalic">t</span>&#59; <span class="elsevierStyleItalic">I</span>&#40;<span class="elsevierStyleItalic">t</span>&#41; &#8211; plasma insulin concentration at time <span class="elsevierStyleItalic">t</span>&#59; <span class="elsevierStyleItalic">X</span>&#40;<span class="elsevierStyleItalic">t</span>&#41; &#8211; insulin concentration in &#8220;remote&#8221; compartment at time <span class="elsevierStyleItalic">t</span>&#59; <span class="elsevierStyleItalic">G<span class="elsevierStyleInf">b</span></span> &#8211; basal plasma glucose concentration&#59; <span class="elsevierStyleItalic">I<span class="elsevierStyleInf">b</span></span> &#8211; basal plasma insulin concentration&#59; <span class="elsevierStyleItalic">G</span>&#40;0&#41; &#8211; <span class="elsevierStyleItalic">G</span><span class="elsevierStyleInf">0</span> &#40;assuming instantaneous mixing of the iv glucose load&#41;&#59; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleInf">1</span>&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleInf">2</span>&#44; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleInf">3</span> and <span class="elsevierStyleItalic">G</span><span class="elsevierStyleInf">0</span> &#8211; unknown parameters in the model that are uniquely identifiable from FSIVGTT&#59; glucose effectiveness &#40;<span class="elsevierStyleItalic">S<span class="elsevierStyleInf">G</span></span>&#41; &#8211; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleInf">1</span> and insulin sensitivity &#8211; <span class="elsevierStyleItalic">p</span><span class="elsevierStyleInf">3</span>&#47;<span class="elsevierStyleItalic">p</span><span class="elsevierStyleInf">2</span>&#46;</p>"
        ]
      ]
      1 => array:7 [
        "identificador" => "fig0010"
        "etiqueta" => "Fig&#46; 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 789
            "Ancho" => 2143
            "Tamanyo" => 97102
          ]
        ]
        "descripcion" => array:1 [
          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">&#40;A&#41; Mean profile using the dynamic analysis of the pattern of glucose infusion during the Rapid Insulin Sensitivity Test &#40;RIST&#41;&#46; The mean RIST curves were obtained by averaging glucose infusion rates at 0&#46;1-min intervals throughout the test &#40;Postprandial RIST &#40;bold line&#41; and the RIST obtained after 24<span class="elsevierStyleHsp" style=""></span>h-fast &#40;simple line&#41;&#41;&#46; &#40;B&#41; Calculation of the area under the curve during the 24 h-fast and postprandial RIST&#44; that corresponds to the total amount of glucose infused to maintain euglycemia over the test period&#44; which is terminated when no further glucose infusion is required &#40;RIST index&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0280"><span class="elsevierStyleSup">56</span></a></p>"
        ]
      ]
      2 => array:5 [
        "identificador" => "eq0005"
        "tipo" => "MULTIMEDIAFORMULA"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "Formula" => array:5 [
          "Matematica" => "KITT&#61;0&#46;693t1&#47;2&#215;100"
          "Fichero" => "si2.jpeg"
          "Tamanyo" => 1578
          "Alto" => 36
          "Ancho" => 134
        ]
      ]
      3 => array:6 [
        "identificador" => "eq0010"
        "etiqueta" => "&#40;1&#41;"
        "tipo" => "MULTIMEDIAFORMULA"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "Formula" => array:5 [
          "Matematica" => "dG&#40;t&#41;dt&#61;&#8722;&#91;p1&#43;X&#40;t&#41;&#93;G&#40;t&#41;&#43;p1Gb"
          "Fichero" => "si3.jpeg"
          "Tamanyo" => 2380
          "Alto" => 32
          "Ancho" => 218
        ]
      ]
      4 => array:6 [
        "identificador" => "eq0015"
        "etiqueta" => "&#40;2&#41;"
        "tipo" => "MULTIMEDIAFORMULA"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "Formula" => array:5 [
          "Matematica" => "dX&#40;t&#41;dt&#61;&#8722;p2X&#40;t&#41;&#43;p3&#91;I&#40;t&#41;&#8722;ib&#93;"
          "Fichero" => "si4.jpeg"
          "Tamanyo" => 2208
          "Alto" => 32
          "Ancho" => 207
        ]
      ]
      5 => array:5 [
        "identificador" => "eq0020"
        "tipo" => "MULTIMEDIAFORMULA"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "Formula" => array:5 [
          "Matematica" => "HOMA&#61;Fasting&#8201;Insulin&#8201;&#40;&#956;IU&#47;ml&#41;&#215;Fasting&#8201;Glucose&#8201;&#40;mmol&#47;l&#41;22&#46;5"
          "Fichero" => "si5.jpeg"
          "Tamanyo" => 4865
          "Alto" => 32
          "Ancho" => 424
        ]
      ]
      6 => array:5 [
        "identificador" => "eq0025"
        "tipo" => "MULTIMEDIAFORMULA"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "Formula" => array:5 [
          "Matematica" => "QUICKI&#61;1log&#40;fasting&#8201;insulin&#44;&#8201;&#956;IU&#47;ml&#41;&#43;log&#8201;&#40;fasting&#8201;glucose&#44;&#8201;mg&#47;dl&#41;"
          "Fichero" => "si6.jpeg"
          "Tamanyo" => 4798
          "Alto" => 60
          "Ancho" => 428
        ]
      ]
      7 => array:5 [
        "identificador" => "eq0030"
        "tipo" => "MULTIMEDIAFORMULA"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "Formula" => array:5 [
          "Matematica" => "ISICederholm&#61;75000&#43;&#40;G0&#8722;G120&#41;&#215;1&#46;15&#215;180&#215;0&#46;19&#215;m120&#215;Gmean&#215;log&#40;Imean&#41;"
          "Fichero" => "si7.jpeg"
          "Tamanyo" => 5037
          "Alto" => 35
          "Ancho" => 401
        ]
      ]
      8 => array:5 [
        "identificador" => "eq0035"
        "tipo" => "MULTIMEDIAFORMULA"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "Formula" => array:5 [
          "Matematica" => "ISI0&#44;120&#61;75&#44;000&#43;&#40;G0&#8722;G120&#41;&#215;0&#46;19&#215;m120&#215;Gmean&#215;log&#40;Imean&#41;"
          "Fichero" => "si8.jpeg"
          "Tamanyo" => 4189
          "Alto" => 35
          "Ancho" => 292
        ]
      ]
      9 => array:5 [
        "identificador" => "eq0040"
        "tipo" => "MULTIMEDIAFORMULA"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "Formula" => array:5 [
          "Matematica" => "Sib&#61;108I0&#215;G0&#215;VD&#8195;Si2h&#61;108I120&#215;G120&#215;VD&#8195;SiM&#61;&#40;0&#46;137&#215;Sib&#41;&#43;Si2h2"
          "Fichero" => "si9.jpeg"
          "Tamanyo" => 5516
          "Alto" => 81
          "Ancho" => 303
        ]
      ]
      10 => array:5 [
        "identificador" => "eq0045"
        "tipo" => "MULTIMEDIAFORMULA"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "Formula" => array:5 [
          "Matematica" => "ISI&#40;Matsuda&#41;&#61;10&#44;000G0&#215;I0&#215;Gmean&#215;Imean"
          "Fichero" => "si10.jpeg"
          "Tamanyo" => 3050
          "Alto" => 39
          "Ancho" => 254
        ]
      ]
      11 => array:5 [
        "identificador" => "eq0050"
        "tipo" => "MULTIMEDIAFORMULA"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "Formula" => array:5 [
          "Matematica" => "ISIBelfiore&#61;2&#40;GS&#47;GN&#41;&#215;&#40;IS&#47;IN&#41;&#43;1"
          "Fichero" => "si11.jpeg"
          "Tamanyo" => 2237
          "Alto" => 35
          "Ancho" => 216
        ]
      ]
      12 => array:5 [
        "identificador" => "eq0055"
        "tipo" => "MULTIMEDIAFORMULA"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "Formula" => array:5 [
          "Matematica" => "MffmI&#61;e2&#46;63&#8722;0&#46;28&#8201;ln&#8201;&#40;I0&#41;&#8722;0&#46;31&#8201;ln&#8201;&#40;TAG0&#41;"
          "Fichero" => "si13.jpeg"
          "Tamanyo" => 2514
          "Alto" => 40
          "Ancho" => 245
        ]
      ]
      13 => array:5 [
        "identificador" => "eq0060"
        "tipo" => "MULTIMEDIAFORMULA"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "Formula" => array:5 [
          "Matematica" => "OGIS&#61;f&#40;G0&#44;&#8201;G90&#44;&#8201;G120&#44;&#8201;I0&#44;&#8201;I90&#44;&#8201;I120&#44;&#8201;DO&#41;"
          "Fichero" => "si14.jpeg"
          "Tamanyo" => 2406
          "Alto" => 15
          "Ancho" => 276
        ]
      ]
      14 => array:5 [
        "identificador" => "eq0065"
        "tipo" => "MULTIMEDIAFORMULA"
        "mostrarFloat" => false
        "mostrarDisplay" => true
        "Formula" => array:5 [
          "Matematica" => "RIST&#8201;Index&#61;AUC&#8201;of&#8201;Glucose"
          "Fichero" => "si15.jpeg"
          "Tamanyo" => 1917
          "Alto" => 12
          "Ancho" => 196
        ]
      ]
    ]
    "bibliografia" => array:2 [
      "titulo" => "References"
      "seccion" => array:1 [
        0 => array:2 [
          "identificador" => "bibs0005"
          "bibliografiaReferencia" => array:72 [
            0 => array:3 [
              "identificador" => "bib0005"
              "etiqueta" => "1"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Glucose clamp technique&#58; a method for quantifying insulin secretion and resistance"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "R&#46;A&#46; DeFronzo"
                            1 => "J&#46;D&#46; Tobin"
                            2 => "R&#46; Andres"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Physiol"
                        "fecha" => "1979"
                        "volumen" => "237"
                        "paginaInicial" => "E214"
                        "paginaFinal" => "E223"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/382871"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            1 => array:3 [
              "identificador" => "bib0010"
              "etiqueta" => "2"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Quantitative insulin sensitivity check index&#58; a simple&#44; accurate method for assessing insulin sensitivity in humans"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "A&#46; Katz"
                            1 => "S&#46;S&#46; Nambi"
                            2 => "K&#46; Mather"
                            3 => "A&#46;D&#46; Baron"
                            4 => "D&#46;A&#46; Follmann"
                            5 => "G&#46; Sullivan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jcem.85.7.6661"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "2000"
                        "volumen" => "85"
                        "paginaInicial" => "2402"
                        "paginaFinal" => "2410"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10902785"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            2 => array:3 [
              "identificador" => "bib0015"
              "etiqueta" => "3"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Quantitation of basal endogenous glucose production in Type II diabetes&#58; importance of the volume of distribution"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "J&#46; Radziuk"
                            1 => "S&#46; Pye"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1007/s00125-002-0841-6"
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetologia"
                        "fecha" => "2002"
                        "volumen" => "45"
                        "paginaInicial" => "1053"
                        "paginaFinal" => "1084"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12189437"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            3 => array:3 [
              "identificador" => "bib0020"
              "etiqueta" => "4"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Estimation of endogenous glucose production during hyperinsulinemic-euglycemic glucose clamps&#46; Comparison of unlabeled and labeled exogenous glucose infusates"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "D&#46;T&#46; Finegood"
                            1 => "R&#46;N&#46; Bergman"
                            2 => "M&#46; Vranic"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes"
                        "fecha" => "1987"
                        "volumen" => "36"
                        "paginaInicial" => "914"
                        "paginaFinal" => "924"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3297886"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            4 => array:3 [
              "identificador" => "bib0025"
              "etiqueta" => "5"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Underestimation of glucose turnover measured with &#91;6-3H&#93;- and &#91;6&#44;6-2H&#93;- but not &#91;6-14C&#93;glucose during hyperinsulinemia in humans"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "M&#46;M&#46; McMahon"
                            1 => "W&#46;F&#46; Schwenk"
                            2 => "M&#46;W&#46; Haymond"
                            3 => "R&#46;A&#46; Rizza"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes"
                        "fecha" => "1989"
                        "volumen" => "38"
                        "paginaInicial" => "97"
                        "paginaFinal" => "107"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2642865"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            5 => array:3 [
              "identificador" => "bib0030"
              "etiqueta" => "6"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effects of glucose ingestion versus infusion on pulsatile insulin secretion&#46; The incretin effect is achieved by amplification of insulin secretory burst mass"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "N&#46; Porksen"
                            1 => "S&#46; Munn"
                            2 => "J&#46; Steers"
                            3 => "J&#46;D&#46; Veldhuis"
                            4 => "P&#46;C&#46; Butler"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes"
                        "fecha" => "1996"
                        "volumen" => "45"
                        "paginaInicial" => "1317"
                        "paginaFinal" => "1323"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8826965"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            6 => array:3 [
              "identificador" => "bib0035"
              "etiqueta" => "7"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Pulsatile&#44; synchronous basal insulin and glucagon secretion in man"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "D&#46;A&#46; Lang"
                            1 => "D&#46;R&#46; Matthews"
                            2 => "M&#46; Burnett"
                            3 => "G&#46;M&#46; Ward"
                            4 => "R&#46;C&#46; Turner"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes"
                        "fecha" => "1982"
                        "volumen" => "31"
                        "paginaInicial" => "22"
                        "paginaFinal" => "26"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/6759209"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            7 => array:3 [
              "identificador" => "bib0040"
              "etiqueta" => "8"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Rapid oscillations in plasma insulin&#44; glucagon&#44; and glucose in obese and normal weight humans"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "B&#46;C&#46; Hansen"
                            1 => "K&#46;C&#46; Jen"
                            2 => "S&#46; Belbez Pek"
                            3 => "R&#46;A&#46; Wolfe"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jcem-54-4-785"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "1982"
                        "volumen" => "54"
                        "paginaInicial" => "785"
                        "paginaFinal" => "792"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7037815"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            8 => array:3 [
              "identificador" => "bib0045"
              "etiqueta" => "9"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Hepatic parasympathetic &#40;HISS&#41; control of insulin sensitivity determined by feeding and fasting"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "W&#46;W&#46; Lautt"
                            1 => "M&#46;P&#46; Macedo"
                            2 => "P&#46; Sadri"
                            3 => "S&#46; Takayama"
                            4 => "F&#46; Duarte Ramos"
                            5 => "D&#46;J&#46; Legare"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Physiol Gastrointest Liver Physiol"
                        "fecha" => "2001"
                        "volumen" => "281"
                        "paginaInicial" => "G29"
                        "paginaFinal" => "G36"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11408252"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            9 => array:3 [
              "identificador" => "bib0050"
              "etiqueta" => "10"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Comparison of insulin sensitivity&#44; clearance&#44; and secretion estimates using euglycemic and hyperglycemic clamps in children"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "G&#46;I&#46; Uwaifo"
                            1 => "S&#46;J&#46; Parikh"
                            2 => "M&#46; Keil"
                            3 => "J&#46; Elberg"
                            4 => "J&#46; Chin"
                            5 => "J&#46;A&#46; Yanovski"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jcem.87.6.8578"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "2002"
                        "volumen" => "87"
                        "paginaInicial" => "2899"
                        "paginaFinal" => "2905"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12050270"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            10 => array:3 [
              "identificador" => "bib0055"
              "etiqueta" => "11"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Clinical investigation into the effect of the intravenous injection of insulin"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "A&#46; Horgaard"
                            1 => "T&#46;H&#46; Thayssen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Acta Med Scand"
                        "fecha" => "1929"
                        "volumen" => "72"
                        "paginaInicial" => "92"
                        "paginaFinal" => "95"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            11 => array:3 [
              "identificador" => "bib0060"
              "etiqueta" => "12"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Estimates of in vivo insulin action in man&#58; comparison of insulin tolerance tests with euglycemic and hyperglycemic glucose clamp studies"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46; Bonora"
                            1 => "P&#46; Moghetti"
                            2 => "C&#46; Zancanaro"
                            3 => "M&#46; Cigolini"
                            4 => "M&#46; Querena"
                            5 => "V&#46; Cacciatori"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jcem-68-2-374"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "1989"
                        "volumen" => "68"
                        "paginaInicial" => "374"
                        "paginaFinal" => "378"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2645308"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            12 => array:3 [
              "identificador" => "bib0065"
              "etiqueta" => "13"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The short insulin tolerance test&#58; feasibility study using venous sampling"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "R&#46;P&#46; Young"
                            1 => "J&#46;A&#46; Critchley"
                            2 => "P&#46;J&#46; Anderson"
                            3 => "M&#46;S&#46; Lau"
                            4 => "K&#46;K&#46; Lee"
                            5 => "J&#46;C&#46; Chan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/(SICI)1096-9136(199605)13:5<429::AID-DIA98>3.0.CO;2-K"
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabet Med"
                        "fecha" => "1996"
                        "volumen" => "13"
                        "paginaInicial" => "429"
                        "paginaFinal" => "433"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8737024"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            13 => array:3 [
              "identificador" => "bib0070"
              "etiqueta" => "14"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Reproducibility of the short insulin tolerance test"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "S&#46; Hirst"
                            1 => "D&#46;I&#46; Phillips"
                            2 => "S&#46;K&#46; Vines"
                            3 => "P&#46;M&#46; Clark"
                            4 => "C&#46;N&#46; Hales"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabet Med"
                        "fecha" => "1993"
                        "volumen" => "10"
                        "paginaInicial" => "839"
                        "paginaFinal" => "842"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8281729"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            14 => array:3 [
              "identificador" => "bib0075"
              "etiqueta" => "15"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Insulin resistance in noninsulin-dependent diabetes mellitus&#46; Does it exist and can it be measured&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "G&#46;M&#46; Reaven"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Med"
                        "fecha" => "1983"
                        "volumen" => "74"
                        "paginaInicial" => "3"
                        "paginaFinal" => "17"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/6344631"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            15 => array:3 [
              "identificador" => "bib0080"
              "etiqueta" => "16"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The short insulin tolerance test for determination of insulin sensitivity&#58; a comparison with the euglycaemic clamp"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "A&#46; Akinmokun"
                            1 => "P&#46;L&#46; Selby"
                            2 => "K&#46; Ramaiya"
                            3 => "K&#46;G&#46; Alberti"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabet Med"
                        "fecha" => "1992"
                        "volumen" => "9"
                        "paginaInicial" => "432"
                        "paginaFinal" => "437"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1611830"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            16 => array:3 [
              "identificador" => "bib0085"
              "etiqueta" => "17"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Is the short insulin tolerance test safe and reproducible&#63;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [
                            0 => "C&#46;C&#46; Chen"
                            1 => "T&#46;Y&#46; Wang"
                            2 => "S&#46;Y&#46; Hsu"
                            3 => "R&#46;H&#46; Chen"
                            4 => "C&#46;T&#46; Chang"
                            5 => "S&#46;J&#46; Chen"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1002/(SICI)1096-9136(1998110)15:11<924::AID-DIA699>3.0.CO;2-H"
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabet Med"
                        "fecha" => "1998"
                        "volumen" => "15"
                        "paginaInicial" => "924"
                        "paginaFinal" => "927"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9827846"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            17 => array:3 [
              "identificador" => "bib0090"
              "etiqueta" => "18"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Evaluation of insulin sensitivity in clinical practice and in research settings"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "L&#46;U&#46; Monzillo"
                            1 => "O&#46; Hamdy"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Nutr Rev"
                        "fecha" => "2003"
                        "volumen" => "61"
                        "paginaInicial" => "397"
                        "paginaFinal" => "412"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/14968910"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            18 => array:3 [
              "identificador" => "bib0095"
              "etiqueta" => "19"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Comparison of impedance to insulin-mediated glucose uptake in normal subjects and in subjects with latent diabetes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "S&#46;W&#46; Shen"
                            1 => "G&#46;M&#46; Reaven"
                            2 => "J&#46;W&#46; Farquhar"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1172/JCI106433"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Invest"
                        "fecha" => "1970"
                        "volumen" => "49"
                        "paginaInicial" => "2151"
                        "paginaFinal" => "2160"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/5480843"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            19 => array:3 [
              "identificador" => "bib0100"
              "etiqueta" => "20"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Glucose&#44; insulin&#44; and somatostatin infusion for the determination of insulin sensitivity in vivo"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "Y&#46; Harano"
                            1 => "H&#46; Hidaka"
                            2 => "K&#46; Takatsuki"
                            3 => "S&#46; Ohgaku"
                            4 => "M&#46; Haneda"
                            5 => "S&#46; Motoi"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Metabolism"
                        "fecha" => "1978"
                        "volumen" => "27"
                        "numero" => "Suppl&#46; 1"
                        "paginaInicial" => "1449"
                        "paginaFinal" => "1452"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/683015"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            20 => array:3 [
              "identificador" => "bib0105"
              "etiqueta" => "21"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Evaluation of octreotide to assess insulin-mediated glucose disposal by the insulin suppression test"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "D&#46; Pei"
                            1 => "C&#46;N&#46; Jones"
                            2 => "R&#46; Bhargava"
                            3 => "Y&#46;D&#46; Chen"
                            4 => "G&#46;M&#46; Reaven"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetologia"
                        "fecha" => "1994"
                        "volumen" => "37"
                        "paginaInicial" => "843"
                        "paginaFinal" => "845"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7988789"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            21 => array:3 [
              "identificador" => "bib0110"
              "etiqueta" => "22"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Assessment of insulin resistance with the insulin suppression test and the euglycemic clamp"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "M&#46;S&#46; Greenfield"
                            1 => "L&#46; Doberne"
                            2 => "F&#46; Kraemer"
                            3 => "T&#46; Tobey"
                            4 => "G&#46; Reaven"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes"
                        "fecha" => "1981"
                        "volumen" => "30"
                        "paginaInicial" => "387"
                        "paginaFinal" => "392"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7014307"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            22 => array:3 [
              "identificador" => "bib0115"
              "etiqueta" => "23"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Continuous infusion of glucose with model assessment&#58; measurement of insulin resistance and beta-cell function in man"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;P&#46; Hosker"
                            1 => "D&#46;R&#46; Matthews"
                            2 => "A&#46;S&#46; Rudenski"
                            3 => "M&#46;A&#46; Burnett"
                            4 => "P&#46; Darling"
                            5 => "E&#46;G&#46; Bown"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetologia"
                        "fecha" => "1985"
                        "volumen" => "28"
                        "paginaInicial" => "401"
                        "paginaFinal" => "411"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3899824"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            23 => array:3 [
              "identificador" => "bib0120"
              "etiqueta" => "24"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Quantitative estimation of insulin sensitivity"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "R&#46;N&#46; Bergman"
                            1 => "Y&#46;Z&#46; Ider"
                            2 => "C&#46;R&#46; Bowden"
                            3 => "C&#46; Cobelli"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Physiol"
                        "fecha" => "1979"
                        "volumen" => "236"
                        "paginaInicial" => "E667"
                        "paginaFinal" => "E677"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/443421"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            24 => array:3 [
              "identificador" => "bib0125"
              "etiqueta" => "25"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A modified protocol for estimation of insulin sensitivity with the minimal model of glucose kinetics in patients with insulin-dependent diabetes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "D&#46;T&#46; Finegood"
                            1 => "I&#46;M&#46; Hramiak"
                            2 => "J&#46; Dupre"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jcem-70-6-1538"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "1990"
                        "volumen" => "70"
                        "paginaInicial" => "1538"
                        "paginaFinal" => "1549"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2189884"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            25 => array:3 [
              "identificador" => "bib0130"
              "etiqueta" => "26"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Direct comparison of standard and insulin modified protocols for minimal model estimation of insulin sensitivity in normal subjects"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "M&#46;J&#46; Quon"
                            1 => "C&#46; Cochran"
                            2 => "S&#46;I&#46; Taylor"
                            3 => "R&#46;C&#46; Eastman"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes Res"
                        "fecha" => "1994"
                        "volumen" => "25"
                        "paginaInicial" => "139"
                        "paginaFinal" => "149"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/7648784"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            26 => array:3 [
              "identificador" => "bib0135"
              "etiqueta" => "27"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Differences between the tolbutamide-boosted and the insulin-modified minimal model protocols"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "M&#46;F&#46; Saad"
                            1 => "G&#46;M&#46; Steil"
                            2 => "W&#46;W&#46; Kades"
                            3 => "M&#46;F&#46; Ayad"
                            4 => "W&#46;A&#46; Elsewafy"
                            5 => "R&#46; Boyadjian"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes"
                        "fecha" => "1997"
                        "volumen" => "46"
                        "paginaInicial" => "1167"
                        "paginaFinal" => "1171"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9200652"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            27 => array:3 [
              "identificador" => "bib0140"
              "etiqueta" => "28"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Equivalence of the insulin sensitivity index in man derived by the minimal model method and the euglycemic glucose clamp"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "R&#46;N&#46; Bergman"
                            1 => "R&#46; Prager"
                            2 => "A&#46; Volund"
                            3 => "J&#46;M&#46; Olefsky"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1172/JCI112886"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Invest"
                        "fecha" => "1987"
                        "volumen" => "79"
                        "paginaInicial" => "790"
                        "paginaFinal" => "800"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/3546379"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            28 => array:3 [
              "identificador" => "bib0145"
              "etiqueta" => "29"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Minimal model&#58; perspective from 2005"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "R&#46;N&#46; Bergman"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1159/000089312"
                      "Revista" => array:7 [
                        "tituloSerie" => "Horm Res"
                        "fecha" => "2005"
                        "volumen" => "64"
                        "numero" => "Suppl&#46; 3"
                        "paginaInicial" => "8"
                        "paginaFinal" => "15"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16439839"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            29 => array:3 [
              "identificador" => "bib0150"
              "etiqueta" => "30"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Reduced glucose effectiveness associated with reduced insulin release&#58; an artifact of the minimal-model method"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "D&#46;T&#46; Finegood"
                            1 => "D&#46; Tzur"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Am J Physiol Endocrinol Metab"
                        "fecha" => "1996"
                        "volumen" => "271"
                        "paginaInicial" => "E485"
                        "paginaFinal" => "E495"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            30 => array:3 [
              "identificador" => "bib0155"
              "etiqueta" => "31"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Assessing the predictive accuracy of QUICKI as a surrogate index for insulin sensitivity using a calibration model"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "H&#46; Chen"
                            1 => "G&#46; Sullivan"
                            2 => "M&#46;J&#46; Quon"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes"
                        "fecha" => "2005"
                        "volumen" => "54"
                        "paginaInicial" => "1914"
                        "paginaFinal" => "1925"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15983190"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            31 => array:3 [
              "identificador" => "bib0160"
              "etiqueta" => "32"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Dilution of the 75-g oral glucose tolerance test increases postprandial glycemia&#58; implications for diagnostic criteria"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "J&#46;L&#46; Sievenpiper"
                            1 => "D&#46;J&#46;A&#46; Jenkins"
                            2 => "R&#46;G&#46; Josse"
                            3 => "V&#46; Vuksan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "CMAJ"
                        "fecha" => "2000"
                        "volumen" => "162"
                        "paginaInicial" => "993"
                        "paginaFinal" => "996"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10763397"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            32 => array:3 [
              "identificador" => "bib0165"
              "etiqueta" => "33"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diagnosis and classification of diabetes mellitus"
                      "autores" => array:1 [
                        0 => array:2 [
                          "colaboracion" => "American Diabetes Association"
                          "etal" => false
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2337/dc10-S062"
                      "Revista" => array:7 [
                        "tituloSerie" => "Diabetes Care"
                        "fecha" => "2010"
                        "volumen" => "33"
                        "numero" => "Suppl&#46; 1"
                        "paginaInicial" => "S62"
                        "paginaFinal" => "S69"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20042775"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            33 => array:3 [
              "identificador" => "bib0170"
              "etiqueta" => "34"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Metabolic responses in a model of insulin resistance&#58; comparison between oral glucose and meal tolerance tests"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "N&#46; Berthiaume"
                            1 => "B&#46;A&#46; Zinker"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Metabolism"
                        "fecha" => "2002"
                        "volumen" => "51"
                        "paginaInicial" => "595"
                        "paginaFinal" => "598"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11979391"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            34 => array:3 [
              "identificador" => "bib0175"
              "etiqueta" => "35"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Evaluation of insulin sensitivity and &#123;beta&#125;-cell function indexes obtained from minimal model analysis of a meal tolerance test"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "G&#46;M&#46; Steil"
                            1 => "Hwu C-m"
                            2 => "R&#46; Janowski"
                            3 => "F&#46; Hariri"
                            4 => "S&#46; Jinagouda"
                            5 => "C&#46; Darwin"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes"
                        "fecha" => "2004"
                        "volumen" => "53"
                        "paginaInicial" => "1201"
                        "paginaFinal" => "1207"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/15111487"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            35 => array:3 [
              "identificador" => "bib0180"
              "etiqueta" => "36"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Insulin sensitivity from meal tolerance tests in normal subjects&#58; a minimal model index"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "A&#46; Caumo"
                            1 => "R&#46;N&#46; Bergman"
                            2 => "C&#46; Cobelli"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jcem.85.11.6982"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "2000"
                        "volumen" => "85"
                        "paginaInicial" => "4396"
                        "paginaFinal" => "4402"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11095485"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            36 => array:3 [
              "identificador" => "bib0185"
              "etiqueta" => "37"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diagnosis and classification of diabetes mellitus"
                      "autores" => array:1 [
                        0 => array:2 [
                          "colaboracion" => "American Diabetes Association"
                          "etal" => false
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2337/dc07-S042"
                      "Revista" => array:7 [
                        "tituloSerie" => "Diabetes Care"
                        "fecha" => "2007"
                        "volumen" => "30"
                        "numero" => "Suppl&#46; 1"
                        "paginaInicial" => "S42"
                        "paginaFinal" => "S47"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/17192378"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            37 => array:3 [
              "identificador" => "bib0190"
              "etiqueta" => "38"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Standards of medical care in diabetes"
                      "autores" => array:1 [
                        0 => array:2 [
                          "colaboracion" => "American Diabetes Association"
                          "etal" => false
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2337/dc10-S011"
                      "Revista" => array:7 [
                        "tituloSerie" => "Diabetes Care"
                        "fecha" => "2010"
                        "volumen" => "33"
                        "numero" => "Suppl&#46; 1"
                        "paginaInicial" => "S11"
                        "paginaFinal" => "S61"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/20042772"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            38 => array:3 [
              "identificador" => "bib0195"
              "etiqueta" => "39"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Insulin sensitivity indices obtained from oral glucose tolerance testing&#58; comparison with the euglycemic insulin clamp"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46; Matsuda"
                            1 => "R&#46; DeFronzo"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes Care"
                        "fecha" => "1999"
                        "volumen" => "22"
                        "paginaInicial" => "1462"
                        "paginaFinal" => "1470"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10480510"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            39 => array:3 [
              "identificador" => "bib0200"
              "etiqueta" => "40"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Insulin release and peripheral sensitivity at the oral glucose tolerance test"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "J&#46; Cederholm"
                            1 => "L&#46; Wibell"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes Res Clin Pract"
                        "fecha" => "1990"
                        "volumen" => "10"
                        "paginaInicial" => "167"
                        "paginaFinal" => "175"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2261853"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            40 => array:3 [
              "identificador" => "bib0205"
              "etiqueta" => "41"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The breakfast tolerance test&#58; a return to physiology"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "P&#46;J&#46; Lefebvre"
                            1 => "A&#46;S&#46; Luyckx"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Diabetes Metab"
                        "fecha" => "1976"
                        "volumen" => "2"
                        "paginaInicial" => "15"
                        "paginaFinal" => "19"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            41 => array:3 [
              "identificador" => "bib0210"
              "etiqueta" => "42"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Postprandial reactive hypoglycemia"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "J&#46;F&#46; Brun"
                            1 => "C&#46; Fedou"
                            2 => "J&#46; Mercier"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes Metab"
                        "fecha" => "2000"
                        "volumen" => "26"
                        "paginaInicial" => "337"
                        "paginaFinal" => "351"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11119013"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            42 => array:3 [
              "identificador" => "bib0215"
              "etiqueta" => "43"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Serum leptin is associated with the perception of palatability during a standardized high-carbohydrate breakfast test"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "E&#46; Raynaud"
                            1 => "J&#46;F&#46; Brun"
                            2 => "A&#46; Perez-Martin"
                            3 => "C&#46; Sagnes"
                            4 => "A&#46;M&#46; Boularan"
                            5 => "C&#46; Fedou"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Clin Sci &#40;Lond&#41;"
                        "fecha" => "1999"
                        "volumen" => "96"
                        "paginaInicial" => "343"
                        "paginaFinal" => "348"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            43 => array:3 [
              "identificador" => "bib0220"
              "etiqueta" => "44"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effects of meal size and composition on incretin&#44; &#91;alpha&#93;-cell&#44; and &#91;beta&#93;-cell responses"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;M&#46; Rijkelijkhuizen"
                            1 => "K&#46; McQuarrie"
                            2 => "C&#46;J&#46; Girman"
                            3 => "P&#46;P&#46; Stein"
                            4 => "A&#46; Mari"
                            5 => "J&#46;J&#46; Holst"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.metabol.2009.07.039"
                      "Revista" => array:6 [
                        "tituloSerie" => "Metabolism"
                        "fecha" => "2010"
                        "volumen" => "59"
                        "paginaInicial" => "502"
                        "paginaFinal" => "511"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19846181"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            44 => array:3 [
              "identificador" => "bib0225"
              "etiqueta" => "45"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Classical and model-based estimates of beta-cell function during a mixed meal vs&#46; an OGTT in a population-based cohort"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "J&#46;M&#46; Rijkelijkhuizen"
                            1 => "C&#46;J&#46; Girman"
                            2 => "A&#46; Mari"
                            3 => "M&#46; Alssema"
                            4 => "T&#46; Rhodes"
                            5 => "G&#46; Nijpels"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1016/j.diabres.2008.11.017"
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes Res Clin Pract"
                        "fecha" => "2009"
                        "volumen" => "83"
                        "paginaInicial" => "280"
                        "paginaFinal" => "288"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19097663"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            45 => array:3 [
              "identificador" => "bib0230"
              "etiqueta" => "46"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Food glycemic index&#44; as given in glycemic index tables&#44; is a significant determinant of glycemic responses elicited by composite breakfast meals"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "T&#46;M&#46; Wolever"
                            1 => "M&#46; Yang"
                            2 => "X&#46;Y&#46; Zeng"
                            3 => "F&#46; Atkinson"
                            4 => "J&#46;C&#46; Brand-Miller"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Am J Clin Nutr"
                        "fecha" => "2006"
                        "volumen" => "83"
                        "paginaInicial" => "1306"
                        "paginaFinal" => "1312"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16762941"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            46 => array:3 [
              "identificador" => "bib0235"
              "etiqueta" => "47"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Effects of meal volume and posture on gastric emptying of solids and appetite"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "S&#46; Doran"
                            1 => "K&#46;L&#46; Jones"
                            2 => "J&#46;M&#46; Andrews"
                            3 => "M&#46; Horowitz"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Am J Physiol"
                        "fecha" => "1998"
                        "volumen" => "275"
                        "numero" => "Pt 2"
                        "paginaInicial" => "R1712"
                        "paginaFinal" => "R1718"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/9791094"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            47 => array:3 [
              "identificador" => "bib0240"
              "etiqueta" => "48"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Comparison of gastric emptying of a solid and a liquid nutritional rehabilitation food"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "L&#46; Achour"
                            1 => "S&#46; Meance"
                            2 => "A&#46; Briend"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1038/sj.ejcn.1601221"
                      "Revista" => array:6 [
                        "tituloSerie" => "Eur J Clin Nutr"
                        "fecha" => "2001"
                        "volumen" => "55"
                        "paginaInicial" => "769"
                        "paginaFinal" => "772"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11528491"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            48 => array:3 [
              "identificador" => "bib0245"
              "etiqueta" => "49"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The effect of incorporating fat into different components of a meal on gastric emptying and postprandial blood glucose and insulin responses"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "K&#46;M&#46; Cunningham"
                            1 => "N&#46;W&#46; Read"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Nutr"
                        "fecha" => "1989"
                        "volumen" => "61"
                        "paginaInicial" => "285"
                        "paginaFinal" => "290"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/2650735"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            49 => array:3 [
              "identificador" => "bib0250"
              "etiqueta" => "50"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Comparison of the metabolic effects of mixed meal and standard oral glucose tolerance test on glucose&#44; insulin and C-peptide response in healthy&#44; impaired glucose tolerance&#44; mild and severe non-insulin-dependent diabetic subjects"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "S&#46; Marena"
                            1 => "G&#46; Montegrosso"
                            2 => "F&#46; De Michieli"
                            3 => "E&#46; Pisu"
                            4 => "G&#46; Pagano"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Acta Diabetol"
                        "fecha" => "1992"
                        "volumen" => "29"
                        "paginaInicial" => "29"
                        "paginaFinal" => "33"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/1520903"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            50 => array:3 [
              "identificador" => "bib0255"
              "etiqueta" => "51"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Insulin resistance caused by hepatic cholinergic interruption and reversed by acetylcholine administration"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "H&#46; Xie"
                            1 => "W&#46;W&#46; Lautt"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Am J Physiol"
                        "fecha" => "1996"
                        "volumen" => "271"
                        "numero" => "Pt&#46; 1"
                        "paginaInicial" => "E587"
                        "paginaFinal" => "E592"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8843755"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            51 => array:3 [
              "identificador" => "bib0260"
              "etiqueta" => "52"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Rapid insulin sensitivity test &#40;RIST&#41;"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "W&#46;W&#46; Lautt"
                            1 => "X&#46; Wang"
                            2 => "P&#46; Sadri"
                            3 => "D&#46;J&#46; Legare"
                            4 => "M&#46;P&#46; Macedo"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Can J Physiol Pharmacol"
                        "fecha" => "1998"
                        "volumen" => "76"
                        "paginaInicial" => "1080"
                        "paginaFinal" => "1086"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/10326829"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            52 => array:3 [
              "identificador" => "bib0265"
              "etiqueta" => "53"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Insulin sensitivity tested with a modified euglycemic technique in cats and rats"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "H&#46; Xie"
                            1 => "L&#46; Zhu"
                            2 => "Y&#46;L&#46; Zhang"
                            3 => "D&#46;J&#46; Legare"
                            4 => "W&#46;W&#46; Lautt"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Pharmacol Toxicol Methods"
                        "fecha" => "1996"
                        "volumen" => "35"
                        "paginaInicial" => "77"
                        "paginaFinal" => "82"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8729433"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            53 => array:3 [
              "identificador" => "bib0270"
              "etiqueta" => "54"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Induction of insulin resistance by cholinergic blockade with atropine in the cat"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "H&#46; Xie"
                            1 => "W&#46;W&#46; Lautt"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "J Auton Pharmacol"
                        "fecha" => "1995"
                        "volumen" => "15"
                        "paginaInicial" => "361"
                        "paginaFinal" => "369"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/8744976"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            54 => array:3 [
              "identificador" => "bib0275"
              "etiqueta" => "55"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A rapid insulin sensitivity test &#40;RIST&#41; in the anesthetized mice"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46;G&#46; Latour"
                            1 => "C&#46;C&#46; Chan"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "Diabetes"
                        "fecha" => "2002"
                        "volumen" => "51"
                        "numero" => "Suppl&#46; 2"
                        "paginaInicial" => "A422"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            55 => array:3 [
              "identificador" => "bib0280"
              "etiqueta" => "56"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Meal-induced insulin sensitization and its parasympathetic regulation in humans"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "R&#46;S&#46; Patarr&#227;o"
                            1 => "W&#46;W&#46; Lautt"
                            2 => "R&#46;A&#46; Afonso"
                            3 => "R&#46;T&#46; Ribeiro"
                            4 => "M&#46;P&#46; Guarino"
                            5 => "A&#46;B&#46; Fernandes"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1139/Y08-080"
                      "Revista" => array:6 [
                        "tituloSerie" => "Can J Physiol Pharmacol"
                        "fecha" => "2008"
                        "volumen" => "86"
                        "paginaInicial" => "880"
                        "paginaFinal" => "888"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/19088809"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            56 => array:3 [
              "identificador" => "bib0285"
              "etiqueta" => "57"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Meal-induced insulin sensitization in conscious and anaesthetized rat models comparing liquid mixed meal with glucose and sucrose"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "P&#46; Sadri"
                            1 => "M&#46;A&#46; Reid"
                            2 => "R&#46;A&#46; Afonso"
                            3 => "J&#46; Schafer"
                            4 => "D&#46;J&#46; Legare"
                            5 => "M&#46;P&#46; Macedo"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Br J Nutr"
                        "fecha" => "2006"
                        "volumen" => "95"
                        "paginaInicial" => "288"
                        "paginaFinal" => "295"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/16469144"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            57 => array:3 [
              "identificador" => "bib0290"
              "etiqueta" => "58"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Insulin sensitivity in skeletal muscle regulated by a hepatic hormone"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:1 [
                            0 => "W&#46;W&#46; Lautt"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:5 [
                        "tituloSerie" => "HISS Can J Appl Physiol"
                        "fecha" => "2005"
                        "volumen" => "30"
                        "paginaInicial" => "304"
                        "paginaFinal" => "312"
                      ]
                    ]
                  ]
                ]
              ]
            ]
            58 => array:3 [
              "identificador" => "bib0295"
              "etiqueta" => "59"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Comparison of the rapid insulin sensitivity test &#40;RIST&#41;&#44; the insulin tolerance test &#40;ITT&#41;&#44; and the hyperinsulinemic euglycemic clamp &#40;HIEC&#41; to measure insulin action in rats"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [
                            0 => "M&#46;A&#46; Reid"
                            1 => "M&#46;G&#46; Latour"
                            2 => "D&#46;J&#46; Legare"
                            3 => "N&#46; Rong"
                            4 => "W&#46;W&#46; Lautt"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Can J Physiol Pharmacol"
                        "fecha" => "2002"
                        "volumen" => "80"
                        "paginaInicial" => "811"
                        "paginaFinal" => "818"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/12269792"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            59 => array:3 [
              "identificador" => "bib0300"
              "etiqueta" => "60"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "The hepatic vagus nerve in the control of insulin sensitivity in the rat"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46;G&#46; Latour"
                            1 => "W&#46;W&#46; Lautt"
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Auton Neurosci"
                        "fecha" => "2002"
                        "volumen" => "95"
                        "paginaInicial" => "125"
                        "paginaFinal" => "130"
                        "link" => array:1 [
                          0 => array:2 [
                            "url" => "https://www.ncbi.nlm.nih.gov/pubmed/11871777"
                            "web" => "Medline"
                          ]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            60 => array:3 [
              "identificador" => "bib0305"
              "etiqueta" => "61"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Insulin resistance of skeletal muscle produced by hepatic parasympathetic interruption"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "H&#46; Xie"
                             …1
                          ]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Am J Physiol"
                        "fecha" => "1996"
                        "volumen" => "270"
                        "numero" => "Pt 1"
                        "paginaInicial" => "E858"
                        "paginaFinal" => "E863"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            61 => array:3 [
              "identificador" => "bib0310"
              "etiqueta" => "62"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Homeostasis model assessment&#58; insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetologia"
                        "fecha" => "1985"
                        "volumen" => "28"
                        "paginaInicial" => "412"
                        "paginaFinal" => "419"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            62 => array:3 [
              "identificador" => "bib0315"
              "etiqueta" => "63"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Use and abuse of HOMA modeling"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes Care"
                        "fecha" => "2004"
                        "volumen" => "27"
                        "paginaInicial" => "1487"
                        "paginaFinal" => "1495"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            63 => array:3 [
              "identificador" => "bib0320"
              "etiqueta" => "64"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Repeatability characteristics of simple indices of insulin resistance&#58; implications for research applications"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1210/jcem.86.11.7880"
                      "Revista" => array:6 [
                        "tituloSerie" => "J Clin Endocrinol Metab"
                        "fecha" => "2001"
                        "volumen" => "86"
                        "paginaInicial" => "5457"
                        "paginaFinal" => "5464"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            64 => array:3 [
              "identificador" => "bib0325"
              "etiqueta" => "65"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Evaluation of the quantitative insulin sensitivity check index as an estimate of insulin sensitivity in humans"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Metabolism"
                        "fecha" => "2002"
                        "volumen" => "51"
                        "paginaInicial" => "235"
                        "paginaFinal" => "237"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            65 => array:3 [
              "identificador" => "bib0330"
              "etiqueta" => "66"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Validation of the insulin sensitivity index &#40;ISI&#40;0&#44;120&#41;&#41;&#58; comparison with other measures"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes Res Clin Pract"
                        "fecha" => "2000"
                        "volumen" => "47"
                        "paginaInicial" => "177"
                        "paginaFinal" => "184"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            66 => array:3 [
              "identificador" => "bib0335"
              "etiqueta" => "67"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Non-steady state&#58; error analysis of Steele&#39;s model and developments for glucose kinetics"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [ …3]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:7 [
                        "tituloSerie" => "Am J Physiol"
                        "fecha" => "1987"
                        "volumen" => "252"
                        "numero" => "Pt 1"
                        "paginaInicial" => "E679"
                        "paginaFinal" => "E689"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            67 => array:3 [
              "identificador" => "bib0340"
              "etiqueta" => "68"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Insulin sensitivity of blood glucose versus insulin sensitivity of blood free fatty acids in normal&#44; obese&#44; and obese-diabetic subjects"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.1053/meta.2001.22518"
                      "Revista" => array:6 [
                        "tituloSerie" => "Metabolism"
                        "fecha" => "2001"
                        "volumen" => "50"
                        "paginaInicial" => "573"
                        "paginaFinal" => "582"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            68 => array:3 [
              "identificador" => "bib0345"
              "etiqueta" => "69"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Use of the oral glucose tolerance test to assess insulin release and insulin sensitivity"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes Care"
                        "fecha" => "2000"
                        "volumen" => "23"
                        "paginaInicial" => "295"
                        "paginaFinal" => "301"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            69 => array:3 [
              "identificador" => "bib0350"
              "etiqueta" => "70"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Oral glucose tolerance test indexes for insulin sensitivity and secretion based on various availabilities of sampling times"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [ …4]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes Care"
                        "fecha" => "2001"
                        "volumen" => "24"
                        "paginaInicial" => "796"
                        "paginaFinal" => "797"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            70 => array:3 [
              "identificador" => "bib0355"
              "etiqueta" => "71"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Diagnosing insulin resistance in the general population"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [ …6]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes Care"
                        "fecha" => "2001"
                        "volumen" => "24"
                        "paginaInicial" => "460"
                        "paginaFinal" => "464"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
            71 => array:3 [
              "identificador" => "bib0360"
              "etiqueta" => "72"
              "referencia" => array:1 [
                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "A model-based method for assessing insulin sensitivity from the oral glucose tolerance test"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:5 [ …5]
                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Diabetes Care"
                        "fecha" => "2001"
                        "volumen" => "24"
                        "paginaInicial" => "539"
                        "paginaFinal" => "548"
                        "link" => array:1 [
                          0 => array:2 [ …2]
                        ]
                      ]
                    ]
                  ]
                ]
              ]
            ]
          ]
        ]
      ]
    ]
    "agradecimientos" => array:1 [
      0 => array:4 [
        "identificador" => "xack87666"
        "titulo" => "Acknowledgements"
        "texto" => "<p id="par0440" class="elsevierStylePara elsevierViewall">We thank Fernandes AB&#44; Afonso RA&#44; Ribeiro RT and In&#234;s S&#46; Lima for helpful scientific discussions&#46;</p>"
        "vista" => "all"
      ]
    ]
  ]
  "idiomaDefecto" => "en"
  "url" => "/16463439/0000000900000001/v1_201407280026/S1646343913000734/v1_201407280026/en/main.assets"
  "Apartado" => array:4 [
    "identificador" => "19187"
    "tipo" => "SECCION"
    "en" => array:2 [
      "titulo" => "Revis&#227;o"
      "idiomaDefecto" => true
    ]
    "idiomaDefecto" => "en"
  ]
  "PDF" => "https://static.elsevier.es/multimedia/16463439/0000000900000001/v1_201407280026/S1646343913000734/v1_201407280026/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/"
  "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1646343913000734?idApp=UINPBA00004N"
]

Article information

ISSN: 16463439
Original language: English

DOI:10.1016/j.rpedm.2013.10.004

The statistics are updated each day

Year/Month	Html	Pdf	Total

2024 October	302	30	332
2024 September	460	32	492
2024 August	424	40	464
2024 July	562	44	606
2024 June	381	39	420
2024 May	494	48	542
2024 April	481	50	531
2024 March	603	30	633
2024 February	736	61	797
2024 January	843	54	897
2023 December	563	60	623
2023 November	811	58	869
2023 October	690	71	761
2023 September	469	38	507
2023 August	388	44	432
2023 July	435	54	489
2023 June	442	59	501
2023 May	549	53	602
2023 April	495	56	551
2023 March	434	58	492
2023 February	211	24	235
2023 January	266	40	306
2022 December	193	32	225
2022 November	223	40	263
2022 October	611	49	660
2022 September	196	56	252
2022 August	202	52	254
2022 July	203	44	247
2022 June	172	54	226
2022 May	149	44	193
2022 April	174	40	214
2022 March	170	45	215
2022 February	201	33	234
2022 January	250	46	296
2021 December	223	25	248
2021 November	208	36	244
2021 October	172	33	205
2021 September	154	64	218
2021 August	131	30	161
2021 July	163	42	205
2021 June	158	44	202
2021 May	202	37	239
2021 April	441	112	553
2021 March	295	73	368
2021 February	182	94	276
2021 January	153	53	206
2020 December	163	37	200
2020 November	186	54	240
2020 October	162	22	184
2020 September	181	40	221
2020 August	120	20	140
2020 July	120	15	135
2020 June	140	26	166
2020 May	144	45	189
2020 April	135	43	178
2020 March	114	22	136
2020 February	132	37	169
2020 January	96	33	129
2019 December	90	19	109
2019 November	104	29	133
2019 October	142	32	174
2019 September	122	21	143
2019 August	161	22	183
2019 July	215	30	245
2019 June	272	35	307
2019 May	317	47	364
2019 April	267	24	291
2019 March	242	289	531
2019 February	224	180	404
2019 January	224	2	226
2018 December	292	16	308
2018 November	314	17	331
2018 October	455	28	483
2018 September	213	14	227
2018 August	127	22	149
2018 July	112	13	125
2018 June	101	17	118
2018 May	100	18	118
2018 April	81	9	90
2018 March	92	17	109
2018 February	46	7	53
2018 January	52	5	57
2017 December	56	18	74
2017 November	68	15	83
2017 October	84	12	96
2017 September	55	17	72
2017 August	82	20	102
2017 July	84	11	95
2017 June	125	21	146
2017 May	158	34	192
2017 April	58	26	84
2017 March	96	12	108
2017 February	310	5	315
2017 January	94	8	102
2016 December	187	35	222
2016 November	249	33	282
2016 October	262	25	287
2016 September	255	70	325
2016 August	176	66	242
2016 July	108	67	175
2016 May	6	0	6
2016 April	338	7	345
2016 March	481	100	581
2016 February	401	74	475
2016 January	403	73	476
2015 December	418	55	473
2015 November	403	88	491
2015 October	482	92	574
2015 September	403	63	466
2015 August	297	69	366
2015 July	392	64	456
2015 June	288	43	331
2015 May	448	51	499
2015 April	383	63	446
2015 March	295	19	314
2015 February	337	23	360
2015 January	306	21	327
2014 December	308	30	338
2014 November	219	35	254
2014 October	184	37	221
2014 September	104	19	123
2014 August	66	31	97
2014 July	7	3	10

Show all

Indexed in:

Follow us:

Statistics

Indexed in:

Follow us:

Statistics

Subscribe to our newsletter