HISTORICAL PERSPECTIVE
From pancreatic extracts to artificial pancreas: History, science and controversies about the discovery of the pancreatic antidiabetic hormone
VII: Early clinical use of pancreatic extracts (1921–1923)
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artificial pancreas: History, science and controversies about the discovery of the pancreatic antidiabetic hormone" "tieneTextoCompleto" => true "paginas" => array:1 [ 0 => array:2 [ "paginaInicial" => "15" "paginaFinal" => "26" ] ] "autores" => array:1 [ 0 => array:4 [ "autoresLista" => "Alberto de Leiva-Hidalgo, Alejandra de Leiva-Pérez, Eulàlia Bruguès-Bruguès" "autores" => array:3 [ 0 => array:4 [ "nombre" => "Alberto" "apellidos" => "de Leiva-Hidalgo" "email" => array:1 [ 0 => "aleiva@fdiabem.org" ] "referencia" => array:5 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 3 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] 4 => array:2 [ "etiqueta" => "*" "identificador" => "cor0005" ] ] ] 1 => array:3 [ "nombre" => "Alejandra" "apellidos" => "de Leiva-Pérez" "referencia" => array:1 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] ] ] 2 => array:3 [ "nombre" => "Eulàlia" "apellidos" => "Bruguès-Bruguès" "referencia" => array:2 [ 0 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:2 [ "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] ] ] ] "afiliaciones" => array:4 [ 0 => array:3 [ "entidad" => "Fundación DIABEM, Barcelona, Spain" "etiqueta" => "<span class="elsevierStyleSup">a</span>" "identificador" => "aff0005" ] 1 => array:3 [ "entidad" => "Servicio de Endocrinología e Instituto de Investigación, Hospital de la Santa Creu i Sant Pau, Barcelona, Spain" "etiqueta" => "<span class="elsevierStyleSup">b</span>" "identificador" => "aff0010" ] 2 => array:3 [ "entidad" => "Centro de Estudios de Historia de la Ciencia (CEHIC), Universitat Autònoma de Barcelona, Barcelona, Spain" "etiqueta" => "<span class="elsevierStyleSup">c</span>" "identificador" => "aff0015" ] 3 => array:3 [ "entidad" => "CIBER-BBN-ISCIII" "etiqueta" => "<span class="elsevierStyleSup">d</span>" "identificador" => "aff0020" ] ] "correspondencia" => array:1 [ 0 => array:3 [ "identificador" => "cor0005" "etiqueta" => "*" "correspondencia" => "Autor para correspondencia." ] ] ] ] "titulosAlternativos" => array:1 [ "es" => array:1 [ "titulo" => "VII: Early clinical use of pancreatic extracts (1921–1923)" ] ] "resumenGrafico" => array:2 [ "original" => 0 "multimedia" => array:7 [ "identificador" => "f0030" "etiqueta" => "Figure 6" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr6.jpeg" "Alto" => 1213 "Ancho" => 996 "Tamanyo" => 72391 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0030" class="elsevierStyleSimplePara elsevierViewall">Elliot P. Joslin (1869-1962).</p>" ] ] ] "textoCompleto" => "<span class="elsevierStyleSections"><p id="p0010" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="f0055"></elsevierMultimedia></p><span id="s0005" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0005">Summary of experimental and clinical experiences with pancreatic extracts (1902-1921)</span><p id="p0015" class="elsevierStylePara elsevierViewall">It is accepted by the great majority that the definitive proof of the role of the pancreas in diabetes mellitus was the publication by O. Minkowski, in 1893, demonstrating that pancreatectomy in dogs induced experimental glycosuria. Minkowski made glycosuria disappear in depancreatised dogs by subcutaneous implants of pancreatic tissue, and he was the first to try, unsuccessfully, to restore the antidiabetic action of the pancreas by the administration of pancreatic extracts either orally and parenterally<a class="elsevierStyleCrossRef" href="#bb0005"><span class="elsevierStyleSup">1</span></a>.</p><p id="p0020" class="elsevierStylePara elsevierViewall">Nevertheless, prior to Minkowski's discovery, other scientists had provided evidence on the relationship between the pancreas and diabetes. In 1709, Johan Conrad Brunner removed the pancreas from dogs, and noted that they displayed extreme thirst and polyuria. His experiments could probably well be considered as the first ones on the internal secretion of the pancreas<a class="elsevierStyleCrossRef" href="#bb0010"><span class="elsevierStyleSup">2</span></a>.</p><p id="p0025" class="elsevierStylePara elsevierViewall">In 1788, Thomas Crawley reported a singular case of diabetes in a subject who died showing stones and signs of tissue damage of the pancreas. In 1869, Paul Langerhans described in his doctoral thesis the pancreatic islets, ignoring their functional role<a class="elsevierStyleCrossRef" href="#bb0015"><span class="elsevierStyleSup">3</span></a>. Etiénne Lancereaux described in 1877 (12 years before the initial observation of J. von Mering and O. Minkowski) a form of diabetes occurring in a group of 12 subjects with pancreatic disorders; he named it <span class="elsevierStyleItalic">pancreatic diabetes.</span> The disorder was heterogeneous; one type was characterized by sudden onset, overt clinical manifestations, decreased weight and more severe pancreatic lesions; the other type, often inherited, was associated with obesity, usually asymptomatic, and depicted a slow progression<a class="elsevierStyleCrossRef" href="#bb0020"><span class="elsevierStyleSup">4</span></a>. Claude Bernard also investigated the hypothesis of pancreatic diabetes; for this purpose, he ligated the pancreatic ducts; after observing the atrophy of the gland without diabetes, he abandoned the hypothesis of pancreatic diabetes, and insisted on the metabolic role of the liver and the influence of central nervous system in glucose<a class="elsevierStyleCrossRef" href="#bb0025"><span class="elsevierStyleSup">5</span></a>.</p><p id="p0030" class="elsevierStylePara elsevierViewall">It would not be until 1901 when Eugene L Opie established the relationship between the hyaline degeneration of the islets of Langerhans and the occurrence of diabetes. In 1906, Wilhelm Heiberg developed a method for counting the islets and found that the number was consistently low in diabetic individuals<a class="elsevierStyleCrossRef" href="#bb0030"><span class="elsevierStyleSup">6</span></a>. In 1909, Jean de Meyer introduced the name of <span class="elsevierStyleItalic">insulin</span> to describe the active substance from the islets of Langerhans<a class="elsevierStyleCrossRef" href="#bb0035"><span class="elsevierStyleSup">7</span></a>. In 1916, Sir Edward A. Sharpey-Schafer (1850-1935), Professor of Physiology at the University of Edinburgh theorised that the islets of Langerhans must secrete a substance which governed carbohydrate metabolism. For this suspected internal secretion of the pancreas, Schafer suggested the name of <span class="elsevierStyleItalic">insuline</span><a class="elsevierStyleCrossRef" href="#bb0040"><span class="elsevierStyleSup">8</span></a>.</p><p id="p0035" class="elsevierStylePara elsevierViewall">J. Rennie and T. Fraser, from Aberdeen Royal Infirmary, published in 1907 clinical experiences carried out between 1902 and 1904, investigating the effects of administering pancreatic islets from various teleostei, in particular the <span class="elsevierStyleItalic">Lophius Piscatorious</span> to 5 diabetic patients, with negative or inconclusive results. In these particular fishes, the islets are anatomically independent from the acinar tissue<a class="elsevierStyleCrossRefs" href="#bb0045"><span class="elsevierStyleSup">9,10</span></a>.</p><p id="p0040" class="elsevierStylePara elsevierViewall">GL Zuelzer did not observe beneficial effects on the first diabetic patient treated with a pancreatic extract. Results were more satisfactory in the following patients, including a 6 year old male child with ketonuria. However, all his patients developed adverse effects: fever, vomiting, stomatitis, profuse sweating<a class="elsevierStyleCrossRefs" href="#bb0050"><span class="elsevierStyleSup">10,11</span></a>. J. Forschbach reproduced the results of Zuelzer in 1909, following Minkowski's advice, and recognised: <span class="elsevierStyleItalic">First (Zuelzer) to produce, successfully, from the pancreas a preparation that eliminates sugar excretion in a shorter or longer period by intravenous administration</span><a class="elsevierStyleCrossRef" href="#bb0060"><span class="elsevierStyleSup">12</span></a>. In 1912, Zuelzer submitted an application to the USA patent office on ACOMATOL on May 6, 1908. The patent was awarded (serial number 431,226), as «pancreas preparation suitable for the treatment of diabetes» on May 28, 1912<a class="elsevierStyleCrossRefs" href="#bb0050"><span class="elsevierStyleSup">10,13</span></a>.</p></span><span id="s0010" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0010">Clinical use of insulin (1922-1923)</span><span id="s0015" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0015">University of Toronto and Toronto General Hospital</span><p id="p0045" class="elsevierStylePara elsevierViewall">Duncan Archibald Graham was Chair of the Department of Medicine and Physician-in -Chief at the Toronto General Hospital in 1921. Fred Banting asked him for permission to treat diabetic patients in the Internal Medicine Ward of Toronto General Hospital (TGH) with the pancreatic extracts. Professor Duncan did not allow him to do it at first Nevertheless, the mediation of John Macleod made it possible to administer the first extract prepared by Banting and Best<a class="elsevierStyleCrossRef" href="#bb0070"><span class="elsevierStyleSup">14</span></a>.</p><p id="p0050" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="b0005"></elsevierMultimedia></p><p id="p0060" class="elsevierStylePara elsevierViewall">Dr. Walter R Campbell, Attending Physician of the Internal Medicine Department, TGH, obtained permission from Leonard Thomson's father to allow him to participate in the first trial of Banting's pancreatic extract<a class="elsevierStyleCrossRef" href="#bb0080"><span class="elsevierStyleSup">16</span></a>. Leonard was a 14 year-old boy with juvenile diabetes diagnosed two years before. On January 11, 1922, Dr. Campbell ordered Dr. Ed Jeffrey to administer, subcutaneously, 7.5<span class="elsevierStyleHsp" style=""></span>ml of the extract into each buttock. <a class="elsevierStyleCrossRef" href="#f0005">Figure 1</a> depicts the daily urine glucose excretion of Leonard from his admission at TGH on December 2, 1921. The Banting's pancreatic extract was not successful; only a slight decrease in glycosuria and a 25% decrease in blood sugar could be observed, together with an aseptical abscess at one injection site<a class="elsevierStyleCrossRef" href="#bb0085"><span class="elsevierStyleSup">17</span></a>.</p><elsevierMultimedia ident="f0005"></elsevierMultimedia><p id="p0065" class="elsevierStylePara elsevierViewall">On the contrary, the graphic illustrates, from January 23 to February 4, the excellent response of the sugar excretion to the administration of the Collip's pancreatic extract<a class="elsevierStyleCrossRefs" href="#bb0090"><span class="elsevierStyleSup">18,19</span></a>. <a class="elsevierStyleCrossRef" href="#f0010">Figure 2</a> shows, in parallel to the marked reduction in the amount of glucose excreted, a substantial reduction of blood glucose and urinary ketone bodies, together with clinical improvement. After this historical experience, Prof. Duncan Graham assigned Drs. W.R. Campbell and A. A. Fletcher to solve all features related to the trial with this new treatment in the wards of the medical Department at the TGH. The successful results achieved with the case of Leonard Thomson were reproduced quite soon. By February 1922, six more patients had been already investigated<a class="elsevierStyleCrossRef" href="#bb0085"><span class="elsevierStyleSup">17</span></a>.</p><elsevierMultimedia ident="f0010"></elsevierMultimedia><p id="p0070" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="b0010"></elsevierMultimedia></p><p id="p0085" class="elsevierStylePara elsevierViewall">The investigators from Toronto University and TGH decided to present the results of the successful clinical experience at the meeting of the Association of American Physicians on May 3, 1922<a class="elsevierStyleCrossRef" href="#bb0100"><span class="elsevierStyleSup">20</span></a>. The general audience was impressed after the lecture given by Macleod.</p><p id="p0090" class="elsevierStylePara elsevierViewall">The Canadian team made a detailed presentation of nine cases of insulin-treated diabetic subjects in a special issue of the Journal of Metabolic Research (Director, F.M. Allen; Editor, FG Banting)<a class="elsevierStyleCrossRef" href="#bb0105"><span class="elsevierStyleSup">21</span></a> (<a class="elsevierStyleCrossRef" href="#f0015">fig. 3</a>).</p><elsevierMultimedia ident="f0015"></elsevierMultimedia><p id="p0095" class="elsevierStylePara elsevierViewall">In the same issue of the Journal of Metabolic Research), Walter R Campbell reported careful clinical observations of the first fourteen cases of diabetic coma treated in the Medicine Clinic, Toronto General Hospital (<a class="elsevierStyleCrossRef" href="#f0015">fig. 3</a>). In one of the reported cases, a woman with glycosuria, acetone odour and dyspnoea, ketoacidosis was complicated by a six month pregnancy. Insulin was given subcutaneously and intravenously at high doses. Large amounts of ketones in in the urine were reduced to negligible values. Ketone bodies in blood also disappeared. Seven cases survived. <span class="elsevierStyleItalic">With the exception of two patients, all those who have died have had an associated infection, sufficiently severe to result fatally apart from the diabetic condition. One of these died from the toxic effects of a sloughing gangrenous foot ten days after being brought out of coma; three had pneumonia and one, pyemic abscess in the kidney. In all but one case, where perhaps insufficient insulin was used, the comatose condition was improved clinically and chemically.</span></p><p id="p0100" class="elsevierStylePara elsevierViewall">In the article, Campbell provided an outstanding lesson about the treatment of diabetic ketoacidosis, which, in many aspects remains as valid today. He pointed out the extraordinary tolerance to insulin in coma, and the key role of water, insulin glucose, and alkali, in the treatment<a class="elsevierStyleCrossRef" href="#bb0110"><span class="elsevierStyleSup">22</span></a>.</p><p id="p0105" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="b0015"></elsevierMultimedia></p><p id="p0115" class="elsevierStylePara elsevierViewall">In general, intravenous insulin was more effective than subcutaneous injection. Interesting clinical observations are depicted in the article <span class="elsevierStyleItalic">(The clinical points on which this requirement for insulin should be based are: acetone odor on the breath; prolonged or irregular breathing; general evidence of dehydration - dry skin, loss of tissue turgor, nausea, emaciation and, particularly, a dry, glazed tongue. A patient with tongue moist at the edges is relatively safe for several hours at least-).</span></p><p id="p0120" class="elsevierStylePara elsevierViewall">Pros and cons of the administration of sodium bicarbonate were discussed. The administration of 20<span class="elsevierStyleHsp" style=""></span>g. of sodium bicarbonate per 84<span class="elsevierStyleHsp" style=""></span>lb of body weight was considered safe. It was also argued that large quantities of carbohydrate with insulin were useful in the treatment of coma. Fluids were considered valuable for promoting diuresis and relieving dehydration, as well as a vehicle for carbohydrate<a class="elsevierStyleCrossRef" href="#bb0110"><span class="elsevierStyleSup">22</span></a>.</p><p id="p0125" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="b0020"></elsevierMultimedia></p><p id="p0145" class="elsevierStylePara elsevierViewall">They observed severe reactions with a blood sugar of 60<span class="elsevierStyleHsp" style=""></span>mg/dL; a blood sugar of 35<span class="elsevierStyleHsp" style=""></span>mg/dL was usually accompanied by unconsciousness. The administration of glucose brought the patients out of hypoglycaemia. Different treatments were tested: glucose (5-20<span class="elsevierStyleHsp" style=""></span>g), orange juice, when the patient can swallow; epinephrine (1/1000 sol., 1<span class="elsevierStyleHsp" style=""></span>ml), when the patient is unconscious.</p><p id="p0150" class="elsevierStylePara elsevierViewall">In the last paragraph of the document, the authors indicated that <span class="elsevierStyleItalic">with the average severe diabetic, hypoglycaemia has not presented a serious problem, but special nursing precautions may well be taken if insulin is administered late in the day, to guard against the possibility of a fatal reaction occurring during sleep</span><a class="elsevierStyleCrossRef" href="#bb0115"><span class="elsevierStyleSup">23</span></a>.</p><p id="p0155" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="b0025"></elsevierMultimedia></p></span></span><span id="s0020" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0020">Other early clinical cases reported in the ISA and Canada-USA</span><p id="p0165" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="b0030"></elsevierMultimedia></p><p id="p0175" class="elsevierStylePara elsevierViewall">In many centers in USA, prominent diabetologists were attending dying diabetic patients in their clinics. Therefore, the University of Toronto and Eli Lilly agreed that a selected group of physicians and institutions would be given the extract as soon as it became available; Macleod sent them details of the method, asking them not to divulge the procedure to those with the intention of producing the extract commercially.</p><p id="p0180" class="elsevierStylePara elsevierViewall">Insulin manufacture was attempted by various specialists; among them Dr. Frederick M. Allen of the Rockefeller Institute of Medical Research in Morristown, New Jersey; H. Rawle Geyelin of Columbia University Presbyterian Hospital in New York; Elliot P. Joslin of Boston; Russell M. Wilder of the Mayo Clinic in Rochester, Minnesota; J.R. Williams of Rochester, New York; Roland T. Woodyatt of Chicago; William D. Sansum of the Potter Metabolic Clinic, Santa Barbara, California.</p><p id="p0185" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="b0035"></elsevierMultimedia></p><elsevierMultimedia ident="f0020"></elsevierMultimedia><p id="p0230" class="elsevierStylePara elsevierViewall">William David Sansum was born on September 25, 1880 in Baraboo, Wisconsin. He was the third child in a family of four boys and four girls. His parents were English, who emigrated to USA. Sansum enrolled in the University of Wisconsin in 1910, where he took his Bachelor of Science degree in 1912. At the age of 32, was admitted to the Rush Medical College in Chicago. At the age of 35, Sansum received the degree of medical doctor. His doctoral thesis was entitled «Studies on the Theory of Diabetes Mellitus». He then became an intern at the Presbyterian Hospital in Chicago under Dr. Roland T. Woodyatt, specialist in metabolic research. He continued as junior and then senior staff at Rush, being very active clinically and academically.</p><p id="p0235" class="elsevierStylePara elsevierViewall">On September 25, 1920, at the age of 40, William D. Sansum, received a letter from George Own Knapp, Santa Barbara, California, the multimillionaire president and founder of the Union Carbide Company, offering him, in his capacity of member of the Board of the Santa Barbara Cottage Hospital, to become the director of the Potter Metabolic Clinic, equipped with outstanding research facilities. Sansum accepted.</p><p id="p0240" class="elsevierStylePara elsevierViewall">Dr. Norman R. Blatherwick was in charge of the laboratory; Loyal C. Maxwell was the Laboratory Technician. Sansum, Blatherwick and Maxwell decided to manufacture insulin from beef, hog, and sheep pancreas, starting on April 1922, using Banting and Best's techniques. Dr. Sansum would get help from R.N. Gehl, a leading meat seller who provided the Potter Metabolic Unit with beef pancreas free of charge. The scientist at the laboratory proceeded with an alcoholic extract, followed by filtering and concentration of the aqueous phase by vacuum distillation at low temperature; the concentrated solution was chilled, and fatty material filtered out; the fíltrate was then treated with sodium chloride, and insulin precipitated; then, the pH was adjusted to 2.5, and a new precipitation generated with alcohol; after another alcohol wash, the extract was finally dissolved in distilled water. The potency of the extract was estimated by comparison with a standard sample provided by Toronto University. The early yields contained no more than 500 units of insulin per pound of pancreas tissue.</p><p id="p0245" class="elsevierStylePara elsevierViewall">Dr. Sansum had under his care 7 diabetic patients beyond hope of survival. The second patient to receive insulin in USA was Charles E. Cowan, a 51 year old patient from Anaheim with severe diabetes developed in 1918, following a bad case of Spanish influenza. His physician was Dr. William David Sansum of the Potter Metabolic Clinic in Santa Barbara, California. Cowan was injected on May 31, 1922, with three cubic centimetres of a potent pancreatic extract, developed by the Potter group («Santa Barbara insulin»), just ten days after the Canadian-made insulin was administered to James Haven at the office of his physician, Dr. John R. Williams in Rochester. Cowan had been already hospitalized in Santa Barbara for 6 months, treated with an 850-calorie diet; his weight was 95 pounds (43 Kg). On the third day after the first dose, glycosuria became negative. One year after the first injection, Cowan's weight was 125 pounds (57 Kg), and he maintained a diet with 2,400 calories. Cowan continued on insulin for the remaining 39 years of his life. For many years, his insulin treatment was kept steady at 40 units of U-80 NPH insulin before breakfast, and, occasionally, 5 units of regular insulin before one of the meals. He was 90 years old when he died at Anaheim on February 10, 1958; he did not suffer retinal disease, kidney failure, neuropathy, hypertension or ischemic foot.</p><p id="p0250" class="elsevierStylePara elsevierViewall">The first case of juvenile-onset diabetes, treated by Dr. Sansum, was Carl Klass, a boy from San Dimas, who became sugar free in collected urine within 24 hours after the first «Santa Barbara insulin» administration. Then insulin was maintained associated to a normal diet. The boy gained weight at the rate of half a pound (250<span class="elsevierStyleHsp" style=""></span>g) per day in the first weeks, looking like a normal happy child in two months.</p><p id="p0255" class="elsevierStylePara elsevierViewall">Dr. Sansum submitted a report to Prof. Macleod in Toronto, with the details of the first 20 diabetic subjects treated in Santa Barbara. Macleod replied advancing the last findings in his lab regarding improvements in the technical production of insulin. When Santa Barbara Hospital Superintendent asked Sansum's permission to bill patients for insulin, his answer was «Never-so long as it is classified as an experimental drug». In fact, Sansum paid over $1,400 from his own pocket to pay for free insulin administered to his patients. Additional equipment was acquired for manufacturing of insulin, including copper distillation stills and a large press.</p><p id="p0260" class="elsevierStylePara elsevierViewall">Dr. Sansum was also a pioneer in the field health education for diabetic patients. Starting in 1922, a program of diabetes education was implemented at Potter Metabolic Unit, and a handbook was provided to instructed patients, along with a hypodermic syringe and a supply of insulin at home for some time.</p><p id="p0265" class="elsevierStylePara elsevierViewall">After visiting Santa Barbara in the summer of 1922, Dr. Henry S. Pritchett, President of the Carnegie Corporation convinced the members of the Executive Board of the Company to provide a cash gift of $15,000 to the Potter Metabolic Unit for future developments. The improved efficiency allowed unlimited supply of insulin, for the local needs, and to reduce the daily cost of insulin per patient in Santa Barbara from $100 to less than $20, before the end of 1923.</p><p id="p0270" class="elsevierStylePara elsevierViewall">The Carnegie Corporation support helped to increase the staff members working at the laboratory. The Potter Clinic became overloaded with diabetic men, women and children to be admitted and receive insulin treatment. Dr. Sansum felt obliged to accept only cases when diabetes coma appeared imminent. The insulin manufacture at Potter laboratory operated day and night, including Sunday. On March 1, 1923, the Potter Metabolic Clinic announced that although the fundamental principle of Dr. Sansum was that <span class="elsevierStyleItalic">no one would ever be turned away for lack of money to pay for treatment,</span> the Clinic was not in the situation to continue supplying free insulin, with the exception of the needy people. The annual budget of the Clinic was $40,000 but the expenses were $60,000. Therefore, from now on the Clinic would charge for its experimental insulin at the rate of 3 cents per unit. At that time, Lilly insulin cost was 5 cents a unit. By the end of 1923, insulin production at Potter's research lab was offering unlimited supply. The cost of manufacturing had been drastically reduced, and the quality of insulin had also improved<a class="elsevierStyleCrossRef" href="#bb0125"><span class="elsevierStyleSup">25</span></a> (<a class="elsevierStyleCrossRef" href="#f0025">fig. 5</a>).</p><elsevierMultimedia ident="f0025"></elsevierMultimedia></span><span id="s0025" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0025">Frederick M. Allen and Elliot P. Joslin: First insulin treated patients</span><p id="p0275" class="elsevierStylePara elsevierViewall">The earliest large clinical trials with insulin in USA were carried out by Joslin, Allen, and Woodyatt<a class="elsevierStyleCrossRefs" href="#bb0130"><span class="elsevierStyleSup">26–29</span></a>.</p><p id="p0280" class="elsevierStylePara elsevierViewall">Frederick Madison Allen (1874-1964) was born in Iowa. Studied Medicine in California. Later, he worked at Harvard University and the Rockefeller Institute. On April, 1921, he opened the Physiatric Institute in Morristown, New Jersey. Along with Elliot Joslin, he was one of the leading diabetologists. Before insulin, Allen became famous through his diet treatment of diabetes, consisting of a drastic reduction of calories, particularly, carbohydrate intake (as low as 8% of total calories). This treatment reduced the incidence of glycosuria and prolonged life for a few years.</p><p id="p0285" class="elsevierStylePara elsevierViewall">Allen visited Toronto before starting to use insulin in Morristown. In August 1922, Allen administered insulin to six severe patients. On August 16, he wrote to Banting expressing his enthusiasm after observing the disappearance of hyperglycaemia, glycosuria and ketonuria, and improved well-being. One of his desperate cases was Elizabeth Hughes. Allen decided, following the wishes of her family, to bring Elizabeth (15 years old) to Toronto. At the end of her first 2 weeks of insulin therapy, Elizabeth was following a normal diet of 2,200 calories; five weeks after arriving in Toronto, Elizabeth had gained over 10 pounds (4.5 Kg); a few months later she had also increased her height.</p><p id="p0290" class="elsevierStylePara elsevierViewall">Allen gave insulin to 161 diabetic patients in the first year of clinical trials.</p><p id="p0295" class="elsevierStylePara elsevierViewall">In addition to Allen and Joslin, the leading group of clinicians involved in early clinical trials with insulin in USA included Dr. H. Rawle Geyelin of New York City; John R Williams from Rochester, New York, who treated the first patient in USA with insulin, Jim Havens; Dr. Russell Wilder from the Mayo Clinic, and Dr. Rollin T. Woodyatt, who worked at the Presbyterian Hospital in Chicago.</p><p id="p0300" class="elsevierStylePara elsevierViewall">Dr. Elliot Proctor Joslin (1869-1962) was born in Oxford, Massachusetts, on the sixth of June, 1869. His father, Allen, was a partner in the Joslin Shoe Factory, and his mother, Sarah Proctor, was related to the founders of the corporate giant Proctor and Gamble. He attended Yale College, and finally Boston in the Medical School at Harvard. Joslin became interested in diabetes while attending Yale, when his aunt developed the disease.</p><p id="p0305" class="elsevierStylePara elsevierViewall">Joslin embarked for the great medical clinics of Germany and Austria, from Freiburg to Vienna and back to Berlin. Upon returning home in the summer of 1897, he served as an intern at the Massachusetts General Hospital for a year, and joined the staff of the Boston City Hospital and the recently founded New England Deaconess Hospital (NEDH), and worked part-time in the Boston Dispensary. He was a man imbued with Protestant morals and socially progressive ideas. Joslin began his private practice in Boston in 1898, at the age of 29 (<a class="elsevierStyleCrossRef" href="#f0030">fig. 6</a>). In 1899 his 60 year old mother also became his patient; she died in 1913, at the age of 74.</p><elsevierMultimedia ident="f0030"></elsevierMultimedia><p id="p0310" class="elsevierStylePara elsevierViewall">In 1908, cooperating with physiologist Francis G. Benedict, Joslin intensively investigated the effect of carbohydrate and calorie restricted diets in diabetic patients admitted to the New England Deaconess Hospital. His monograph <span class="elsevierStyleItalic">The treatment of Diabetes Mellitus</span> (1916) included the main findings from 1,000 cases; Joslin observed a 20% reduction in mortality with the combination of diabetes education, diet and exercise. In 1918 he published the first edition of <span class="elsevierStyleItalic">Diabetic Manual- for the Doctor and Patient,</span> the pioneering patient handbook; there have been 14 editions; its current version is published by the Joslin Diabetes Center as <span class="elsevierStyleItalic">The Joslin Guide to Diabetes.</span></p><p id="p0315" class="elsevierStylePara elsevierViewall">Elizabeth Mudge was the first insulin-treated patient by Elliott P. Joslin (<a class="elsevierStyleCrossRef" href="#f0035">fig. 7</a>). She received the first injection on August 7, 1922. Elizabeth was a nurse and her diabetes was diagnosed in July 1917. Under Joslin's care, she lost weight, so that by August 1922 she weighed 71 pounds (32 Kg). Elliot P. Joslin received the first insulin supply on August 6, 1922. He felt too nervous to make the first injection himself; therefore, he asked his associate Dr. Howard Root to administer the first dose to Miss Mudge, a 42 year-old former nurse, and now an invalid. Six weeks after receiving insulin daily, she was able to walk four miles a day. A similar experience was the case of Dorothy Z., a 5-year old girl who could not climb stairs before insulin treatment; and also the case of Annie N, a Finnish child who after two days of treatment played and would not stay in bed.</p><elsevierMultimedia ident="f0035"></elsevierMultimedia><p id="p0320" class="elsevierStylePara elsevierViewall">Joslin realized that insulin meant the end of an era in diabetes history, but, unfortunately, not the end of diabetes<a class="elsevierStyleCrossRef" href="#bb0150"><span class="elsevierStyleSup">30</span></a>. Joslin created the Diabetes Teaching Unit, where he started the whole educational aspect of diabetes. He was the first physician to have diabetes teaching nurses to visit, treat and educate diabetic children at their homes and to develop special care for diabetic children at summer camps (<a class="elsevierStyleCrossRef" href="#f0040">fig. 8</a>).</p><elsevierMultimedia ident="f0040"></elsevierMultimedia></span><span id="s0030" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0030">First European cases of insulin treatment</span><span id="s0035" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0035">Romania (N.C. Paulescu)</span><p id="p0325" class="elsevierStylePara elsevierViewall">In Bucharest, Paulescu intensively engaged himself in purifying the pancreatic extract; in addition, he carried out limited clinical experiments. Under the successive influence of hydrochloric acid and caustic soda, he obtained a clear aqueous pancreatic extract, with a lower protein content. He also observed that 96% ethanol partly precipitated the proteins of the extract; he then evaporated the alcohol of the extract at low temperature over 50<span class="elsevierStyleHsp" style=""></span>ºC and destroyed the active ingredient of the extract, which later reconstituted with physiological saline<a class="elsevierStyleCrossRef" href="#bb0105"><span class="elsevierStyleSup">21</span></a>. He was afraid of using the parenteral delivery of the pancreatic extract in diabetic subjects, because of previously observed side effects; therefore, he used (without success) the administration of the pancreatic extract by an <span class="elsevierStyleItalic">enema</span> in two clinical observations (one case of <span class="elsevierStyleItalic">slim diabetes</span> in a 43-yearold man, on February 25, 1922, and several times afterwards, and another case of <span class="elsevierStyleItalic">fat diabetes</span> in a 52-year-old woman, on March 3)<a class="elsevierStyleCrossRef" href="#bb0160"><span class="elsevierStyleSup">32</span></a>.The observed results led him to the following conclusions<a class="elsevierStyleCrossRef" href="#bb0065"><span class="elsevierStyleSup">13</span></a>:</p><p id="p0330" class="elsevierStylePara elsevierViewall"><elsevierMultimedia ident="b0040"></elsevierMultimedia></p></span><span id="s0045" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0045">Spain</span><p id="p0345" class="elsevierStylePara elsevierViewall">In his book <span class="elsevierStyleItalic">The Discovery of Insulin,</span> Michael Bliss pointed out that, with the exception of the pioneer experience of Georg. Zuelzer, the first European to use insulin was Dr. R. Carrasco-Formiguera, who spent one year at the Department of Physiology, directed by Professor B. Cannon, in Harvard (1921-1922). He was present in New Haven when Banting made his first presentation on pancreatic extracts<a class="elsevierStyleCrossRef" href="#bb0165"><span class="elsevierStyleSup">33</span></a>.</p><p id="p0350" class="elsevierStylePara elsevierViewall">In September 1922, Carrasco-Formiguera and his associate, Dr. Pere González, were able to produce an impure pancreatic extract containing insulin in the Municipal Laboratory of Barcelona. They used dogs and rabbits as experimental animals<a class="elsevierStyleCrossRef" href="#bb0170"><span class="elsevierStyleSup">34</span></a>.</p><p id="p0355" class="elsevierStylePara elsevierViewall">On October 3, 1922, Carrasco (<a class="elsevierStyleCrossRef" href="#f0045">fig. 9</a>) administered 10<span class="elsevierStyleHsp" style=""></span>ml. of the extract to the patient Francesc Pons. Although the results of this experiment were positive, the patient died when no additional extract was available. Finally, Carrasco was able to treat other patients when he undertook to supervise the manufacture and distribution of insulin in Spain<a class="elsevierStyleCrossRefs" href="#bb0175"><span class="elsevierStyleSup">35,36</span></a>. No other Europeans were in the condition to use insulin until 1923. In a document published in 1924, Carrasco explained that at the end of 1923 he had already treated 80 diabetic patients with insulin<a class="elsevierStyleCrossRef" href="#bb0180"><span class="elsevierStyleSup">36</span></a>; in 22 of them, surgical complications were associated (<a class="elsevierStyleCrossRef" href="#f0050">fig. 10</a>).</p><elsevierMultimedia ident="f0045"></elsevierMultimedia><elsevierMultimedia ident="f0050"></elsevierMultimedia></span><span id="s0050" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0050">England</span><p id="p0360" class="elsevierStylePara elsevierViewall">In June 1922, JJR Macleod asked the Medical Research Council (MRC) of England to accept the donation, from the University of Toronto, of the complete rights to the patent of pancreatic extracts<a class="elsevierStyleCrossRef" href="#bb0165"><span class="elsevierStyleSup">33</span></a>. The MRC appeared sceptical about the miracle of insulin. Drs. Henry H. Dale and Harold Dudley visited Toronto in September 2002, as well as Eli Lilly headquarters in Indianapolis and several American Hospitals. After their return, they reported to the MRC with high enthusiasm and recommended to accept the control of the British patent. Clinical trials started in England in the month of December, 1922. Approximately 50 diabetic patients received insulin in Britain in the winter of 1922-23<a class="elsevierStyleCrossRef" href="#bb0165"><span class="elsevierStyleSup">33</span></a>. One of the first people in England to receive insulin was the Treasurer of the Royal College of Physicians of Edinburgh, Norman Purvis Walker (1862-1942), who would become President of both this College and the General Medical Council. In April, 1932, the supplies of Lilly and Burroughs Wellcome made insulin available to most insulin-treated patients in England.</p></span><span id="s0055" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0055">Scandinavia</span><p id="p0365" class="elsevierStylePara elsevierViewall">Torsten Deckert wrote that insulin came to Denmark thanks to Birthe Marie Krogh (1874-1943), the wife of August Krogh. She was a physician, and became a Doctor of Medical Sciences in 1914<a class="elsevierStyleCrossRef" href="#bb0190"><span class="elsevierStyleSup">38</span></a>.</p><p id="p0370" class="elsevierStylePara elsevierViewall">Schack August Steenberg Krogh received the Nobel Prize in 1920. He was invited to lecture at the Mayo Clinic, Johns Hopkins, and several other universities in USA. Marie developed diabetes, probably diagnosed in 1921. Dr. Hans Christian Hagedorn accepted her care. He prescribed a starvation diet, and glycosuria disappeared. In September 1922, August and Marie Krogh went to USA, arriving in Boston. Elliott P. Joslin told them he was conducting clinical experiments with an insulin preparation provided by the University of Toronto. Marie and August were guests at JJR Macleod's home on November 23-25, 1922. With the assistance of Macleod, Krogh was able to negotiate an agreement with the Governors of the University of Toronto to produce and use insulin in Scandinavia. Immediately, after returning to Copenhagen, Krogh and Hagedorn decided to work as a team. Hagedorn would produce the pancreatic extracts from pancreas of cattle and fish in his private laboratory; Krogh would measure the biological activity of the extracts in the Laboratory of Zoo physiology. On December 21, they achieved an active preparation from ox pancreas, successfully tested in rabbits. They also developed a new standardisation method for insulin, using mice as experimental animals. Before the end of 1922 Krogh and Hagedorn reached an agreement for manufacturing insulin in Denmark with August Kongsted, the owner of Lovens Kemisk Fabrik<a class="elsevierStyleCrossRef" href="#bb0190"><span class="elsevierStyleSup">38</span></a>. Kongsted decided to be responsible for the expenses related to the experiments, production and distribution; once an insulin market was created, he would claim to cover all expenses but would not ask for any profit from sales to the Scandinavian countries. One condition was the Loven trademark (lion, Leo in Latin) to be displayed on the ampoules. Hagedorn and Krogh carried out the experimental work without payment. Therefore, at the end of 1923, the price of 100 units of insulin in the USA was 4 kroner; 3.5 in England, and 2.5 in Denmark<a class="elsevierStyleCrossRef" href="#bb0190"><span class="elsevierStyleSup">38</span></a>.</p><p id="p0375" class="elsevierStylePara elsevierViewall">A significant advance was the achievement by George Walden, Eli Lilly's first Chemist, that the precipitation of insulin at its isoelectric point yielded a method of purification by isoelectric fractionation which allowed largescale production of insulin. Therefore, early in 1923 the supply of insulin was adequate to meet the requirements of many institutions selected for its clinical use<a class="elsevierStyleCrossRef" href="#bb0195"><span class="elsevierStyleSup">39</span></a>. The purity of insulin was increased, and the duration of insulin solutions greatly improved, these advances were immediately incorporated by the Danish investigators.</p><p id="p0380" class="elsevierStylePara elsevierViewall">In the morning on March 13, 1923, the first subcutaneous injection of insulin was given to a diabetic patient admitted with diabetic coma in the Municipal Hospital of Copenhagen, under the responsibility of the Consultant, Dr. Sophus Bang. After administering several doses, the blood sugar fell from 740<span class="elsevierStyleHsp" style=""></span>mg/dL to 390, the Kussmaul respiration stopped and the consciousness recovered. Nevertheless, the patient developed heart failure in the afternoon and died during the night. In the month of April, seven severe patients were successfully put on insulin. Hagedorn presented a report on these clinical experiences to the Danish Society for Internal Medicine on June 23, and to the 11th Nordic Congress for Internal Medicine in July. In May 1923, Krogh, Hagedorn and Kongsted created the Nordisk Insulinlaboratorium, ready to make insulin available to Scandinavian Centers, with no more limitations on supplies<a class="elsevierStyleCrossRef" href="#bb0190"><span class="elsevierStyleSup">38</span></a>.</p></span><span id="s0060" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0060">Germany and France</span><p id="p0385" class="elsevierStylePara elsevierViewall">In Germany, the effects of the war, and the uncontrolled inflation delayed the manufacturing of insulin until 1924. In France, the situation was equally inadequate in 1922 and 1923.</p></span></span></span>" "textoCompletoSecciones" => array:1 [ "secciones" => array:7 [ 0 => array:2 [ "identificador" => "s0005" "titulo" => "Summary of experimental and clinical experiences with pancreatic extracts (1902-1921)" ] 1 => array:3 [ "identificador" => "s0010" "titulo" => "Clinical use of insulin (1922-1923)" "secciones" => array:1 [ 0 => array:2 [ "identificador" => "s0015" "titulo" => "University of Toronto and Toronto General Hospital" ] ] ] 2 => array:2 [ "identificador" => "s0020" "titulo" => "Other early clinical cases reported in the ISA and Canada-USA" ] 3 => array:2 [ "identificador" => "s0025" "titulo" => "Frederick M. Allen and Elliot P. Joslin: First insulin treated patients" ] 4 => array:3 [ "identificador" => "s0030" "titulo" => "First European cases of insulin treatment" "secciones" => array:5 [ 0 => array:2 [ "identificador" => "s0035" "titulo" => "Romania (N.C. Paulescu)" ] 1 => array:2 [ "identificador" => "s0045" "titulo" => "Spain" ] 2 => array:2 [ "identificador" => "s0050" "titulo" => "England" ] 3 => array:2 [ "identificador" => "s0055" "titulo" => "Scandinavia" ] 4 => array:2 [ "identificador" => "s0060" "titulo" => "Germany and France" ] ] ] 5 => array:2 [ "identificador" => "xack36444" "titulo" => "Acknpwledgement" ] 6 => array:1 [ "titulo" => "<span class="elsevierStyleSectionTitle" id="st0070">References</span>" ] ] ] "pdfFichero" => "main.pdf" "tienePdf" => true "multimedia" => array:19 [ 0 => array:7 [ "identificador" => "f0005" "etiqueta" => "Figure 1" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr1.jpeg" "Alto" => 1244 "Ancho" => 2009 "Tamanyo" => 500744 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0005" class="elsevierStyleSimplePara elsevierViewall">Banting et al<a class="elsevierStyleCrossRef" href="#bb0085"><span class="elsevierStyleSup">17</span></a>.</p>" ] ] 1 => array:7 [ "identificador" => "f0010" "etiqueta" => "Figure 2" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr2.jpeg" "Alto" => 1134 "Ancho" => 2008 "Tamanyo" => 451307 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0010" class="elsevierStyleSimplePara elsevierViewall">Banting et al<a class="elsevierStyleCrossRef" href="#bb0085"><span class="elsevierStyleSup">17</span></a>.</p>" ] ] 2 => array:7 [ "identificador" => "f0015" "etiqueta" => "Figure 3" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr3.jpeg" "Alto" => 1407 "Ancho" => 2008 "Tamanyo" => 429605 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0015" class="elsevierStyleSimplePara elsevierViewall">Fletcher et al<a class="elsevierStyleCrossRef" href="#bb0115"><span class="elsevierStyleSup">23</span></a>.</p>" ] ] 3 => array:7 [ "identificador" => "f0020" "etiqueta" => "Figure 4" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr4.jpeg" "Alto" => 1343 "Ancho" => 2008 "Tamanyo" => 237899 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0020" class="elsevierStyleSimplePara elsevierViewall">Compiled group of photographs of various patients successfully treated at the early insulin period.</p>" ] ] 4 => array:7 [ "identificador" => "f0025" "etiqueta" => "Figure 5" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr5.jpeg" "Alto" => 1024 "Ancho" => 1891 "Tamanyo" => 181664 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0025" class="elsevierStyleSimplePara elsevierViewall">A. William D. Sansum, MD in 1920 (1880-1948). B. The Potter Metabolic Clinic in 1920. Courtesy of Dr. Lois Jovanovic, Chief Officer, Sansum Diabetes Research Foundation.</p>" ] ] 5 => array:7 [ "identificador" => "f0030" "etiqueta" => "Figure 6" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr6.jpeg" "Alto" => 1213 "Ancho" => 996 "Tamanyo" => 72391 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0030" class="elsevierStyleSimplePara elsevierViewall">Elliot P. Joslin (1869-1962).</p>" ] ] 6 => array:7 [ "identificador" => "f0035" "etiqueta" => "Figure 7" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr7.jpeg" "Alto" => 1213 "Ancho" => 997 "Tamanyo" => 112225 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0035" class="elsevierStyleSimplePara elsevierViewall">Elizabeth Mudge, RN. She received the first insulin injection given in New England (USA), in 1922.</p>" ] ] 7 => array:7 [ "identificador" => "f0040" "etiqueta" => "Figure 8" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr8.jpeg" "Alto" => 893 "Ancho" => 1005 "Tamanyo" => 101642 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0040" class="elsevierStyleSimplePara elsevierViewall">Dr. Elliot P. Joslin, pioneer of patient education, self-care and empowerment.</p>" ] ] 8 => array:7 [ "identificador" => "f0045" "etiqueta" => "Figure 9" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr9.jpeg" "Alto" => 1035 "Ancho" => 946 "Tamanyo" => 219944 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0045" class="elsevierStyleSimplePara elsevierViewall">Rossend Carrasco-Formiguera introduced insulin treatment in Europe.</p>" ] ] 9 => array:7 [ "identificador" => "f0050" "etiqueta" => "Figure 10" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => true "mostrarDisplay" => false "figura" => array:1 [ 0 => array:4 [ "imagen" => "gr10.jpeg" "Alto" => 718 "Ancho" => 1417 "Tamanyo" => 75157 ] ] "descripcion" => array:1 [ "en" => "<p id="sp0050" class="elsevierStyleSimplePara elsevierViewall">Rossend Carrasco-Formiguera, at the end of 1923 had already treated 80 diabetic patients with insulin.</p>" ] ] 10 => array:5 [ "identificador" => "f0055" "tipo" => "MULTIMEDIAFIGURA" "mostrarFloat" => false "mostrarDisplay" => true "figura" => array:1 [ 0 => array:4 [ "imagen" => "fx1.jpeg" "Alto" => 1031 "Ancho" => 1879 "Tamanyo" => 208074 ] ] ] 11 => array:5 [ "identificador" => "b0005" "tipo" => "MULTIMEDIATEXTO" "mostrarFloat" => false "mostrarDisplay" => true "texto" => array:1 [ "textoCompleto" => "<span class="elsevierStyleSections"><p id="p0055" class="elsevierStylePara elsevierViewall">Duncan Archibald Graham (1882-1974), born on a farm near Ivan, Ontario, held the first position in the British Empire of Chair of Clinical Medicine, established by John Craig Eaton at the University of Toronto in 1919. He was Chair of the Department of Medicine and Physician-in -Chief at the Toronto General Hospital, until 1947. From 1933 to 1935, he was the President of the Royal College of Physicians and Surgeons of Canada. From 1940 to 1941, he was the President of the Canadian Medical Association. He received honorary degrees from the Universities of Western Ontario, Toronto, and Queen's<a class="elsevierStyleCrossRef" href="#bb0075"><span class="elsevierStyleSup">15</span></a>.</p></span>" ] ] 12 => array:5 [ "identificador" => "b0010" "tipo" => "MULTIMEDIATEXTO" "mostrarFloat" => false "mostrarDisplay" => true "texto" => array:1 [ "textoCompleto" => "<span class="elsevierStyleSections"><p id="p0075" class="elsevierStylePara elsevierViewall">The immediate consequences of these clinical observations at the Department of Medicine, were reported to the American Diabetes Association by Walter Campbell:</p><p id="p0080" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">The situation created in the medical world by the discovery of insulin was, I think, unprecedented…The necessity for expanded clinical facilities was immediate and pressing. With Professor Graham directing, a clinic was formed to carry further the clinical investigations, with Banting, Fletcher and I taking charge of the patients. We worked together literally night and day and Professor Graham was not the least tireless of the group. It was absorbing work and each day someone in the laboratory or the clinic had a new fact to add - a new hypothesis to test. The pooling of facts and ideas was an important element in the rapid progress in both laboratory and clinic</span>…<a class="elsevierStyleCrossRef" href="#bb0080"><span class="elsevierStyleSup">16</span></a></p></span>" ] ] 13 => array:5 [ "identificador" => "b0015" "tipo" => "MULTIMEDIATEXTO" "mostrarFloat" => false "mostrarDisplay" => true "texto" => array:1 [ "textoCompleto" => "<span class="elsevierStyleSections"><p id="p0110" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Apparently, the ordinary carbohydrate equivalent value of the insulin, as found in other patients, bears no relation to the requirement during severe acidosis and coma… large quantities of carbohydrate are useful in the treatment of coma with insulin for three reasons: (1) it prevents hypoglycaemia when large doses of insulin are used; (2) it furnishes energy and reduces to a minimum the incomplete combustion of fat and protein, and thus limits ketone production; (3) it aids in the combustion of ketones already present in the blood and tissues. In the severe cases, glucose may be given intravenously… Fluids are valuable in the treatment as a vehicle for carbohydrate, for promoting diuresis and for relieving dehydration. Water, broths and various fruit juices may be used… The judicious use of alkali may prove of value in some cases of diabetic coma. As a therapeutic measure, alkali, if necessary at all, should be given as early as possible, and… the administration should be by the vein… At the same time, the harmful effect of an overdose to patients not really requiring alkali must be guarded against… One might introduce in all cases 20 gm of sodium bicarbonate per 84<span class="elsevierStyleHsp" style=""></span>lb. body weight with safety… Further amounts of alkali might be introduced later if chemical evidence of its necessity is obtained</span>.</p></span>" ] ] 14 => array:5 [ "identificador" => "b0020" "tipo" => "MULTIMEDIATEXTO" "mostrarFloat" => false "mostrarDisplay" => true "texto" => array:1 [ "textoCompleto" => "<span class="elsevierStyleSections"><p id="p0130" class="elsevierStylePara elsevierViewall">Finally, in the November-December issue of the Journal of Metabolic Research, Almon Fletcher and Walter Campbell made an excellent clinical description of insulin-induced hypoglycaemia<a class="elsevierStyleCrossRef" href="#bb0115"><span class="elsevierStyleSup">23</span></a>:</p><p id="p0135" class="elsevierStylePara elsevierViewall">.<span class="elsevierStyleItalic">.. The initial symptom may be a feeling of nervousness or tremulousness, sometimes a feeling of excessive hunger, at other times a feeling of weakness or a sense of goneness… The reaction may go no further than this… More usually it is rapidly followed by objective signs-most frequently a sweat which may be very profuse; pallor and flushing is common; sometimes a change in the pulse rate… At times there is a feeling of heat or cold, sometimes of faintness.</span></p><p id="p0140" class="elsevierStylePara elsevierViewall"><span class="elsevierStyleItalic">Some have complained of vertigo; others of diplopia… Much more severe manifestations are observed with further lowering of the blood sugar. Marked excitement, emotional instability, sensory and motor aphasia, dysarthria, delirium, disorientation, confusion… Syncope or collapse may occur, rarely going on to a state of unconsciousness… Bradycardia has occurred… loss of sphincter control… When a single dose of insulin is given there occurs a fall in the blood sugar percentage which reaches a low point, sometimes as early as two hours, sometimes as late as twelve after the administration, and tends to return to the original level at a variable rate</span> (<a class="elsevierStyleCrossRef" href="#f0015">fig. 3</a>).</p></span>" ] ] 15 => array:5 [ "identificador" => "b0025" "tipo" => "MULTIMEDIATEXTO" "mostrarFloat" => false "mostrarDisplay" => true "texto" => array:1 [ "textoCompleto" => "<span class="elsevierStyleSections"><p id="p0160" class="elsevierStylePara elsevierViewall">In the University of Toronto, Best was placed in charge of Connaught's Laboratory for insulin manufacturing; Macleod and Collip to the Carnegie Corporation with a Grant to pursue experimental research and development at the Marine Biological Station in St. Andrew's, New Brunswick, conducted personally by Macleod, and at the University of Alberta by Collip. An ad hoc Committee at the University of Toronto decided that Banting would have a university appointment and facilities shared with Graham, Campbell and Fletcher at the Toronto General Hospital.</p></span>" ] ] 16 => array:5 [ "identificador" => "b0030" "tipo" => "MULTIMEDIATEXTO" "mostrarFloat" => false "mostrarDisplay" => true "texto" => array:1 [ "textoCompleto" => "<span class="elsevierStyleSections"><p id="p0170" class="elsevierStylePara elsevierViewall">CC Sutter and JR Murlin published a case report of an adult severe diabetic subject admitted with ketosis at the Rochester General Hospital (July 1922) and treated with a pancreatic extract, able to reduce blood sugar, urine sugar, and ketone bodies, after subcutaneous administration<a class="elsevierStyleCrossRefs" href="#bb0050"><span class="elsevierStyleSup">10,24</span></a>. Murlin applied for a patent on his antidiabetic pancreatic extract in July 1923 (finally granted in 1925).</p></span>" ] ] 17 => array:5 [ "identificador" => "b0035" "tipo" => "MULTIMEDIATEXTO" "mostrarFloat" => false "mostrarDisplay" => true "texto" => array:1 [ "textoCompleto" => "<span class="elsevierStyleSections"><p id="p0190" class="elsevierStylePara elsevierViewall">Leonard Thompson, the first patient treated with insulin at the age of 14, died at the age of 27. He worked as an assistant in a drug and chemicals factory. He was never a well-controlled patient, injecting daily an average of 85 units of insulin. In 1932 he was admitted again at Toronto General Hospital in diabetic coma. In his final illness he suffered influenza, followed by pneumonia combined with severe ketoacidosis. The autopsy revealed a small and atrophied pancreas, with only a few islets. His pancreas is displayed in the anatomical museum at the Banting Institute.</p><p id="p0195" class="elsevierStylePara elsevierViewall">The following two photos were taken of John L, a patient of Dr. H.R.Geyelin, before and after insulin been administered.</p><p id="p0200" class="elsevierStylePara elsevierViewall">Dr. Joseph Gilchrist, physician and patient, was a classmate of Frederick Banting.</p><p id="p0205" class="elsevierStylePara elsevierViewall">James D. Havens, the son of an important executive of Eastman Kodak, was the first patient treated with insulin in USA. His personal physician was Dr. John R. Williams in the city of Rochester, under the supervision of Banting (Havens became a member of the National Academy of Arts; he died in 1960, due to colon cancer).</p><p id="p0210" class="elsevierStylePara elsevierViewall">Elizabeth Hughes, daughter of Charles E. Hughes, US Secretary of State. Elizabeth. Hughes was successful in raising 3 children, all born by caesarean section. She was physically active and travelled a lot. She died suddenly after a myocardial infarction, at the age of 74, after being diabetic for 60 years.</p><p id="p0215" class="elsevierStylePara elsevierViewall">The last 2 photos appeared in <span class="elsevierStyleItalic">JAMA,</span> they were taken on December 15, 1922, before initiating insulin treatment (the 3 year-old child's weight was 15 pounds (7 Kg), and on February 15, 1923, with a new weight of 29 pounds (13 Kg) (<a class="elsevierStyleCrossRef" href="#f0020">fig. 4</a>).</p><p id="p0220" class="elsevierStylePara elsevierViewall">Dr. Nathaniel Bowditch Potter (1869-1919) was considered one of most relevant experts in Metabolic Medicine. Initially he worked in New York, becoming Professor of Clinical Medicine at Columbia University, and Chief of the Medical Division of St. Mark's Hospital. At the age of 47, he was diagnosed with diabetes, and developed kidney disease, cardiovascular atherosclerotic disease, and pulmonary tuberculosis.</p><p id="p0225" class="elsevierStylePara elsevierViewall">In 1917, Dr. Potter became a member of the senior staff of Cottage Hospital at Santa Barbara, CA, and the Director of a new Metabolic Clinic, integrated into the facilities of Cottage Hospital. In 1919, G. O. Knapp, founder of Union Carbide; CKG Billings, a high executive of Union Carbide; and F.F. Peabody of Cluett, Peabody & Company, made it possible to inaugurate the Potter Metabolic Wing at Cottage Hospital, equipped with the finest laboratory and clinic for research work in Medicine. Unfortunately, in June 1919, Dr. Potter's disease progressed to diabetic coma which caused his death on July 5, 1919. The Medical Director of Santa Barbara Cottage Hospital, G.O. Knapp, following the recommendation of the Chief of Staff (Dr. Franklin R. Nuzum, previously a close associate of Dr. Woodyatt, at Rush Medical College in Chicago), requested an interview with Dr. William D. Sansum to offer him the post of Director of the Potter Metabolic Wing.</p></span>" ] ] 18 => array:5 [ "identificador" => "b0040" "tipo" => "MULTIMEDIATEXTO" "mostrarFloat" => false "mostrarDisplay" => true "texto" => array:1 [ "textoCompleto" => "<span class="elsevierStyleSections"><span id="s0040" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="st0040">Treatment of human diabetes (N.C. Paulescu, 1922)</span><p id="p0335" class="elsevierStylePara elsevierViewall">The introduction into the organism of a diabetic patient of a pancreatic extract, rendered free from proteins using acids and alkalis, using the <span class="elsevierStyleItalic">intravenous route,</span> must certainly be very <span class="elsevierStyleItalic">efficient</span> in attenuating or temporary suppressing metabolic emergencies. But this administration determines the appearance of <span class="elsevierStyleItalic">bouts of fever,</span> which make it inapplicable in medical practice. The introduction of this extract using the <span class="elsevierStyleItalic">subcutaneous route,</span> must also be <span class="elsevierStyleItalic">efficient.</span> But it produces <span class="elsevierStyleItalic">fever and sometimes abscesses…</span></p><p id="p0340" class="elsevierStylePara elsevierViewall">The introduction of an aqueous pancreatic extract via the <span class="elsevierStyleItalic">oral or intestinal</span> (enemas) <span class="elsevierStyleItalic">route is not efficacious.</span> However, this kind of treatment, repeated for many times, appears to produce in time, a significant fall in the level of urinary glucose.</p></span></span>" ] ] ] "lecturaRecomendada" => array:1 [ 0 => array:3 [ "vista" => "all" "titulo" => "<span class="elsevierStyleSectionTitle" id="st0070">References</span>" "seccion" => array:1 [ 0 => array:1 [ "bibliografiaReferencia" => array:39 [ 0 => array:3 [ "identificador" => "bb0005" "etiqueta" => "1." 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"referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The history of the discovery of insulin" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "J.B. Collip" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "J Biol Chem" "fecha" => "1923" "volumen" => "LVI" "paginaInicial" => "513" ] ] ] ] ] ] 18 => array:3 [ "identificador" => "bb0095" "etiqueta" => "19." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The original method as used for the isolation of insulin in semipure form for the treatment of the first clinical cases" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "J.B. Collip" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Biochem" "fecha" => "1923" "volumen" => "55" "paginaInicial" => "40" "paginaFinal" => "41" ] ] ] ] ] ] 19 => array:3 [ "identificador" => "bb0100" "etiqueta" => "20." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The Effect Produced on Diabetes by Extracts of the Pancreas" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:7 [ 0 => "F.G. Banting" 1 => "C.H. Best" 2 => "J.B. Collip" 3 => "W.R. Campbell" 4 => "A.A. Fletcher" 5 => "J.J.R. Macleod" 6 => "E.C. Nobel" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:4 [ "tituloSerie" => "Transactions of the Association of American Physicians" "fecha" => "1922" "paginaInicial" => "1" "paginaFinal" => "11" ] ] ] ] ] ] 20 => array:3 [ "identificador" => "bb0105" "etiqueta" => "21." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Insulin in the treatment of Diabetes Mellitus I" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:3 [ 0 => "F.G. Banting" 1 => "W.R. Campbell" 2 => "A.A. Fletcher" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Metabol Res" "fecha" => "1922" "volumen" => "II" "paginaInicial" => "547" "paginaFinal" => "604" ] ] ] ] ] ] 21 => array:3 [ "identificador" => "bb0110" "etiqueta" => "22." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Ketosis, acidosis and coma treated by insulin" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "W.R. Campbell" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Metabol Res" "fecha" => "1922" "volumen" => "II" "paginaInicial" => "605" "paginaFinal" => "635" ] ] ] ] ] ] 22 => array:3 [ "identificador" => "bb0115" "etiqueta" => "23." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The blood sugar following insulin administration and the symptom complex -hypoglycemia" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "A.A. Fletcher" 1 => "W.R. Campbell" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Metabol Res" "fecha" => "1922" "volumen" => "2" "paginaInicial" => "637" "paginaFinal" => "649" ] ] ] ] ] ] 23 => array:3 [ "identificador" => "bb0120" "etiqueta" => "24." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Three months study of the influence of the antidiabetic substance on a case of severe diabetes" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "C.C. Sutter" 1 => "J.R. Murlin" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Proc Soc Exp Biol Med" "fecha" => "1922" "volumen" => "20" "paginaInicial" => "68" "paginaFinal" => "69" ] ] ] ] ] ] 24 => array:3 [ "identificador" => "bb0125" "etiqueta" => "25." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Thompson. Continuing Quest: Dr. William David Sansum's Crusade against Diabetes" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "A. Walker" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:4 [ "titulo" => "Sansum Medical Research Foundation" "fecha" => "1977" "editorial" => "Santa Barbara" "editorialLocalizacion" => "California" ] ] ] ] ] ] 25 => array:3 [ "identificador" => "bb0130" "etiqueta" => "26." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical Observations with Insulin. I. The Use of Insulin in Diabetes Treatment" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:2 [ 0 => "F. Allen" 1 => "J.W. Sherrill" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "J Metabol Res" "fecha" => "1922" "volumen" => "2" "paginaInicial" => "804" "paginaFinal" => "985" ] ] ] ] ] ] 26 => array:3 [ "identificador" => "bb0135" "etiqueta" => "27." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Clinical Observations with Insulin.3. The influence of fat and total calories on diabetes and the Insulin requirement" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "F. Allen" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Metabol Res" "fecha" => "1923" "volumen" => "3" "paginaInicial" => "61" "paginaFinal" => "176" "itemHostRev" => array:3 [ "pii" => "S0090429508007437" "estado" => "S300" "issn" => "00904295" ] ] ] ] ] ] ] 27 => array:3 [ "identificador" => "bb0140" "etiqueta" => "28." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The Routine Treatment of Diabetes with Insulin" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "E.P. Joslin" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Am Med Ass" "fecha" => "1923" "volumen" => "80" "paginaInicial" => "1581" "paginaFinal" => "1583" "itemHostRev" => array:3 [ "pii" => "S0210480610004675" "estado" => "S300" "issn" => "02104806" ] ] ] ] ] ] ] 28 => array:3 [ "identificador" => "bb0145" "etiqueta" => "29." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The Clinical Use of Insulin" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "R.T. Woodyatt" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "J Metabol Res" "fecha" => "1922" "volumen" => "2" "paginaInicial" => "793" "paginaFinal" => "801" "itemHostRev" => array:3 [ "pii" => "S0022534708026876" "estado" => "S300" "issn" => "00225347" ] ] ] ] ] ] ] 29 => array:3 [ "identificador" => "bb0150" "etiqueta" => "30." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Bitter Sweet: Diabetes, Insulin, and the Transformation of Illness" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "F. Chris" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:3 [ "fecha" => "2003" "editorial" => "Chapel Hill" "editorialLocalizacion" => "The University of North Carolina Press" ] ] ] ] ] ] 30 => array:3 [ "identificador" => "bb0155" "etiqueta" => "31." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Quelques reactions chimiques et physiques, appliquées a l’extrait aqueux du pancréas, pour le débarraser des substances protéiques en excès" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "N.C. Paulescu" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Archives Internationales de Physiologie" "fecha" => "1923" "volumen" => "21" "paginaInicial" => "71" "paginaFinal" => "85" ] ] ] ] ] ] 31 => array:3 [ "identificador" => "bb0160" "etiqueta" => "32." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Divers procédes pour introduire l’extract pancréatique dans l’organisme d’un animal diabetique" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "N.C. Paulescu" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Archives Internationales de Physiologie" "fecha" => "1923" "volumen" => "21" "paginaInicial" => "215" "paginaFinal" => "238" ] ] ] ] ] ] 32 => array:3 [ "identificador" => "bb0165" "etiqueta" => "33." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The discovery of insulin" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "B. Michael" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:3 [ "fecha" => "1982" "editorial" => "The University of Chicago Press" "editorialLocalizacion" => "Chicago" ] ] ] ] ] ] 33 => array:3 [ "identificador" => "bb0170" "etiqueta" => "34." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Insulin in Diabetes" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "R. Carrasco-Formiguera" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Brit Med J" "fecha" => "1922" "volumen" => "9" "paginaInicial" => "1143" "paginaFinal" => "1144" ] ] ] ] ] ] 34 => array:3 [ "identificador" => "bb0175" "etiqueta" => "35." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Insulina. Estudio fisiológico y clínico" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "Rossend Carrasco-Formiguera" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:4 [ "edicion" => "2. ª ed" "fecha" => "1924" "editorial" => "Instituto Bioquímico Hermes" "editorialLocalizacion" => "Barcelona" ] ] ] ] ] ] 35 => array:3 [ "identificador" => "bb0180" "etiqueta" => "36." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:1 [ "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "R. Carrasco-Formiguera" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:3 [ "fecha" => "1972" "editorial" => "Israel Journal of Medical Sciences" "editorialLocalizacion" => "Reminiscences of a witness and participant" ] ] ] ] ] ] 36 => array:3 [ "identificador" => "bb0185" "etiqueta" => "37." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "La insulina en las afecciones quirúrgicas de los diabéticos" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "R. Carrasco Formiguera" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:6 [ "tituloSerie" => "Revista Española de Medicina y Cirugía" "fecha" => "1924" "volumen" => "7" "paginaInicial" => "379" "paginaFinal" => "394" "itemHostRev" => array:3 [ "pii" => "S0140673604155906" "estado" => "S300" "issn" => "01406736" ] ] ] ] ] ] ] 37 => array:3 [ "identificador" => "bb0190" "etiqueta" => "38." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "Hagedorn and Danish Insulin" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "H.C. Torsten Deckert" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Libro" => array:3 [ "fecha" => "2000" "editorial" => "The Poul Kristensen Publishing Co." "editorialLocalizacion" => "Herning- Denmark" ] ] ] ] ] ] 38 => array:3 [ "identificador" => "bb0195" "etiqueta" => "39." "referencia" => array:1 [ 0 => array:2 [ "contribucion" => array:1 [ 0 => array:2 [ "titulo" => "The search for insulin" "autores" => array:1 [ 0 => array:2 [ "etal" => false "autores" => array:1 [ 0 => "I. Murray" ] ] ] ] ] "host" => array:1 [ 0 => array:1 [ "Revista" => array:5 [ "tituloSerie" => "Scottish Med J" "fecha" => "1969" "volumen" => "14" "paginaInicial" => "286" "paginaFinal" => "295" ] ] ] ] ] ] ] ] ] ] ] "agradecimientos" => array:1 [ 0 => array:3 [ "identificador" => "xack36444" "titulo" => "Acknpwledgement" "texto" => "<p id="p0390" class="elsevierStylePara elsevierViewall">The authors thank Dr. Lois Jovanovic, Chief Officer, Sansum Research Diabetes Institute (Santa Barbara, CA, USA), for her kind help, facilitating reports, written documents and pictures from her own research files.</p>" ] ] ] "idiomaDefecto" => "en" "url" => "/11343230/0000002700000001/v1_201305021322/S1134323011700047/v1_201305021322/en/main.assets" "Apartado" => array:4 [ "identificador" => "7323" "tipo" => "SECCION" "es" => array:2 [ "titulo" => "Historical perspective" "idiomaDefecto" => true ] "idiomaDefecto" => "es" ] "PDF" => "https://static.elsevier.es/multimedia/11343230/0000002700000001/v1_201305021322/S1134323011700047/v1_201305021322/en/main.pdf?idApp=UINPBA00004N&text.app=https://www.elsevier.es/" "EPUB" => "https://multimedia.elsevier.es/PublicationsMultimediaV1/item/epub/S1134323011700047?idApp=UINPBA00004N" ]
| Year/Month | Html | Total | |
|---|---|---|---|
| 2024 November | 26 | 2 | 28 |
| 2024 October | 237 | 26 | 263 |
| 2024 September | 208 | 43 | 251 |
| 2024 August | 231 | 23 | 254 |
| 2024 July | 193 | 23 | 216 |
| 2024 June | 178 | 14 | 192 |
| 2024 May | 137 | 13 | 150 |
| 2024 April | 232 | 19 | 251 |
| 2024 March | 293 | 14 | 307 |
| 2024 February | 131 | 20 | 151 |
| 2024 January | 164 | 15 | 179 |
| 2023 December | 121 | 28 | 149 |
| 2023 November | 165 | 27 | 192 |
| 2023 October | 211 | 27 | 238 |
| 2023 September | 129 | 16 | 145 |
| 2023 August | 121 | 24 | 145 |
| 2023 July | 100 | 17 | 117 |
| 2023 June | 107 | 28 | 135 |
| 2023 May | 128 | 26 | 154 |
| 2023 April | 110 | 22 | 132 |
| 2023 March | 118 | 21 | 139 |
| 2023 February | 111 | 18 | 129 |
| 2023 January | 119 | 17 | 136 |
| 2022 December | 101 | 37 | 138 |
| 2022 November | 129 | 35 | 164 |
| 2022 October | 136 | 41 | 177 |
| 2022 September | 94 | 27 | 121 |
| 2022 August | 104 | 33 | 137 |
| 2022 July | 115 | 22 | 137 |
| 2022 June | 129 | 28 | 157 |
| 2022 May | 143 | 26 | 169 |
| 2022 April | 166 | 31 | 197 |
| 2022 March | 180 | 45 | 225 |
| 2022 February | 200 | 20 | 220 |
| 2022 January | 198 | 31 | 229 |
| 2021 December | 128 | 21 | 149 |
| 2021 November | 143 | 43 | 186 |
| 2021 October | 138 | 42 | 180 |
| 2021 September | 141 | 17 | 158 |
| 2021 August | 112 | 10 | 122 |
| 2021 July | 86 | 14 | 100 |
| 2021 June | 73 | 16 | 89 |
| 2021 May | 125 | 5 | 130 |
| 2021 April | 429 | 25 | 454 |
| 2021 March | 244 | 29 | 273 |
| 2021 February | 151 | 32 | 183 |
| 2021 January | 197 | 24 | 221 |
| 2020 December | 213 | 27 | 240 |
| 2020 November | 210 | 27 | 237 |
| 2020 October | 127 | 11 | 138 |
| 2020 September | 94 | 16 | 110 |
| 2020 August | 138 | 23 | 161 |
| 2020 July | 109 | 10 | 119 |
| 2020 June | 98 | 23 | 121 |
| 2020 May | 122 | 24 | 146 |
| 2020 April | 166 | 8 | 174 |
| 2020 March | 115 | 13 | 128 |
| 2020 February | 105 | 14 | 119 |
| 2020 January | 114 | 17 | 131 |
| 2019 December | 88 | 26 | 114 |
| 2019 November | 82 | 24 | 106 |
| 2019 October | 74 | 16 | 90 |
| 2019 September | 110 | 22 | 132 |
| 2019 August | 73 | 14 | 87 |
| 2019 July | 114 | 14 | 128 |
| 2019 June | 117 | 38 | 155 |
| 2019 May | 236 | 43 | 279 |
| 2019 April | 130 | 48 | 178 |
| 2019 March | 110 | 21 | 131 |
| 2019 February | 98 | 21 | 119 |
| 2019 January | 67 | 13 | 80 |
| 2018 December | 60 | 21 | 81 |
| 2018 November | 80 | 17 | 97 |
| 2018 October | 119 | 46 | 165 |
| 2018 September | 102 | 9 | 111 |
| 2018 August | 124 | 6 | 130 |
| 2018 July | 53 | 5 | 58 |
| 2018 June | 55 | 2 | 57 |
| 2018 May | 84 | 7 | 91 |
| 2018 April | 51 | 1 | 52 |
| 2018 March | 41 | 3 | 44 |
| 2018 February | 130 | 1 | 131 |
| 2018 January | 101 | 7 | 108 |
| 2017 December | 129 | 1 | 130 |
| 2017 November | 101 | 4 | 105 |
| 2017 October | 41 | 5 | 46 |
| 2017 September | 40 | 5 | 45 |
| 2017 August | 32 | 12 | 44 |
| 2017 July | 22 | 14 | 36 |
| 2017 June | 26 | 20 | 46 |
| 2017 May | 43 | 17 | 60 |
| 2017 April | 46 | 9 | 55 |
| 2017 March | 38 | 23 | 61 |
| 2017 February | 130 | 2 | 132 |
| 2017 January | 23 | 1 | 24 |
| 2016 December | 31 | 3 | 34 |
| 2016 November | 65 | 7 | 72 |
| 2016 October | 61 | 6 | 67 |
| 2016 September | 29 | 4 | 33 |
| 2016 August | 22 | 1 | 23 |
| 2016 July | 29 | 6 | 35 |
| 2016 June | 106 | 20 | 126 |
| 2016 May | 110 | 38 | 148 |
| 2016 April | 100 | 34 | 134 |
| 2016 March | 109 | 21 | 130 |
| 2016 February | 105 | 24 | 129 |
| 2016 January | 117 | 20 | 137 |
| 2015 December | 99 | 27 | 126 |
| 2015 November | 131 | 20 | 151 |
| 2015 October | 125 | 24 | 149 |
| 2015 September | 96 | 13 | 109 |
| 2015 August | 134 | 5 | 139 |
| 2015 July | 197 | 4 | 201 |
| 2015 June | 122 | 6 | 128 |
| 2015 May | 131 | 12 | 143 |
| 2015 April | 139 | 18 | 157 |
| 2015 March | 225 | 21 | 246 |
| 2015 February | 232 | 13 | 245 |
| 2015 January | 80 | 8 | 88 |
| 2014 December | 111 | 7 | 118 |
| 2014 November | 115 | 9 | 124 |
| 2014 October | 128 | 11 | 139 |
| 2014 September | 117 | 11 | 128 |
| 2014 August | 73 | 2 | 75 |
| 2014 July | 98 | 6 | 104 |
| 2014 June | 107 | 2 | 109 |
| 2014 May | 87 | 4 | 91 |
| 2014 April | 88 | 3 | 91 |
| 2014 March | 100 | 3 | 103 |
| 2014 February | 76 | 4 | 80 |
| 2014 January | 73 | 2 | 75 |
| 2013 December | 89 | 6 | 95 |
| 2013 November | 69 | 4 | 73 |
| 2013 October | 67 | 6 | 73 |
| 2013 September | 45 | 2 | 47 |
| 2013 August | 19 | 1 | 20 |
| 2013 July | 10 | 0 | 10 |
| 2011 January | 302 | 0 | 302 |
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