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Maturity-onset diabetes of the young: From a molecular basis perspective toward the clinical phenotype and proper management
Maturity onset diabetes of the young: de la base molecular al fenotipo clínico y el manejo adecuado
Sofia Castro Oliveiraa,b,f,
Corresponding author
sofiacastro.oliveira@gmail.com

Corresponding author.
, João Sérgio Nevesa,b,f, Antonio Pérezc,d,e, Davide Carvalhoa,b,f
a Department of Endocrinology, Diabetes and Metabolism, Centro Hospitalar Universitário de São João, Porto, Portugal
b Faculty of Medicine of the Universidade do Porto, Porto, Portugal
c Department of Endocrinology and Nutrition, Hospital Santa Creu i Sant Pau, Barcelona, Spain
d Department of Medicine, Universitat Autònoma de Barcelona, Bellaterra, Spain
e CIBER de Diabetes y Enfermidades Metabólicas Asociadas (CIBERDEM), Madrid, Spain
f Instituto de Investigação e Inovação em Saúde, Universidade do Porto, Porto, Portugal
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="sec0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0025">Introduction</span><p id="par0005" class="elsevierStylePara elsevierViewall">Maturity-onset diabetes of the young &#40;MODY&#41; is a monogenic form of diabetes that comprises a heterogeneous group of disorders characterized by primary defect in pancreatic &#946;-cell function&#44; early onset &#40;classically presenting before the age of 25&#41; and autosomal dominant inheritance&#44; with absence of autoimmunity or&#44; for most of the cases&#44; ketosis&#46;<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">1&#44;2</span></a> Other monogenic forms of diabetes comprises neonatal diabetes&#44; syndromic forms and mitochondrial diabetes &#40;maternally inherited diabetes and deafness&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0360"><span class="elsevierStyleSup">3</span></a> Commonly misdiagnosed as Type 1 Diabetes Mellitus &#40;T1DM&#41; or Type 2 Diabetes Mellitus &#40;T2DM&#41;&#44; MODY has an estimated prevalence of 1&#8211;5&#37; in the diabetic population&#44; thought frequently undervalued&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">4&#44;5</span></a></p><p id="par0010" class="elsevierStylePara elsevierViewall">The molecular basis of MODY was recognized a couple decades ago&#44; since genetic mutations result in diabetes primarily through their effects on &#946;-cell dysfunction&#46; Moreover&#44; the clinical features of patients with MODY are currently known to be heterogeneous&#44; depending on the genetic etiology&#46;<a class="elsevierStyleCrossRefs" href="#bib0375"><span class="elsevierStyleSup">6&#44;7</span></a></p><p id="par0015" class="elsevierStylePara elsevierViewall">In fact&#44; 14 MODY subtypes has been described so far&#44; referred from 1 to 14&#44; according to the order of the discovery&#44; with mutations in 14 different genes &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#44; <a class="elsevierStyleCrossRef" href="#fig0005">Fig&#46; 1</a>&#41;&#46; Several of these genes encodes for transcription factors&#44; namely&#58; <span class="elsevierStyleItalic">hepatocyte nuclear factor</span> &#40;HNF&#41; 4&#945; &#40;related to MODY 1&#41;&#44; HNF-1&#945; &#40;related to MODY 3&#41;&#44; <span class="elsevierStyleItalic">insulin promoter factor 1</span> &#40;IPF-1&#41; &#40;related to MODY 4&#41;&#44; HNF-1&#946; &#40;related to MODY 5&#41;&#44; <span class="elsevierStyleItalic">neurogenic differentiation factor 1</span> &#40;NeuroD1&#41;&#44; also known as <span class="elsevierStyleItalic">&#946;-cell E-box transactivator 2</span> &#40;BETA2&#41; &#40;related to MODY 6&#41;&#44; <span class="elsevierStyleItalic">Kruppel-like factor 11</span> &#40;KLF11&#41; &#40;related to MODY 7&#41; and <span class="elsevierStyleItalic">paired box gene 4</span> &#40;PAX 4&#41; &#40;related to MODY 9&#41;&#46; With regard to the others&#44; glucokinase &#40;<span class="elsevierStyleItalic">GCK</span>&#41; gene encodes GCK enzyme &#40;related to MODY 2&#41;&#46; Insulin &#40;<span class="elsevierStyleItalic">INS</span>&#41; gene encodes for proinsulin precursor of insulin &#40;related to MODY 8&#41;&#46; Carboxyl-ester lipase &#40;<span class="elsevierStyleItalic">CEL</span>&#41; gene encodes CEL lipase enzyme &#40;related to MODY 10&#41;&#46; B lymphoid tyrosine kinase &#40;<span class="elsevierStyleItalic">BLK</span>&#41; gene encodes BLK protein &#40;related to MODY 11&#41;&#46; ATP-binding cassette transporter sub-family C member 8 &#40;<span class="elsevierStyleItalic">ABCC8</span>&#41; gene encodes ABCC8 protein &#40;related to MODY 12&#41;&#46; Potassium voltage-gated channel subfamily J member 11 &#40;<span class="elsevierStyleItalic">KCNJ11</span>&#41; gene encodes human BIR &#40;&#946;-cell inward rectifier or Kir6&#46;20&#41; &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41; &#40;related to MODY 13&#41;&#46; Finally&#44; Adaptor Protein Phosphotyrosine interacting with PH domain and Leucine zipper 1 <span class="elsevierStyleItalic">&#40;APPL1</span>&#41; gene &#40;related to MODY 14&#41; encodes APPL1 adapter protein&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">4&#44;8</span></a></p><elsevierMultimedia ident="tbl0005"></elsevierMultimedia><elsevierMultimedia ident="fig0005"></elsevierMultimedia><elsevierMultimedia ident="fig0010"></elsevierMultimedia><p id="par0020" class="elsevierStylePara elsevierViewall">Among these&#44; the most common MODY subtypes are MODY 3 and MODY 2&#46; MODY 1&#44; 5&#44; and 4 are rare&#44; whereas MODY 6&#8211;14 comprises a group of very rare forms of MODY&#46;<a class="elsevierStyleCrossRefs" href="#bib0370"><span class="elsevierStyleSup">5&#44;8</span></a></p><p id="par0025" class="elsevierStylePara elsevierViewall">MODY&#39;s early diagnosis still remains a challenge for physicians&#44; with important future implications&#44; since it will allow treatment optimization&#44; prognosis definition and genetic counseling of family members&#46;<a class="elsevierStyleCrossRefs" href="#bib0350"><span class="elsevierStyleSup">1&#44;7</span></a></p><p id="par0030" class="elsevierStylePara elsevierViewall">In this sense&#44; this review intends to be an update of the state of art of all currently known MODY&#39;s subtypes and the way of dealing with&#44; also seeking to disclose MODY&#39;s future management based on the latest research on this field&#46;</p></span><span id="sec0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0030">Gene mutations involved in the different MODY&#39;s forms&#44; the respective phenotype outcomes and management</span><p id="par0035" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">HNF-1&#945;</span> and <span class="elsevierStyleItalic">GCK</span> products represents the most common forms of MODY phenotypes &#40;30&#8211;65&#37; and 30&#8211;50&#37;&#44; respectively&#41;&#44; followed by <span class="elsevierStyleItalic">HNF-4&#945;</span> &#40;5&#8211;10&#37;&#41; and <span class="elsevierStyleItalic">HNF-1&#946;</span> &#40;&#60;5&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">8</span></a> The remaining genetic subtypes&#44; being rarer causes of MODY &#40;&#60;1&#37;&#41;&#44; have limited data available with few published literature&#46;<a class="elsevierStyleCrossRef" href="#bib0385"><span class="elsevierStyleSup">8</span></a></p><span id="sec0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0035">HNF-1&#945; and HNF-4&#945; &#40;MODY 3 and MODY 1&#41;</span><p id="par0040" class="elsevierStylePara elsevierViewall">The hepatic transcription factors HNF-1&#945; and HNF-4&#945; are responsible for the gene&#39;s regulation in the liver&#44; pancreatic islet cells&#44; kidneys&#44; and genital tissues&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">9&#8211;11</span></a> Mutations in the genes encoding these transcription factors may account for some MODY subtypes&#44; such as MODY 3 and 1&#44; respectively&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">9&#8211;11</span></a></p><p id="par0045" class="elsevierStylePara elsevierViewall">In fact&#44; in pancreatic &#946;-cells&#44; these transcription factors regulate the expression of the <span class="elsevierStyleItalic">INS</span> gene&#44; as well as the expression of genes encoding proteins involved in the transport and metabolism of glucose&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">9&#44;10&#44;12</span></a> In the liver&#44; these proteins regulate lipoprotein biosynthesis&#46;<a class="elsevierStyleCrossRefs" href="#bib0390"><span class="elsevierStyleSup">9&#44;10</span></a> The expression of HNF-1&#945; is partially regulated by HNF-4&#945;&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">11&#44;13</span></a></p><p id="par0050" class="elsevierStylePara elsevierViewall">The pathophysiological mechanisms of MODY related with mutations in the <span class="elsevierStyleItalic">HNF-1&#945;</span> &#40;MODY 3&#41; and <span class="elsevierStyleItalic">HNF-4&#945;</span> &#40;MODY 1&#41; genes are very similar&#44; since <span class="elsevierStyleItalic">HNF-1&#945;</span> expression is regulated by <span class="elsevierStyleItalic">HNF-4&#945;</span>&#46;<a class="elsevierStyleCrossRefs" href="#bib0400"><span class="elsevierStyleSup">11&#44;13</span></a></p><p id="par0055" class="elsevierStylePara elsevierViewall">Fasting hyperglycemia is relatively mild in these patients&#44; albeit they have significantly higher glycemic levels 2<span class="elsevierStyleHsp" style=""></span>h after oral glucose overload compared to those with mutated <span class="elsevierStyleItalic">GCK</span>&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">12&#44;14</span></a> In MODY 3 and MODY 1 hyperglycemia tends to increase over time and&#44; thus&#44; for most patients&#44; pharmacological treatment with oral antidiabetic drugs &#40;OADs&#41; or insulin will be required &#40;30&#8211;40&#37; demands insulin&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">14&#44;15</span></a> Evidence has shown that glucose-induced insulin secretion declines by 1&#8211;4&#37; per year in patients with MODY 3&#46;<a class="elsevierStyleCrossRefs" href="#bib0420"><span class="elsevierStyleSup">15&#44;16</span></a> In addition&#44; along with transient neonatal hyperinsulinemic hypoglycemia&#44; macrosomia&#44; and gestational diabetes&#44; are also common features of these MODY subtypes&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">14&#44;17</span></a></p><p id="par0060" class="elsevierStylePara elsevierViewall">These patients may have the full spectrum of diabetes complications&#46; In fact&#44; microvascular complications&#44; particularly retinopathy and nephropathy&#44; are as frequent as in T1DM or T2DM<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">14&#44;16</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><p id="par0065" class="elsevierStylePara elsevierViewall">In addition to the effects in &#946;-cells&#44; since <span class="elsevierStyleItalic">HNF-1&#945;</span> and <span class="elsevierStyleItalic">HNF-4&#945;</span> are also expressed in other organs&#44; these subjects present extrapancreatic manifestations&#44; affecting renal and hepatic functions&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">12&#44;18</span></a> In fact&#44; reduced glucose renal reabsorption &#40;<span class="elsevierStyleItalic">i&#46;e&#46;</span>&#44; a low renal threshold for glucose&#41; and glycosuria represents a MODY 3 hallmark&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">12&#44;19</span></a> On the other hand&#44; HNF-4&#945; deficiency is related with a reduction in triglyceride concentration&#44; as well as in serum levels of apolipoproteins AI&#44; AII&#44; CIII&#44; and lipoprotein Lp&#40;a&#41;<a class="elsevierStyleCrossRef" href="#bib0445"><span class="elsevierStyleSup">20</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><p id="par0070" class="elsevierStylePara elsevierViewall">In regard to treatment&#44; an important distinctive feature of <span class="elsevierStyleItalic">HNF-1&#945;</span> mutations is the particularly sensitivity to the hypoglycemic effects of sulfonylureas&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">12&#44;21</span></a> In a randomized cross-over study comparing individuals diagnosed with MODY 3 with those with T2DM&#44; a <span class="elsevierStyleItalic">4-fold</span> increased response to <span class="elsevierStyleItalic">gliclazide</span> was found for MODY 3 subjects&#44; whereas the response to metformin was similar in both groups&#46;<a class="elsevierStyleCrossRef" href="#bib0450"><span class="elsevierStyleSup">21</span></a><span class="elsevierStyleItalic">Nateglinide</span> has also been used in these patients&#44; suggesting that prandial secretagogues may be a useful alternative&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">16&#44;22</span></a> Although glycemic control could be sustained for several years&#44; most patients will eventually move toward insulin treatment due to a progressive &#946;-cell dysfunction&#46;<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">16</span></a></p><p id="par0075" class="elsevierStylePara elsevierViewall">Similarly&#44; a low dose of sulfonylureas &#40;12&#46;5&#37; or less of the maximum authorized dose&#41; seems to be an effective treatment for patients with <span class="elsevierStyleItalic">HNF-4&#945;</span> mutations&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">14</span></a></p></span><span id="sec0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0040">GCK &#40;MODY 2&#41;</span><p id="par0080" class="elsevierStylePara elsevierViewall">GCK enzyme is expressed&#44; at high concentrations&#44; in pancreatic and hepatic cells&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">18</span></a> It catalyses the phosphate transfer from ATP to glucose&#44; generating glucose-6-phosphate&#44; whose metabolism&#44; in turn&#44; stimulates the secretion of insulin by &#946;-cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">18&#44;23</span></a> Therefore&#44; GCK acts as a &#8220;glucose sensor&#8221; in &#946;-cells&#46; Moreover&#44; in the liver&#44; GCK plays a key role in the glucose hepatic storage as glycogen&#44; particularly in the postprandial state&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">16&#44;18</span></a> Heterozygous inactivating mutations in the <span class="elsevierStyleItalic">GCK</span> gene leads to a partial deficiency of this enzyme&#44; which is responsible for MODY 2&#59; homozygous inactivating mutations induce the complete <span class="elsevierStyleItalic">GCK</span> deficiency and consequently&#44; neonatal diabetes mellitus&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">4&#44;23</span></a></p><p id="par0085" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">GCK</span>-related MODY &#40;MODY 2&#41; is a common form&#44; especially in children and women with history of gestational diabetes&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">12&#44;16</span></a> In MODY 2&#44; hyperglycemia is mild&#44; non-progressive&#44; and asymptomatic at the time of diagnosis&#44; not associated with vascular complications common in other types of diabetes&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">7&#44;24</span></a> Less than 50&#37; of genetic carriers will develop diabetes&#44; whereas nearly 50&#37; of women may develop gestational diabetes&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">18</span></a> Noteworthy&#44; in MODY 2 families&#44; birth weight of newborn infants relies on both fetal and maternal mutation status&#46; In the absence of GCK mutation in the baby&#44; he may be at risk for macrosomia and increased birth weight in approximately 500<span class="elsevierStyleHsp" style=""></span>g&#44; as a result of the exposure to maternal hyperglycemia&#46; When the mutation is inherited from the mother&#44; baby has similar homeostatic glucose set points and&#44; thus&#44; normal birth weight&#46; On the other hand&#44; if the mutation is inherited from the father&#44; insulin secretion in the baby is reduced and birth weight is decreased in about 500<span class="elsevierStyleHsp" style=""></span>g<a class="elsevierStyleCrossRef" href="#bib0425"><span class="elsevierStyleSup">16</span></a> &#40;<a class="elsevierStyleCrossRef" href="#tbl0005">Table 1</a>&#41;&#46;</p><p id="par0090" class="elsevierStylePara elsevierViewall">The general consensus has pointed out that for most patients with MODY 2 pharmacological treatment will not be necessary&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">12&#44;14</span></a> Exceptionally&#44; some subjects will demand insulin therapy&#44; namely in cases of severe hyperglycemia &#40;&#8804;2&#37; of MODY 2&#41; and pregnant women&#44; in which insulin treatment could be necessary in order to prevent excessive fetal growth&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">12&#44;18</span></a></p></span><span id="sec0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0045">HNF-1&#946; &#40;MODY 5&#41;</span><p id="par0095" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">HNF-1&#946;</span> gene belongs to the homeodomain-containing family of transcription factors&#44; being involved in embryonic development of several organs&#44; including kidneys&#44; urinary tract&#44; liver&#44; and pancreas&#46;<a class="elsevierStyleCrossRef" href="#bib0470"><span class="elsevierStyleSup">25</span></a> Mutations in this gene may account for another MODY subtype&#44; designated MODY 5&#46;<a class="elsevierStyleCrossRefs" href="#bib0435"><span class="elsevierStyleSup">18&#44;26</span></a> Its plausible that the affected subjects may develop renal disease&#44; characterized by renal cysts&#44; renal dysplasia&#44; renal malformations&#44; or hypoplastic glomerulocystic kidney disease&#46; In fact&#44; <span class="elsevierStyleItalic">HNF-1&#946;</span> mutation is specifically associated with non-diabetic renal disease&#44; with renal function ranging from mild to terminal renal insufficiency&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">16&#44;27</span></a> Pancreatic atrophy&#44; abnormalities of the female genital tract and abnormal liver function among affected individuals can also be observed&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">14&#44;25</span></a> Birth weight is reduced by nearly 900<span class="elsevierStyleHsp" style=""></span>g due to a decreased insulin secretion in uterus&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">4&#44;7</span></a> About a half of MODY 5 subjects present diabetes at youth&#44; as those with MODY 3&#46;<a class="elsevierStyleCrossRef" href="#bib0415"><span class="elsevierStyleSup">14</span></a> However&#44; unlike the latter&#44; <span class="elsevierStyleItalic">HNF-1&#946;</span> mutations are related with insulin resistance and hyperuricemia&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">16&#44;28</span></a></p><p id="par0100" class="elsevierStylePara elsevierViewall">Thereby&#44; the low insulin sensitivity of MODY 5 patients suggests an insulin sensitizer&#44; such as metformin or pioglitazone&#44; as the oral drug of choice&#46;<a class="elsevierStyleCrossRef" href="#bib0485"><span class="elsevierStyleSup">28</span></a> Actually&#44; these subjects do not respond particularly well to sulfonylureas&#44; and usually require early insulin therapy&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">7&#44;24</span></a></p></span><span id="sec0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0050">IPF-1 &#40;MODY 4&#41;</span><p id="par0105" class="elsevierStylePara elsevierViewall">IPF-1 is a pancreatic homeodomain transcription factor &#40;also known as IDX-1&#44; STF-1 and PDX-1&#41; that regulates both early pancreatic development and the expression of key endocrine &#946;-cell-specific genes&#44; most notably insulin&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">29</span></a> Targeted disruption of the <span class="elsevierStyleItalic">IPF-1</span> gene in mice results in pancreatic agenesis&#46; In a human subject with pancreatic agenesis&#44; this phenotype was attributable to homozygosity for an inactivating mutation of <span class="elsevierStyleItalic">IPF-1</span> gene&#46; Heterozygous carriers of the mutation develop MODY 4&#46;<a class="elsevierStyleCrossRef" href="#bib0490"><span class="elsevierStyleSup">29</span></a></p><p id="par0110" class="elsevierStylePara elsevierViewall">The current insights of <span class="elsevierStyleItalic">IPF-1</span>-related MODY &#40;MODY 4&#41; are mainly based on studies in a few families&#44; including a family with MODY 2 and MODY 4 combined mutations&#46;<a class="elsevierStyleCrossRefs" href="#bib0490"><span class="elsevierStyleSup">29&#8211;32</span></a> Molecular studies in a child with neonatal diabetes and exocrine pancreatic insufficiency &#8211; as a result of congenital agenesis of the pancreas &#8211; revealed the presence of the homozygous form of the <span class="elsevierStyleItalic">IPF-1</span> mutation&#59; the parents were carriers of the heterozygous form of this mutation&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">33</span></a> The whole family evaluation had revealed a high prevalence of a mild form of diabetes&#44; with autosomal dominant transmission&#44; along with the heterozygous mutation in the <span class="elsevierStyleItalic">IPF-1</span>&#46;<a class="elsevierStyleCrossRef" href="#bib0510"><span class="elsevierStyleSup">33</span></a> For the carriers of this mutation&#44; the onset of diabetes may occur at more advanced ages &#40;around the age of 35&#41;&#44; compared to other MODY subtypes&#44; and can be treated with diet&#44; OAD and&#47;or possibly insulin&#44; for the most severe cases&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">7&#44;33</span></a> In an Italian family with Pro to Thr substitution &#40;P33T&#41; in the IPF1 transactivation domain the clinical phenotype goes from gestational diabetes&#44; MODY4 to T2DM&#46;<a class="elsevierStyleCrossRef" href="#bib0500"><span class="elsevierStyleSup">31</span></a></p></span><span id="sec0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0055">NeuroD1 &#40;MODY 6&#41;</span><p id="par0115" class="elsevierStylePara elsevierViewall">The transcription factor NeuroD1 &#40;also known as BETA2&#41; was isolated based on its ability to activate the transcription of the <span class="elsevierStyleItalic">INS</span> gene&#44; being fundamental for the normal development of pancreatic islets&#46;<a class="elsevierStyleCrossRef" href="#bib0515"><span class="elsevierStyleSup">34</span></a> Mutations in NeuroD1 encoding genes may be responsible for another MODY subtype&#44; designated MODY 6&#46;<a class="elsevierStyleCrossRef" href="#bib0435"><span class="elsevierStyleSup">18</span></a></p><p id="par0120" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">NeuroD1</span>-related MODY is characterized by permanent neonatal diabetes and a consistent pattern of neurological abnormalities including cerebellar hypoplasia&#44; learning difficulties&#44; sensorineural deafness&#44; and visual impairment&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">16&#44;35&#44;36</span></a> This syndrome highlights the key role of <span class="elsevierStyleItalic">NeuroD1</span> in both the development of the endocrine pancreas and the central nervous system in humans&#46;<a class="elsevierStyleCrossRef" href="#bib0525"><span class="elsevierStyleSup">36</span></a> The optimal therapeutic approach is yet to be disclosed&#44; since the related literature is scarce though it suggests OAD or insulin requirement&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">7&#44;35</span></a></p></span><span id="sec0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0060">KLF11 &#40;MODY 7&#41;</span><p id="par0125" class="elsevierStylePara elsevierViewall">KLF11 is a transcription factor present in pancreatic &#946;-cells that acts as a negative regulator of exocrine cell growth&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">37</span></a> KLF11 also plays a key role as a glucose-induced regulator of <span class="elsevierStyleItalic">INS</span> gene&#44; through binding to insulin promoter&#44; as other MODY subtypes already mentioned&#46;<a class="elsevierStyleCrossRef" href="#bib0535"><span class="elsevierStyleSup">38</span></a> In addition&#44; increased repression of the catalase 1 promoter has been reported&#44; suggesting a role in the clearance of free radicals that can turn these cells more susceptible to oxidative stress&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">4&#44;37</span></a><span class="elsevierStyleItalic">KLF11</span>-related MODY is often associated with pancreatic malignancy&#46;<a class="elsevierStyleCrossRef" href="#bib0530"><span class="elsevierStyleSup">37</span></a></p></span><span id="sec0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0065">CEL &#40;MODY 8&#41;</span><p id="par0130" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">CEL</span> gene encodes CEL enzyme involved in digesting milk and hydrolyzing dietary esters in duodenum and is also responsible for the hydration and absorption of cholesterol and liposoluble molecules&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">39</span></a> Current literature supports the involvement of CEL&#44; also known as bile salt-dependent lipase &#40;BSDL&#41;&#44; in the pathophysiology of these pancreatic diseases&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">40</span></a> This enzyme is normally secreted by the exocrine pancreas and is diverted within the intestinal lumen to participate in the hydrolysis of dietary lipids&#46; CEL is not transcribed into &#946;-cells&#44; being mainly expressed in pancreatic acinar tissues and lactating mammary glands&#46;<a class="elsevierStyleCrossRef" href="#bib0540"><span class="elsevierStyleSup">39</span></a> Despite the underlying pathophysiological mechanisms are yet to be fully understood&#44; mutations in this gene are responsible for an exocrine and endocrine pancreatic dysfunction associated with another MODY subtype&#44; MODY 8&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">4&#44;39&#44;41</span></a></p><p id="par0135" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">CEL</span>-related MODY is associated with pancreatic atrophy&#44; fibrosis and lipomatosis together with exocrine insufficiency and later endocrine dysfunction and diabetes&#46; Fat infiltration is an early event in non-diabetic carriers of mutations in the variable number of tandem repeat &#40;VNTR&#41; region of CEL&#44; with signs of exocrine dysfunction that meet the criteria for chronic pancreatitis&#46;<a class="elsevierStyleCrossRefs" href="#bib0545"><span class="elsevierStyleSup">40&#44;41</span></a> Dyslipidemia is associated with an inflammatory status in patients with diabetes&#46; It is known that branched fatty esters of hydroxyl fatty acids &#40;FAHFAs&#41; present protective effects against diabetes&#44; with anti-inflammatory activities&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">42</span></a> A recent study demonstrates that FAHFAs are the preferred substrates for CEL&#46;<a class="elsevierStyleCrossRef" href="#bib0555"><span class="elsevierStyleSup">42</span></a> Any perturbation in the BSDL variant homeostasis&#44; associated with different enzymatic properties&#44; leading to its retention within the cell&#44; could induce active degradation of these protective endogenous FAHFAs&#46; Suppression of the anti-inflammatory activity of FAHFAs upon BSDL hydrolysis may cause diabetes&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">40</span></a> Overall&#44; these data suggested that deletion in VNTR&#44; such as c&#46;1686delT&#44; leads to modification of the CEL specificity&#46; Therefore&#44; it can be hypothesized that any BSDL&#47;CEL variant with VNTR mutations may have different specificity from that of the non-mutated enzyme&#46;<a class="elsevierStyleCrossRef" href="#bib0545"><span class="elsevierStyleSup">40</span></a></p></span><span id="sec0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0070">PAX4 &#40;MODY 9&#41;</span><p id="par0140" class="elsevierStylePara elsevierViewall">PAX 4 is a transcription factor member of PAX family that regulates fetal development&#44; cancer growth and also represses the promoter activity of insulin and glucagon&#46;<a class="elsevierStyleCrossRef" href="#bib0560"><span class="elsevierStyleSup">43</span></a> PAX4 is required for the regeneration of &#946;-cells in adults and its mutation blocks or inhibits &#946;-cell growth and proliferation&#46;<a class="elsevierStyleCrossRefs" href="#bib0560"><span class="elsevierStyleSup">43&#44;44</span></a> In this sense&#44; mutations in this gene leads to impaired glucose-dependent insulin secretion and were reported as the cause of a monogenetic form of diabetes&#44; designated MODY 9&#46;<a class="elsevierStyleCrossRefs" href="#bib0565"><span class="elsevierStyleSup">44&#44;45</span></a> Some PAX4 mutations induced increased susceptibility of &#946;-cell to apoptosis upon high glucose exposure&#46; <span class="elsevierStyleItalic">PAX4</span>-related MODY 9 has been linked with ketosis-prone diabetes&#46;<a class="elsevierStyleCrossRef" href="#bib0575"><span class="elsevierStyleSup">46</span></a></p></span><span id="sec0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0075">INS &#40;MODY 10&#41;</span><p id="par0145" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">INS</span> gene encodes the proinsulin precursor of insulin molecule&#46;<a class="elsevierStyleCrossRefs" href="#bib0580"><span class="elsevierStyleSup">47&#44;48</span></a> It has been reported that a mutation in this gene cause a defect in the <span class="elsevierStyleItalic">nuclear factor kappa-light-chain-enhancer of activated &#946;-cells</span> &#40;NF-&#954;B&#41; transcription factor&#44; leading to reduced structural stability of insulin molecule associated with a very rare form of MODY subtype&#44; designated as MODY 10&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">4&#44;49</span></a><span class="elsevierStyleItalic">INS</span>-related MODY &#40;MODY 10&#41; is also linked with neonatal diabetes&#46;<a class="elsevierStyleCrossRef" href="#bib0585"><span class="elsevierStyleSup">48</span></a></p></span><span id="sec0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0080">BLK &#40;MODY 11&#41;</span><p id="par0150" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">BLK-B</span> gene&#44; expressed in pancreatic &#946;-cells&#44; encodes a nonreceptor tyrosine kinase of the <span class="elsevierStyleItalic">src</span> family of proto-oncogenes and plays a major role in thymopoiesis in immature T cells&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">4&#44;50</span></a> Moreover&#44; it promotes the glucose-dependent insulin synthesis and secretion through the upregulation of PDX-1 and NKx-6 transcription factors&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">50</span></a> The <span class="elsevierStyleItalic">BLK</span> gene mutation mainly affects MIN6 &#946;-cells &#40;a highly differentiated &#946;-cell line&#41; and&#44; therefore&#44; is responsible for another MODY subtype&#44; MODY 11&#46;<a class="elsevierStyleCrossRef" href="#bib0595"><span class="elsevierStyleSup">50</span></a></p><p id="par0155" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">BLK</span>-related MODY is linked with a higher prevalence of the obese phenotype compared with other MODY&#39;s individuals&#46;<a class="elsevierStyleCrossRef" href="#bib0600"><span class="elsevierStyleSup">51</span></a></p></span><span id="sec0065" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0085">ABCC8 &#40;MODY 12&#41;</span><p id="par0160" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">ABCC8</span> gene encodes the sulfonylurea receptor 1 &#40;SUR 1&#41; subunit of ATP-sensitive potassium &#40;K<span class="elsevierStyleInf">ATP</span>&#41; channel found across pancreatic &#946;-cells membrane&#44; being involved in the insulin secretion process<a class="elsevierStyleCrossRefs" href="#bib0605"><span class="elsevierStyleSup">52&#44;53</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Mutations in this gene results in sulfonylureas responsive MODY&#44; termed MODY 12&#44; which clinical features are similar to those of HNF-1&#945;&#47;4&#945; related MODY&#44; being associated with neonatal diabetes&#44; and can occur due to both activating or inactivating mutations of <span class="elsevierStyleItalic">ABCC8</span> gene&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">4&#44;52</span></a></p></span><span id="sec0070" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0090">KCNJ11 &#40;MODY 13&#41;</span><p id="par0165" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">KCNJ11</span> gene encodes Kir6&#46;20 subunit of the pancreatic &#946;-cells ATP-sensitive potassium &#40;K<span class="elsevierStyleInf">ATP</span>&#41; channel&#44; playing a role in structure modulation of this channel and&#44; thus&#44; in insulin secretion<a class="elsevierStyleCrossRef" href="#bib0615"><span class="elsevierStyleSup">54</span></a> &#40;<a class="elsevierStyleCrossRef" href="#fig0010">Fig&#46; 2</a>&#41;&#46; Therefore&#44; <span class="elsevierStyleItalic">KCNJ11</span> gene mutations&#44; responsible for another MODY subtype&#44; designated MODY 13&#44; leads to impaired fasting glucose or impaired glucose tolerance&#44; due to the disrupted subunit interaction&#46; Likewise <span class="elsevierStyleItalic">INS</span>-related MODY &#40;MODY 10&#41; and <span class="elsevierStyleItalic">ABCC8</span>-related MODY &#40;MODY 12&#41;&#44; MODY 13 is associated with neonatal diabetes being also sensitive to sulfonylurea therapy&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">4&#44;54</span></a></p></span><span id="sec0075" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0095">APPL1 &#40;MODY 14&#41;</span><p id="par0170" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">APPL1</span> gene is widely expressed in all insulin target tissues and organs including the liver&#44; adipose tissue&#44; skeletal muscle&#44; and pancreas&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">55</span></a> In pancreatic islets&#44; APPL1 adapter protein co-localizes with insulin&#44; indicating that is abundantly expressed in pancreatic &#946;-cells where it acts as a physiological regulator of insulin secretion&#44; binding to AKT2&#44; a key molecule in the insulin signaling pathway&#46; Mutations in <span class="elsevierStyleItalic">APPL1</span> gene can cause APPL1 loss-of-function leading to MODY 14 phenotype&#46;<a class="elsevierStyleCrossRef" href="#bib0620"><span class="elsevierStyleSup">55</span></a> In addition&#44; evidences from a zebrafish-based model have also linked <span class="elsevierStyleItalic">APPL1</span> overexpression with dysmorphic phenotypes and delay in the development&#46;<a class="elsevierStyleCrossRef" href="#bib0625"><span class="elsevierStyleSup">56</span></a></p></span><span id="sec0080" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0100">MODY-x</span><p id="par0175" class="elsevierStylePara elsevierViewall">A significant percentage of patients with clinical characteristics of MODY&#44; has an unknown causative gene &#40;MODY-x&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">16&#44;57</span></a> The identification of additional genes related to MODY will clarify the molecular basis of diabetes in these patients&#46; Frayling et al&#46; conducted a multicenter study with several researchers from Oxford&#44; Lille and Malmo&#44; stressing the need to continue the search for new mutations in families with MODY-x&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">58</span></a> In this study&#44; 3 loci with Heterogeneity Logarithm of Odds &#40;HLOD&#41; scores &#62;1&#46;0 on chromosomes 3&#44; 16 and 20 were identified&#44; albeit the required level of significance of 3&#46;3 has not been achieved&#46; The identification of these 3 loci confirms the vast genetic heterogeneity in families with MODY-x&#46;<a class="elsevierStyleCrossRef" href="#bib0635"><span class="elsevierStyleSup">58</span></a></p><p id="par0180" class="elsevierStylePara elsevierViewall">Further research will be needed in order to get a deeper knowledge on MODY&#39;s pathophysiological mechanisms and&#44; therefore&#44; allow an individualized approach accordingly to each subtype&#44; with the subsequent improvement on patient outcomes&#46;<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">4&#44;7</span></a></p></span></span><span id="sec0085" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0105">Diagnosis</span><p id="par0185" class="elsevierStylePara elsevierViewall">First and foremost&#44; the diagnosis of MODY requires a high index of suspicion&#46;<a class="elsevierStyleCrossRefs" href="#bib0640"><span class="elsevierStyleSup">59&#44;60</span></a> In fact&#44; MODY&#39;s diagnosis still remains a challenge&#44; since this heterogeneous group of monogenic disorders comprises a large clinical spectrum and it usually overlaps with other types of diabetes&#46; Consequently&#44; many patients remain undiagnosed&#46; Although MODY affects only a small part of diabetic subjects and its diagnosis is rare&#44; it has important implications for the prognosis and treatment of patients&#44; as well as for family members genetic counseling&#46;<a class="elsevierStyleCrossRef" href="#bib0465"><span class="elsevierStyleSup">24</span></a></p><p id="par0190" class="elsevierStylePara elsevierViewall">The definitive diagnosis of MODY requires a molecular genetic study&#46; These genetic tests are performed by direct sequencing of MODY genes &#40;sensitivity &#62;99&#37;&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0465"><span class="elsevierStyleSup">24&#44;60</span></a> The standard approach includes sequential screening of the three most common MODY genes&#58; <span class="elsevierStyleItalic">HNF-1&#945;</span>&#44; <span class="elsevierStyleItalic">GCK</span>&#44; and <span class="elsevierStyleItalic">HNF-4&#945;</span>&#46;<a class="elsevierStyleCrossRefs" href="#bib0650"><span class="elsevierStyleSup">61&#44;62</span></a> However&#44; with the advent of next-generation sequencing &#40;NGS&#41; technology&#44; there has been a significant improvement in the speed and scalability of the genetic sequencing and an extended profile is also currently available&#46;<a class="elsevierStyleCrossRefs" href="#bib0640"><span class="elsevierStyleSup">59&#44;61</span></a></p><p id="par0195" class="elsevierStylePara elsevierViewall">After a strong clinical suspicion&#44; the genetic mutation diagnosis must be performed in order to accurately define MODY subtype and lead to the identification of other affected family members&#46; Furthermore&#44; the optimal treatment and risk for diabetes complications relies on the genetic defect&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">7&#44;59</span></a></p><p id="par0200" class="elsevierStylePara elsevierViewall">Although <span class="elsevierStyleItalic">de novo</span> mutations can arise&#44; cascade screening of family members is essential to ensure those with diabetes get the correct diagnostic label and those at risk of inheriting the mutation are tested for diabetes and&#47;or consider predictive genetic testing&#46;<a class="elsevierStyleCrossRefs" href="#bib0425"><span class="elsevierStyleSup">16&#44;59</span></a></p><p id="par0205" class="elsevierStylePara elsevierViewall">Indications for genetic testing for MODY includes the following major diagnosis criteria widely accepted<a class="elsevierStyleCrossRefs" href="#bib0365"><span class="elsevierStyleSup">4&#44;63</span></a>&#58;<ul class="elsevierStyleList" id="lis0005"><li class="elsevierStyleListItem" id="lsti0005"><span class="elsevierStyleLabel">-</span><p id="par0210" class="elsevierStylePara elsevierViewall">Hyperglycemia usually diagnosed before the age of 25 in at least 1 and ideally 2 family members&#59;</p></li><li class="elsevierStyleListItem" id="lsti0010"><span class="elsevierStyleLabel">-</span><p id="par0215" class="elsevierStylePara elsevierViewall">Autosomal dominant inheritance&#44; with a vertical transmission of diabetes through at least 3 generations&#44; and a similar phenotype shared by diabetic family members&#59;</p></li><li class="elsevierStyleListItem" id="lsti0015"><span class="elsevierStyleLabel">-</span><p id="par0220" class="elsevierStylePara elsevierViewall">Absence of insulin therapy at least 5 years after diagnosis or significant C-peptide levels even in a patient on insulin treatment&#59;</p></li><li class="elsevierStyleListItem" id="lsti0020"><span class="elsevierStyleLabel">-</span><p id="par0225" class="elsevierStylePara elsevierViewall">Insulin levels that are often in the normal range&#44; although inappropriately low for the degree of hyperglycemia&#44; suggesting a primary defect in &#946;-cell function&#59;</p></li><li class="elsevierStyleListItem" id="lsti0025"><span class="elsevierStyleLabel">-</span><p id="par0230" class="elsevierStylePara elsevierViewall">Overweight or obesity is rarely associated &#40;and is not required for the development of diabetes&#41;&#46;</p></li></ul></p><p id="par0235" class="elsevierStylePara elsevierViewall">Notwithstanding&#44; other remarkable MODY features encompasses&#58; mild diabetes on presentation without significant ketosis&#59; absence of pancreatic autoantibodies&#59; glycosuria inappropriately observed along with euglycemia or mild hyperglycemia&#44; in the absence of albuminuria and poorly controlled diabetes &#40;low renal threshold that results in glycosuria is a typical MODY 3 feature&#41;&#59; marked sensitivity to insulin secretagogues &#40;sulfonylureas&#41; in HNF-1&#945; and HNF-4&#945; subtypes&#59; as well as no typical features of TIDM or T2DM&#46;<a class="elsevierStyleCrossRefs" href="#bib0355"><span class="elsevierStyleSup">2&#44;4&#44;16</span></a></p><p id="par0240" class="elsevierStylePara elsevierViewall">In order to achieve a more cost-effective approach&#44; avoiding unnecessary genetic testing&#44; a prediction model was developed to discriminate MODY patients from T1DM and T2DM&#44; using logistic regression for that propose&#46;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">64</span></a> The model&#44; referred as <span class="elsevierStyleItalic">The MODY Probability Calculator</span>&#44; offers a more standardized approach to select individuals for genetic testing&#46; This online calculator &#40;developed by Beverley Shields&#44; University of Exeter&#59; available at&#58; <a href="https://www.diabetesgenes.org/mody-probability-calculator/"><span class="elsevierStyleUnderline">https&#58;&#47;&#47;www&#46;diabetesgenes&#46;org&#47;mody-probability-calculator&#47;</span></a>&#41;&#44; combines broad clinical information to predict the probability of testing positive for MODY and includes&#58; age at diagnosis&#44; body mass index&#44; HbA1c level&#44; therapy &#40;insulin or OADs&#41; and family history&#46; When matched with traditional criteria&#44; the prediction model improved the sensitivity and specificity for identifying MODY&#46; However&#44; this model was only validated in one European cohort of Caucasian individuals&#44; lacking&#44; therefore&#44; a more generalized validation to other ethnicities&#46;<a class="elsevierStyleCrossRef" href="#bib0665"><span class="elsevierStyleSup">64</span></a></p><span id="sec0090" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0110">Differential diagnosis</span><p id="par0245" class="elsevierStylePara elsevierViewall">In view of the high cost and limited availability of genetic testing&#44; substantial efforts have recently been made to identify a specific&#44; inexpensive and readily disposable non-genetic biomarker to discriminate between MODY and other types of diabetes&#46; Along with the clinical features&#44; it would aid in prioritizing patient for genetic testing &#40;<a class="elsevierStyleCrossRef" href="#tbl0010">Table 2</a>&#41;&#46;<a class="elsevierStyleCrossRefs" href="#bib0380"><span class="elsevierStyleSup">7&#44;59&#44;65</span></a></p><elsevierMultimedia ident="tbl0010"></elsevierMultimedia><p id="par0250" class="elsevierStylePara elsevierViewall">It has been documented that in adults with diabetes for more than 5 years&#44; the urinary C-peptide&#47;creatinine ratio is higher in MODY 3 or MODY 1 when compared to T1DM &#40;sensitivity 97&#37; and specificity 96&#37;&#41;&#46;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">66</span></a> Furthermore&#44; other biomarkers proposed for discrimination between MODY 3&#44; MODY 1 and T2DM include 1&#44;5-anhydroglucitol&#44; the complement factors C5 and C8&#44; apolipoprotein M and transthyretin&#44; although none of them have enough specificity or sensitivity to be clinically&#46;<a class="elsevierStyleCrossRef" href="#bib0675"><span class="elsevierStyleSup">66</span></a> So far&#44; one of the most promising biomarkers is <span class="elsevierStyleItalic">high-sensitivity</span> C-reactive protein &#40;<span class="elsevierStyleItalic">hs</span>-CRP&#41;&#44; which is significantly lower in MODY 3 than in TIDM&#44; T2DM&#44; MODY 2 and even in non-diabetic individuals&#46;<a class="elsevierStyleCrossRefs" href="#bib0680"><span class="elsevierStyleSup">67&#44;68</span></a></p><p id="par0255" class="elsevierStylePara elsevierViewall">In fact&#44; for most cases&#44; the onset of MODY arises in childhood or adolescence&#44; resembling T1DM&#46; However&#44; in these patients there is no complete lack of insulin and&#44; therefore&#44; insulin therapy will not be required&#44; at least at an early stage of the disease&#46; In some patients OADs or insulin therapy may be necessary&#44; as a rapid progression of hyperglycemia can occur&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">12&#44;16</span></a> The presence of autoantibodies for T1DM often precludes further testing for monogenic diabetes&#44; since it makes MODY very unlikely&#44; albeit positive autoantibodies in patients with monogenic diabetes has been reported&#46;<a class="elsevierStyleCrossRef" href="#bib0690"><span class="elsevierStyleSup">69</span></a> Thereby&#44; a biomarker screening such as the combination of C-peptide and antibody screening &#40;autoantibodies to GAD&#44; insulin&#44; the tyrosine phosphatases IA-2 and IA-2b&#44; and ZnT8&#41; should be performed prior to consideration of genetic testing for MODY&#46;<a class="elsevierStyleCrossRefs" href="#bib0405"><span class="elsevierStyleSup">12&#44;59</span></a> Actually&#44; recent population-based studies have pointed toward this biomarker screening as an easy and cost-effective approach capable to discriminate patients with MODY&#46;<a class="elsevierStyleCrossRef" href="#bib0670"><span class="elsevierStyleSup">65</span></a></p><p id="par0260" class="elsevierStylePara elsevierViewall">On the other hand&#44; it is more difficult to differentiate between MODY and T2DM&#46; The absence of insulin resistance features&#44; particularly in adolescents with presumed T2DM&#44; is suspicious for MODY&#44; though no biochemical tests that reliably differentiate between these two diseases are currently available&#46;<a class="elsevierStyleCrossRefs" href="#bib0415"><span class="elsevierStyleSup">14&#44;16</span></a> Usually&#44; MODY behaves in the same fashion as an adult T2DM but has some specific features in the glycemic control MODY&#46;</p></span></span><span id="sec0095" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0115">Conclusion</span><p id="par0265" class="elsevierStylePara elsevierViewall">MODY is a genetically and clinically heterogeneous group of disorders&#46; Its identification still remains a challenge for physicians&#44; being largely underdiagnosed&#44; though it has important implications for the individual and their families&#46;</p><p id="par0270" class="elsevierStylePara elsevierViewall">Recent advances on the genetic determinants and pathophysiology of MODY allowed a better understanding of its underlying molecular mechanisms and&#44; therefore&#44; have been very promising and insightful&#44; providing us several profitable approaches in this field&#46; Further studies will make possible to set up new therapeutic strategies&#44; with drugs able to prevent&#44; correct or at least delay the decline of pancreatic &#946;-cell function&#46; Moreover&#44; with the sustained increase of genomic and metabolomic development&#44; rapid screening tools for MODY mutations will become readily available and a self-directed assessment will afford for a more personalized treatment and&#44; ultimately&#44; for a better patient care&#46;</p></span><span id="sec0100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0120">Authors&#8217; contribution</span><p id="par0275" class="elsevierStylePara elsevierViewall">All the authors contributed equally to this work&#46;</p></span><span id="sec0105" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0125">Funding sources</span><p id="par0280" class="elsevierStylePara elsevierViewall">The authors have no funding to disclose related to this review&#46;</p></span><span id="sec0110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="sect0130">Conflict of interests</span><p id="par0285" class="elsevierStylePara elsevierViewall">The authors declare no conflict of interests&#46;</p></span></span>"
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        "resumen" => "<span id="abst0005" class="elsevierStyleSection elsevierViewall"><p id="spar0005" class="elsevierStyleSimplePara elsevierViewall">Maturity-onset diabetes of the young &#40;MODY&#41; comprises a heterogeneous group of monogenic disorders characterized by primary defect in pancreatic &#946;-cell function&#44; early onset and autosomal dominant inheritance&#44; accounting for about 1&#8211;5&#37; of all diabetes diagnoses&#46; Mutations in 14 genes are responsible for the majority of all MODY cases described so far&#46; The clinical phenotype relies on genetic defects&#44; with important implications in the optimal treatment and prognosis definition&#46; MODY&#39;s early diagnosis remains a challenge&#44; since this group of inherited disorders comprises a large clinical spectrum and it usually overlaps with other types of diabetes&#44; requiring a high index of suspicion even if the definitive statement demands a molecular genetic study&#46;</p><p id="spar0010" class="elsevierStyleSimplePara elsevierViewall">Recent advances on the genetic determinants and pathophysiology of MODY have allowed a better understanding of its underlying molecular mechanisms&#44; providing a proper genetic counseling and early diagnosis&#46; These new management insights will make possible to set up new therapeutic strategies&#44; with drugs able to prevent&#44; correct or at least delay the decline of pancreatic &#946;-cell function&#44; thus affording for a more personalized treatment and&#44; ultimately&#44; for a better patient care&#46;</p></span>"
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        "resumen" => "<span id="abst0010" class="elsevierStyleSection elsevierViewall"><p id="spar0015" class="elsevierStyleSimplePara elsevierViewall">La diabetes tipo MODY &#40;del ingl&#233;s&#44; <span class="elsevierStyleItalic">maturity onset diabetes of the young</span>&#41; comprende un grupo heterog&#233;neo de enfermedades monog&#233;nicas caracterizadas por un defecto primario de la funci&#243;n de las c&#233;lulas &#946;-pancre&#225;ticas&#44; con inicio precoz y herencia autos&#243;mica dominante&#44; que representa aproximadamente el 1-5&#37; de las diabetes diagnosticadas&#46; Las mutaciones descritas hasta la actualidad en 14 genes son responsables de la mayor&#237;a de los casos de la diabetes tipo MODY&#46; El fenotipo cl&#237;nico depende del defecto gen&#233;tico&#44; y su identificaci&#243;n es importante para definir el tratamiento y el pron&#243;stico&#46; El diagn&#243;stico temprano de la diabetes tipo MODY sigue siendo un reto&#44; puesto que abarca un largo espectro de manifestaciones que se solapan con las de otros tipos de diabetes&#44; exigiendo as&#237; un elevado grado de sospecha cl&#237;nica y el diagn&#243;stico definitivo necesita del estudio gen&#233;tico molecular&#46;</p><p id="spar0020" class="elsevierStyleSimplePara elsevierViewall">Los progresos recientes en el conocimiento de los determinantes gen&#233;ticos y de la fisiopatolog&#237;a de la diabetes tipo MODY han permitido una mejor comprensi&#243;n de los mecanismos moleculares subyacentes de estos procesos&#44; y han facilitado un adecuado asesoramiento gen&#233;tico y el diagn&#243;stico precoz&#46; Estos nuevos conocimientos el abordaje permitir&#225;n el desarrollo de nuevas estrategias terap&#233;uticas con f&#225;rmacos capaces de prevenir&#44; reparar o al menos retrasar el deterioro de la funci&#243;n de las c&#233;lulas &#946;-pancre&#225;ticas&#46; Todo ello posibilitar&#225; un tratamiento m&#225;s personalizado y&#44; en &#250;ltima instancia&#44; una mejor atenci&#243;n del paciente&#46;</p></span>"
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        "tipo" => "MULTIMEDIAFIGURA"
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        "mostrarDisplay" => false
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr1.jpeg"
            "Alto" => 1297
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            "Tamanyo" => 218906
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          "en" => "<p id="spar0025" class="elsevierStyleSimplePara elsevierViewall">&#946;-Cell transcription factor network&#46;</p>"
        ]
      ]
      1 => array:8 [
        "identificador" => "fig0010"
        "etiqueta" => "Figure 2"
        "tipo" => "MULTIMEDIAFIGURA"
        "mostrarFloat" => true
        "mostrarDisplay" => false
        "fuente" => "Adapted from Ref&#46; <a class="elsevierStyleCrossRef" href="#bib0610">53</a>&#46;"
        "figura" => array:1 [
          0 => array:4 [
            "imagen" => "gr2.jpeg"
            "Alto" => 1034
            "Ancho" => 1667
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          "en" => "<p id="spar0030" class="elsevierStyleSimplePara elsevierViewall">Sulfonylurea receptor &#40;SUR&#41; components&#58; 1 &#8211; SUR encoded by ABCC8 gene&#59; 2 &#8211; potassium voltage-gated channel&#59; Kir 6&#46;20 &#8211; encoded by subfamily J member 11 &#40;KCNJ11&#41; gene&#46;</p>"
        ]
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        "identificador" => "tbl0005"
        "etiqueta" => "Table 1"
        "tipo" => "MULTIMEDIATABLA"
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        "detalles" => array:1 [
          0 => array:3 [
            "identificador" => "at1"
            "detalle" => "Table "
            "rol" => "short"
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        "tabla" => array:2 [
          "leyenda" => "<p id="spar0040" class="elsevierStyleSimplePara elsevierViewall">MODY&#44; maturity-onset diabetes of the young&#59; OADs&#44; oral antidiabetic drugs&#59; OGTT&#44; oral glucose tolerance test&#59; Apo AI&#44; AII and CIII&#44; apolipoproteins AI&#44; AII and CIII&#59; Lp&#40;a&#41;&#44; lipoprotein Lp&#40;a&#41;&#59; TG&#44; triglycerides&#59; HNF&#44; hepatocyte nuclear factor&#59; GCK&#44; Glucokinase&#59; IPF-1&#44; insulin promoter factor-1&#59; NeuroD1&#44; neurogenic differentiation factor 1&#59; BETA2&#44; &#946;-cell E-box transactivator 2&#59; KLF11&#44; Kruppel-like factor 11&#59; CEL&#44; bile salt dependent lipase&#59; PAX 4&#44; paired box gene 4&#59; INS&#44; insulin&#59; BLK&#44; B lymphoid tyrosine kinase gene&#59; ABCC8&#44; ATP-binding cassette transporter sub-family C member 8 gene&#59; KCNJ11&#44; potassium voltage-gated channel subfamily J member 11 gene&#59; APPL1&#44; Adaptor Protein&#44; Phosphotyrosine interacting with PH domain and Leucine zipper 1&#46;</p>"
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            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MODY subtype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Gene&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Relative prevalence&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Pathophysiology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Clinical phenotype&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Frequency of microvascular complications&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Proper management&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">1&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">HNF-4&#945;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&#8211;10&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#946;-Cell dysfunction &#40;mainly insulin secretory defect&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Transient neonatal hyperinsulinemia and hypoglycemia with associated macrossomia&#59;Gestational diabetes&#59;Progressive insulin secretory defect&#59;Low serum levels of triglycerides&#44; Apo AI&#44; AII and CIII&#59;Marked sensitivity to sulfonylureas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Common&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sensitive to sulfonylureas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">2&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">GCK</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30&#8211;50&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#946;-Cell dysfunction &#40;glucose-sensing defect&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Stable&#44; mild fasting hyperglycemia throughout life&#59;Typically asymptomatic&#59; diagnosis often incidental&#59;Gestational diabetes&#59;Variation in birth weight&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diet and exercise&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">3&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">HNF-1&#945;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">30&#8211;65&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#946;-Cell dysfunction &#40;mainly insulin secretory defect&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Transient neonatal hyperinsulinemia and hypoglycemia for some&#59;OGTT frequently needed to make an early diagnosis&#59;Diminished renal threshold for glycosuria&#59;Progressive insulin secretory defect&#59;Marked sensitivity to sulfonylureas&#44; and fair results with nateglinide&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Common&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low-dose to sulfonylureas or meglitinides&#59; GLP-1 agonists also used&#59;Insulin may be required&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">4&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">IPF 1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;1&#37; &#40;rare&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#946;-Cell dysfunction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pancreatic agenesis &#40;homozygosis form&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diet&#59; OADs&#59; insulin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">5&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">HNF-1&#946;</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;5&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#946;-Cell dysfunction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Intrauterine growth restriction&#59;Renal abnormalities and insufficiency at young age&#59;Urogenital tract anomalies&#59;Diabetes often diagnosed later&#59;Liver test abnormalities&#59;Pancreatic atrophy or partial agenesis&#44; exocrine pancreatic dysfunction&#59;Hyperuricemia&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Common&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">A minority response to sulfonylureas&#59;Insulin is commonly required&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">6&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">Neuro D1 or BETA2</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;1&#37; &#40;very rare&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#946;-Cell dysfunction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pancreatic anomalies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diet&#59; OADs&#59; insulin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">7&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">KLF11</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;1&#37; &#40;very rare&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Decreased glucose sensitivity of &#946;-cells&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pancreatic malignancy&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">OADs&#59; insulin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">8&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">CEL</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;1&#37; &#40;very rare&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pancreatic endocrine and exocrine dysfunction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Pancreatic atrophy and exocrine pancreatic insufficiency&#59;Fibrosis and lipomatosis with posterior diabetes development&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">OADs&#59; insulin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">9&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">PAX 4</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;1&#37; &#40;very rare&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#946;-Cell dysfunction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Ketosis-prone diabetes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diet&#59; OADs&#59; insulin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">10&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">INS</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;1&#37; &#40;very rare&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#946;-Cell dysfunction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Neonatal diabetesPhenotype variability&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diet&#59; OADs&#59; insulin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">11&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">BLK</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;1&#37; &#40;very rare&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Insulin secretion defect&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Overweight&#47;obesity for some&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diet&#59; OADs&#59; insulin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">12&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">ABCC8</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;1&#37; &#40;very rare&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ATP-sensitive potassium channel dysfunction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Similar to <span class="elsevierStyleItalic">HNF-1&#945;</span> and <span class="elsevierStyleItalic">HNF-4&#945;</span> related MODY subtypes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Sulfonylureas&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">13&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">KCNJ11</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;1&#37; &#40;very rare&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">ATP-sensitive potassium channel dysfunction&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Similar to <span class="elsevierStyleItalic">HNF-1&#945;</span> and <span class="elsevierStyleItalic">HNF-4&#945;</span> related MODY subtypes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diet&#59; sulfonylureas&#59; insulin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">14&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t"><span class="elsevierStyleItalic">APPL1</span>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#60;1&#37; &#40;very rare&#41;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Insulin secretion defect&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Dysmorphic phenotype and delay in the development&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Unknown&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diet&#59; OADs&#59; insulin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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          "en" => "<p id="spar0035" class="elsevierStyleSimplePara elsevierViewall">The different MODY subtypes and their related molecular basis&#44; clinical features and proper management&#46;</p>"
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        "etiqueta" => "Table 2"
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        "tabla" => array:3 [
          "leyenda" => "<p id="spar0050" class="elsevierStyleSimplePara elsevierViewall">T1DM&#44; Type 1 Diabetes Mellitus&#59; T2DM&#44; Type 2 Diabetes Mellitus&#59; <span class="elsevierStyleItalic">hs</span>-CRP&#44; high sensitivity C-reactive protein&#46;</p>"
          "tablatextoimagen" => array:1 [
            0 => array:2 [
              "tabla" => array:1 [
                0 => """
                  <table border="0" frame="\n
                  \t\t\t\t\tvoid\n
                  \t\t\t\t" class=""><thead title="thead"><tr title="table-row"><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">Features&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">T1DM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">T2DM&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th><th class="td" title="\n
                  \t\t\t\t\ttable-head\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t" scope="col" style="border-bottom: 2px solid black">MODY&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t\t\t</th></tr></thead><tbody title="tbody"><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Disease onset&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SuddenUsually&#60;35 years old&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SlowUsually&#62;35 years old&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">SlowUsually&#60;25 years old&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Family history of diabetes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Minor relevance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Relevant&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Essential&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Etiology&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Polygenic<a class="elsevierStyleCrossRef" href="#tblfn0005"><span class="elsevierStyleSup">a</span></a> and immunologic&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Polygenic and environmental factors<a class="elsevierStyleCrossRef" href="#tblfn0010"><span class="elsevierStyleSup">b</span></a>&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Monogenic<a class="elsevierStyleCrossRef" href="#tblfn0015"><span class="elsevierStyleSup">c</span></a> with negligible environmental factors&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Insulin dependent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">No&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Diabetic ketoacidosis&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Common&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Obesity&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Generally absent&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Common&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Insulin resistance&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Common&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Beta-cell antibodies&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">&#62;90&#37;&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Negative&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Rare&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">C-peptide levels&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Low&#47;undetectable&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Normal&#47;high&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Normal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">hs-CRP&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Normal&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Mild chronic elevation&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Normal&#47;low&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Micro&#47;macrovascular complications&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Yes&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">From rare to common&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr><tr title="table-row"><td class="td-with-role" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t ; entry_with_role_rowhead " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">First-line treatment&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Insulin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">Metformin&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td><td class="td" title="\n
                  \t\t\t\t\ttable-entry\n
                  \t\t\t\t  " align="left" valign="\n
                  \t\t\t\t\ttop\n
                  \t\t\t\t">DietSulfonylureas&#47;meglitinide&#47;other OADsInsulin may be required&nbsp;\t\t\t\t\t\t\n
                  \t\t\t\t</td></tr></tbody></table>
                  """
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                    0 => array:2 [
                      "titulo" => "Classification and diagnosis of diabetes&#58; Standards of Medical Care in Diabetes &#8211; 2019"
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                          "etal" => false
                          "autores" => array:1 [
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                        "fecha" => "2019"
                        "volumen" => "42"
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                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "J&#46; Urbanov&#225;"
                            1 => "L&#46; Brunerov&#225;"
                            2 => "J&#46; Bro&#382;"
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                        ]
                      ]
                    ]
                  ]
                  "host" => array:1 [
                    0 => array:1 [
                      "Revista" => array:4 [
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                0 => array:2 [
                  "contribucion" => array:1 [
                    0 => array:2 [
                      "titulo" => "Not quite type 1 or type 2&#44; what now&#63; Review of monogenic&#44; mitochondrial&#44; and syndromic diabetes"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:4 [
                            0 => "R&#46; Yeung"
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                  "contribucion" => array:1 [
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                    0 => array:1 [
                      "Revista" => array:6 [
                        "tituloSerie" => "Neth&#46; J&#46; Med&#46;"
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                  "contribucion" => array:1 [
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                      "titulo" => "MODY&#58; history&#44; genetics&#44; pathophysiology&#44; and clinical decision making"
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                          "etal" => false
                          "autores" => array:2 [
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                            1 => "G&#46;I&#46; Bell"
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                    ]
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                  "host" => array:1 [
                    0 => array:2 [
                      "doi" => "10.2337/dc11-0035"
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                      "titulo" => "Maturity-onset diabetes of the young&#58; what do clinicians need to know&#63;"
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                        0 => array:2 [
                          "etal" => false
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                  ]
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                    0 => array:2 [
                      "doi" => "10.4093/dmj.2015.39.6.468"
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                0 => array:2 [
                  "contribucion" => array:1 [
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                      "titulo" => "Maturity-onset diabetes of the young overview&#46; GeneReviews&#174; &#91;Internet&#93;"
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                        0 => array:2 [
                          "etal" => false
                          "autores" => array:3 [
                            0 => "R&#46; Naylor"
                            1 => "A&#46;K&#46; Johnson"
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                    ]
                  ]
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                        "fecha" => "2018"
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              "identificador" => "bib0390"
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              "referencia" => array:1 [
                0 => array:2 [
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                      "titulo" => "The maturity-onset diabetes of the young &#40;MODY1&#41; transcription factor HNF-4&#945; regulates expression of genes required for glucose transport and metabolism"
                      "autores" => array:1 [
                        0 => array:2 [
                          "etal" => false
                          "autores" => array:2 [
                            0 => "M&#46; Stoffel"
                            1 => "S&#46;A&#46; Duncan"
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                        "tituloSerie" => "Proc&#46; Natl&#46; Acad&#46; Sci&#46; U&#46;S&#46;A&#46;"
                        "fecha" => "1997"
                        "volumen" => "94"
                        "paginaInicial" => "13209"
                        "paginaFinal" => "13214"
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                0 => array:2 [
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                    0 => array:2 [
                      "titulo" => "Mutations in the hepatocyte nuclear factor-1alpha gene in maturity-onset diabetes of the young &#40;MODY 3&#41;"
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                        0 => array:2 [
                          "etal" => true
                          "autores" => array:6 [
                            0 => "K&#46; Yamagata"
                            1 => "N&#46; Oda"
                            2 => "P&#46;J&#46; Kaisaki"
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