Acta Diabetologica (2022) 59:1635–1651 https://doi.org/10.1007/s00592-022-01976-y ORIGINAL ARTICLE I‑European research, the cradle of the discovery of the antidiabetic hormone: the pioneer roles and the relevance of Oskar Minkowski and Eugène Gley Alberto de Leiva‑Hidalgo1,2,3 · Alejandra de Leiva‑Pérez3 Received: 12 July 2022 / Accepted: 21 August 2022 / Published online: 14 October 2022 © The Author(s) 2022 Abstract Aims The introduction of hormonal treatment in severe diabetes in 1922 represented a clinical and social impact similar to that of antibiotic therapy. In October 1923, the Assembly of the Karolinska Institute decided to award the Nobel Prize in Physiology or Medicine to the Canadian Frederick Grant Banting and the Scottish John James Rickard Macleod, researchers at the University of Toronto (UT), for "the discovery of insulin a year before". A few weeks later, European and American researchers protested the decision. The controversy remains to this day. Methods We have conducted a comprehensive review of primary and critical sources focused on theorganotherapy of animal and human diabetes mellitus since 1889, when Oskar Minkowski demonstrated the induction of experimental diabetes by total pancreatectomy in the dog, until the spring of 1923, when the Nobel Foundation had already received all the nomina- tions for the award in Physiology or Medicine. Results The in-depth analysis of all these sources revealed that Europe was the cradle of the discovery of the antidiabetic hormone. The discovery involved multiple research steps headed by a long list of key investigators, mainly European. Conclusion Marcel Eugène Émile Gley was the first to demonstrate the presence of the “antidiabetic principle” in extracts from “sclerosed” pancreas. The French physiologist pioneered the successful reduction of glycosuria and diabetic symptoms by the parenteral administration of pancreatic extracts to depancreatized dogs in experiments developed between 1890 and 1905, antedating insulin in two decades. Keywords Organotherapy · Diabetes · Pancreatectomy · Pancreatic extracts · Antidiabetic hormone Pancreas: exocrine gland unaware of the functions of the gland and its main duct, never published the discovery. He engraved an anatomical The discovery in 1642 of the main pancreatic duct by Johann drawing of the pancreas on copper plates. The original plate Georg Wirsüng (1589–1643) in Padua was decisive for the is exhibited in the Palazzo del Bo in Padua. In 1654 Francis subsequent definition of the pancreas as an important secre- Glisson described the sphincter muscle surrounding Vater's tory gland in the process of digestion. Wirsüng, who was ampulla; in 1711, the anatomy of the ampulla was detailed by Abraham Vater (1684–1761). In 1887, Ruggero Oddi Managed By Antonio Secchi. (1864–1913) characterised the circular and longitudinal muscle fibres wrapped around the end of the bile and pan- Alberto de Leiva-Hidalgo and Alejandra de Leiva-Pérez have creatic ducts, which justifies it being known as the sphincter contributed equally to this work. of Oddi. The first description of the accessory duct has been attributed to Giovanni Domenico Santorini (1681–1737), not * Alberto de Leiva‑Hidalgo aleiva@fdiabem.org without some controversy. Franciscus Sylvius (Frans de le Boë), professor at the University of Leiden, and teacher of 1 Instituto Interuniversitario López Piñero, University De Graaf, also published the existence of the second duct of Valencia, Valencia, Spain (Fig. 1) [1, 2]. 2 Universidad Autónoma de Barcelona, Barcelona, Spain Claude Bernard's scientific work between 1843 and 1878 3 Fundación DIABEM, Barcelona, Spain comprised more than three hundred scientific papers. Most 13 Vol.:(0123456789) 1636 Acta Diabetologica (2022) 59:1635–1651 Fig. 1  Left image: F.G. Wirsüng (1642). Original copperplate exhib- Henry Gray (1918) Anatomy of the Human Body, Fig. 1100. Provo, ited in the Palazzo del Bò, Padua (Edizione Universitarie Patavine, Utah. Brigham Young University: Lea & Fibiger; p. 1202. Internet Padua) [1]. Right image: Illustration of the pancreatic-duodenal area. Archives. https://​www.​bartl​eby.​com/​107/​illus​1100.​html of them were reports of his laboratory experiments presented Claude Bernard (1813–1878): the internal to scientific societies, mainly the Académie des Sciences and environment (“milieu intérieur”) the Société de Biologie. Other important contributions were and the birth of endocrinology his lectures given to students at the Collège de France, the Sorbonne and the Musée d' Histoire Naturelle [3]. Between 1846 and 1848, Bernard reported that sugar was In 1843 he defended his doctoral thesis, which was the present in the blood of normal animals, even in the fasting first in a long series of publications on digestion and nutri- period. He also observed that the concentration of sugar tion [4]. His complete work on the exocrine function of the in the liver was higher than in the portal vein. While sugar pancreas, a classic document of pancreatic physiology that was found in very high amounts in the liver, it was practi- included experiments on pancreatectomised dogs, was pub- cally absent in most organs [6, 7]. lished in 1856 (Fig. 2) [5]. Fig. 2  Bernard C (1856): “Mémoire sur le pancréas et sur le rôle du suc pancréatique dans les phénomènes digestifs”. First edition. Published in vol I of Supplement aux Comptes Rendus, pp 379–563. Selected plates [5] 13 Acta Diabetologica (2022) 59:1635–1651 1637 In March 1853 Bernard defended his second doctoral thesis, dysenteric process in his native village of St Julien, near this time in the natural sciences. His experiments confirmed his Lyon, he wrote a fundamental text in his scientific biogra- idea that the liver was a glucose-synthesising laboratory [8]. phy, Introduction à l'étude de la médecine expérimentale, He published an article on the isolation of hepatic glycogen creating for posterity the foundations of scientific research in 1857, almost simultaneously with Christian Hensen, who in medicine and the interaction between clinic and labora- demonstrated that glycogen was a carbohydrate [9]. tory [17]. Bernard hypothesised that, after intestinal absorption, Bernard was also interested in the pathogenesis of dia- sugar was converted to hepatic glycogen. He attributed betic disease [12, 13, 18]. In 1877 he prepared 21 lectures excess secretion to diabetes, as a consequence of three pos- on diabetes at the Collège de France (Fig. 3) [19]. sible processes: (a) hepatic failure of glycogen production; (b) exacerbated glycogenolysis; or (c) decreased sugar combustion, mainly in muscle [10]. Bernard refuted the First description of the histology hypothesis of the pancreatic origin of diabetes, observing of the pancreas: Paul Langerhans (1847– that atrophy of the pancreas secondary to ligation of the 1888) pancreatic ductal system was not associated with experi- mental diabetes, [11–13]. Bernard's demonstration of the Before 1869 the pancreas had been described as a racemose hepatic synthesis of glycogen and the hepatic release of gland, containing infiltrated fat. glucose into the blood was the basis for his proposal of the Berlin student Paul Langerhans, who was influenced by "internal environment" (milieu intérieur) and homeostasis, Rudolph Virchow and Julius Cohnheim, worked in Vir- anticipating the birth of endocrinology [14]. chow’s laboratory at the Berlin Pathological Institute [20]. By detecting the presence of glucose in the cerebrospi- Langerhans’s early observations were made on rabbit, sala- nal fluid, Bernard postulated that the excessive conver- mander, guinea pig, dog, cat, pigeon, snake, frog, hen and, sion of glycogen to glucose could be the consequence of finally, man [21]. In 1869, he reported his findings on the brain lesions/alterations responsible for hyperglycaemia- histology of human pancreas [22]. glucosuria, similar to what was observed experimentally In his doctoral thesis, Langerhans described in detail with the "piqûre diabétique". He stimulated the floor of the the ductal system of the gland by injecting Prussian blue fourth ventricle with a needle, inducing a transient hyper- dye and glycerine. In macerated fragments of the pan- glycaemia lasting less than 24 h. The connection between creas he discovered polyhedral cells with clear cytoplasm, the vasomotor centre and a putative diabetic centre in the grouped in small masses (Haüflein) of various sizes in medulla would make possible an increased conversion of diameter (0.1–0.25 mm), which, in contrast to the cen- glycogen to glucose by virtue of a vasomotor disturbance troacinar cells, did not show any transition to the ductal in the liver, of neurogenic origin [15, 16]. epithelium. This investigation was the first comprehen- As early as 1858, Bernard planned to write a treatise sive description of pancreatic histology (Fig. 4) [23]. on experimental medicine. While convalescing from a Fig. 3  Claude Bernard. Oil painting by Charles Auguste Mengin (1870). (Internet Archives). Leçons sur le diabète et la glycogenèse animale. Sacarimeter used by Bernard (1877) [19] 13 1638 Acta Diabetologica (2022) 59:1635–1651 Langerhans made it clear that he ignored the function of due to its intestinal adhesion and profuse vascularisation, nor these cells [21–24]. The French histologist Edouard Laguesse the neighbouring area of the duodenum. The dogs showed immortalised Paul Langerhans 24 years later by giving his polyuria and polydipsia; they survived several months, with name to these cellular islets without an excretory duct [25]. the exception of those that died of infectious processes. Brun- Another area of interest for Langerhans was the skin. ner did not relate these findings to diabetes [1]. In 1868, he reported dendritic cells in the epidermis; the We owe the first allusion to the relationship between pan- significance of these cells remained an enigma for over a creas and diabetes to Richard Bright (1789–1858), who in century; it has been discovered that they are immunocom- 1833 reported a clinical case of pancreatic cancer with liver petent cells involved in many dermatological diseases [26]. metastases associated with a syndrome of polyuria-polydip- In November 1871, Langerhans was appointed lecturer (Pri- sia and concentrated urine with a "very sweet taste" [27]. vatdozent) and two years later, Associate Professor of Pathology Étienne Lancereaux (1829–1910) practised clinical and Anatomy at the Faculty of Medicine, University of Freiburg. medicine from 1869 in several hospitals in Paris as direc- In September 1874 he was diagnosed with pulmonary tubercu- tor of several Internal Medicine teams (Lourcone, 1874; St. losis. He resigned from his professorship and decided to spend Antoine, 1876; Pitié, 1878, and finally Hôtel Dieu, 1889). the last years of his life in Madeira, where he died in 1888. [20]. His main area of interest was the clinicopathological aspects of diabetes mellitus. A member of the French Academy of Medicine, he was elected president in 1903. In 1877 he Diabetes mellitus: a pancreatic disease coined the term pancreatic diabetes to describe two cases of young subjects who died with severe diabetes and showed The Swiss Johann Conrad Brunner (1653–1727) performed pancreatic atrophy at autopsy (Fig. 5) [28]. ligatures of the Wirsung duct, pancreatectomies and the com- Lancereaux made a clear distinction between diabète bination of both procedures, publishing his findings in 1683. maigre and diabète gras. He considered diabetes as a syn- He was only able to perform incomplete pancreatectomies; it drome rather than a disease [29–35]. was impossible for him to resect the upper region of the gland Fig. 4  Photograph, Paul Langerhans (unknown author and date). Dissertation. University of Berlin, 1869 [23] [1] 13 Acta Diabetologica (2022) 59:1635–1651 1639 Lancereaux contacted Bernard to discuss these findings in Meeting of the Medical Society of Rhein-Westphalen, on detail. At his insistence, the physiologist agreed to carry out November 18, 1928, in Köln. Rachmiel Levine translated further experiments and to administer pancreatic extract to the conference from Muenchener Medizinische Wochen- pancreatectomised dogs. Unfortunately, Bernard died a year schrift (76:311–315; 22 February, 1929) and the text was later without being able to fulfil his promise [1]. reproduced by the American Diabetes Association in 1989 on the occasion of the 100th anniversary of the first publica- tion by J. von Mering and O. Minkowski. We extracted here Oskar Minkowski: the discovery some paragraphs of this historical event [38]: of pancreatic diabetes (1889) (…) Had we realized that all previous attempts at pancrea- Oskar Minkowski (1858–1931) belonged to a family of Jew- tectomy had led to nothing of note and that no less a person ish descent from Eastern Europe, who made important con- than Claude Bernard had stated that it was impossible for dogs to survive the total surgical removal of the pancreas, we tributions to the science of the time. Born in Alexoten, near would have certainly not dared to make a new attempt at this Kaunas (now Lithuania), he studied medicine at Freiburg, procedure. Strasbourg and Könisberg, where he completed his doctorate (…) We undertook our investigation for purposes other than to in 1881. He went with his mentor, Professor Bernhard Nau- study the regulation of carbohydrate metabolism. (…) “I tried to tie all the ducts of the pancreas in order to show nyn, to the University of Strasbourg, where he received the that neutral fat is absorbed more slowly than fatty acid, but I appointment of Associate Professor in 1891. His academic could not totally prevent the appearance of pancreatic juice in career continued in Köln, Greisfald and finally in Breslau the lumen of the intestine”, said von Mering. (Professor and Chair of the Department of Medicine), retir- (…) Why didn’t you extirpate the gland? I asked…Please, give me a dog and I will try to do a total extirpation of the pan- ing in 1926. Among his many contributions in the field of creas…The same day von Mering transferred a dog to me… diabetes mellitus were the identification of beta-hydroxybu- Von Mering and I removed the gland in toto; I endeavoured tyric acid in urine, the finding of decreased blood levels of to do this under meticulously clean surgical conditions…We carbon dioxide tension and the incorporation of alkalis in the did not think of diabetes; hence, we did not test the urine for glucose. treatment of diabetic ketoacidosis [36]. (…) On several occasions the dog emptied his bladder spontane- Minkowski combined great talent and intuition with ously on the floor and I reproached the lab assistant that the surgical skills. “A lucky combination of serendipity, intel- animal was not properly trained. “I did train him”, he stated, ligence and surgical dexterity”, explained the legendary “but this animal is quite peculiar. No sooner does he empty his bladder completely when he has to urinate again and again”. landmark of the development of diabetes after complete I followed a subconscious hunch. I gathered a few drops of pancreatectomy in 1889 [37]. urine off the floor into a pipette and tested for glucose; it 40 years after the discovery, Minkowski presented the produced a strong reduction signifying more than 10% sugar analysis of the milestone experiment at the 25th Anniversary content… Fig. 5  Étienne Lancereaux. Author and date unknown. The National Library of Medicine. Plate depicting atrophy of the pancreas in a case of severe diabetes [29] 13 1640 Acta Diabetologica (2022) 59:1635–1651 Minkowski confirmed the pancreatic origin of diabetes (cats, rabbits, rats, guinea pigs, batrachians and birds) and in experiments with three other dogs. The second and third in humans (Fig. 8) [45]. She obtained excellent glandular animals died after two days due to duodenum necrosis; both images using staining solutions to highlight the ductal sys- developed glycosuria before they died. The fourth animal tem and vascularisation. survived and from the second day after the operation showed Animals survived up to 197 days after ligation of the a persistent diabetes. Minkowski presented the first paper at ductal system. Acinar hypotrophy/atrophy ("degeneration") the Strasbourg Medical Society in May 1889, at the Interna- was not associated with glycosuria in any case in serial tional Congress of Physiology in Basel and in a lecture at the measurements over one month. As the disappearance of the Society of Naturalists in Heidelberg in September 1889. Von acinar tissue and ductal system was greater than that of the Mering and O. Minkowski published the first two reports connective tissue, the degenerated gland maintained its lobu- under joint authorship [39, 40]. The first publication was a lar appearance in most cases. short paper in 1889 (Fig. 6) [39] and more extensive reports Dewitt also carried out histological and metabolic stud- appeared in 1890, 1892 and 1893 [40–43]. The primacy of ies after the death of the animals. Dividing the pancreas discovery undoubtedly belongs to Minkowski [44]. into small fractions, she investigated the digestion of starch After the first experiment, von Mering did not partici- with iodine and Fehling's solution, the fat content by the pate in further research, directing his excellent academic emulsification process, and of protein content by Biuret's career elsewhere. He was the discoverer of the drugs veronal colorimetric test. She also determined the glycolytic activ- and paracetamol and the glycosuric action of phloridzin. ity of the pancreatic extract (Pavy method) before and after Oskar Minkowski provided the first conclusive evidence of exposure to elevated temperatures for 24 h, using muscle the impact of the pancreas on diabetes (Fig. 7) and demon- tissue as a target. The results of these studies allowed her to strated that the disease is due to the absence of the pancre- conclude the following: atic active substance that is transported by the bloodstream, a discovery considered the most important in the history of 1. The histology of the islets of Langerhans showed no diabetes [37]. differences among the vertebrate species investigated. Between 1904 and 1906, at the Department of Medicine 2. The structure of the islets remained practically and Pathology of the University of Michigan (headed by unchanged in the "degenerated pancreas". George Dock), Lydia Maria Adams DeWitt (1859–1923) 3. The "pancreatic degeneration" was not accompanied by carried out interesting studies on the morphological and glycosuria in any case. microscopic analysis of the endocrine and exocrine pan- 4. The islets of Langerhans release a secretion into the creas and on the pathophysiology of diabetes. She investi- bloodstream that has no digestive function. gated the morphology and microscopic anatomy of acinar tissue and islets of Langerhans in various animal species Fig. 6  In 1889 Oskar Minkowski, with help from Joseph von Mering, discovered that diabetes is a pancreatic disease [39] 13 Acta Diabetologica (2022) 59:1635–1651 1641 Fig. 7  Left: Portrait of Oskar Minkowski. Naunyn-Schmiedebergs (1893) Untersuchungen über den Diabetes mellitus nach Exstirpation Archiv für Experimentelle Pathologie und Pharmakologie Collection des Pankreas. Leizpig: F.C.W. Vogel [42] BIU Santé-Licence ouverte. Unknown author. Right: Minkowski O 5. Secretion from the islets of Langerhans exerts a potent distributed fibrous tissue with affected islets as the remain- glycolytic effect, confirming its character as an "active ing elements in association to atrophied cells [49]. principle" on carbohydrate metabolism [46]. Opie was the first to describe hyaline degeneration of the islets of Langerhans, in which the parenchymatous Eugene Lindsay Opie (1873–1971) received his PhD cells are replaced by hyaline material [50]. This alteration in Medicine from Johns Hopkins Medical School. Under is most evident in the tail of the gland. Hyaline trans- the tutelage of Wiliam H. Welch he remained at the institu- formation resides in the accumulation of a homogeneous tion as a fellow, assistant and instructor in pathology [47]. material between the islet cells and the capillary wall that Quite soon, Opie won wide recognition for his outstanding stains intensely with eosin and picric acid. Hyaline degen- observations related to disease of the pancreas. In 1899 he eration occurs as scattered globular masses. In some cases, reported the relation between haemochromatosis and dia- the hyaline substance occupies almost the whole islet area. betes [48]. In certain cases of diabetes, Opie reported an infiltrative Opie described two forms of chronic inflammation of process unrelated to hyaline degeneration, indistinctly the gland: a) interlobular pancreatitis, comprising fibrous aggressive against acinar cells and islets, corresponding tissue proliferation, affecting the islets of Langerhans only to foci of haemorrhagic necrosis, coinciding with an acute/ in very advanced stage of the sclerotic process; this vari- subacute clinical course in a significant fraction of affected ety typically appears after the occlusion of the pancreatic patients [51]. In 1903, at the age of 30, only five years after duct; b) interacinar pancreatitis, showing more diffusely finished medical school, Opie published his classic book Disease of the Pancreas (Fig. 9) [52]. 13 1642 Acta Diabetologica (2022) 59:1635–1651 Fig. 8  Picture of Lydia Maria Adams DeWitt. Unknown Author and Unknown Date. (Internet Archives). Dissection of the pancreas of the cat clearly reveals the ductal system and its relationship to the venous system (DeWitt, 1906) [46] In 1904, Opie joined the Rockefeller Institute. Between of a cannula introduced into Wirsüng's canal, he injected 1910 and 1923 he became member of the faculty at Wash- molten paraffin [54]. ington University Medical School in St. Louis, and in Hédon then removed the entire vertical portion of the 1932, he became professor of Pathology at Cornell Medi- gland, which was easy to separate from the rest, and ligated cal School. In 1940 he returned to the Rockefeller Institute its attachment to the head of the pancreas. After 8–15 days, to concentrate on research, and he remained active into his he would again open the abdomen (incision at the level of nineties [1]. the right hypochondrium) and perform the entire exeresis. The removed pancreas showed atrophy and sclerosis, with a loss of up to two-thirds of its original volume. Within Experimental diabetes: pioneering 24–48 h of complete pancreatectomy, the animals showed contributions of Emmanuel Charles Èdouard glycosuria, increased azoturia, polyuria, polydipsia, and Hédon (1863–1933) voracious appetite. Despite increased food intake, they lost weight and muscle mass. Operated animals survived for 15 Emmanuel Hédon was born in Burie. He was professor of to 30 days, occasionally up to 3 months. They did not die Physiology at the University of Montpellier and elected as a result of the surgical trauma but as a consequence of member of the French Academy of Medicine in 1914. In the disease caused by the removal of the pancreas. In all 1891, he described his two-stage pancreatectomy proce- cases of complete ablation of the pancreas, severe glyco- dure, using the dog as an experimental animal (Fig. 10) suria was detected within 24–48 h (average 50 g/L). After [53]. reaching the maximum, glycosuria decreased until death Hédon confirmed Minkowski's criteria which consid- of the animal, disappearing two to three days earlier. Dia- ered the main operative rules in complete pancreatectomy betes associated with complete pancreatectomy in the dog to be: (a) ensure haemostasis; (b) preserve the vascularisa- was similar to that known in man as "lean diabetes" [53]. tion of the duodenum to prevent necrosis; (c) observe strict In several lectures (9 April, 1 August and 4 October) in antisepsis. In all his operations he ligated the pancreati- 1892, Hédon presented to the Société de Biologie (Paris) coduodenal vascular trunk. In the first operative stage he the details of the procedure and the results obtained with the made a central abdominal incision (above the linea alba) subcutaneous autotransplantation of the pancreas, as well as and exposed the duct of Wirsüng, close to the duodenal the peculiarities of experimental diabetes. junction. After ligating the accessory duct, with the help 13 Acta Diabetologica (2022) 59:1635–1651 1643 Fig. 9  Portrait of Eugene L. Opie. Images from the History of Medicine (IHM). National Library of Medicine (NLM Image ID: B020236. http://​ resou​rce.​nlm.​nih.​gov/​10142​4810 [1]. Drawing of the islands of Langerhans cells partly transformed into hyaline material (Opie, 1903) [52] Fig. 10  Emmanuel Hédon. Photograph of P. Sollelliano (Collection BIU Santé Medecine, Université de Paris). In 1891 he described his original technique of complete pancreatectomy of the dog, performed in two operative stages [53] 13 1644 Acta Diabetologica (2022) 59:1635–1651 The autotransplantation procedure consisted of fixing the Organotherapy of diabetes: initial stage lower portion of the pancreas under the skin of the dog's abdomen, preserving the vascular connection to ensure glan- The discovery of internal secretions led to the origin of dular nutrition, while adhesions between the pancreas and organotherapy or opotherapy, a procedure that uses extracts the subcutaneous cellular tissue were being formed. When from animal organs to replace an absent or insufficient inter- the surgical wound healed, the pancreatic fragment only nal secretion in the organism. communicated with the abdominal cavity through two very In 1884, Victor Horsley demonstrated the induction of an thin vessels (artery and vein) that passed through the scar experimental model of myxedema by removing the thyroid tissue of the wound. In the first days after the operation, gland from an ape [60]. In 1891, George Murray adminis- the retention of pancreatic juice in the glandular channels tered a fresh extract of sheep thyroid hypodermically to a caused the glandular fragment to increase in volume and 46-year-old woman with florid myxedema [61]. The patient form a tumour under the skin the size of an egg. Through survived to the age of 74 years thanks to thyroid organo- the healed wound runs a small fistulous fragment through therapy, subsequently also successfully administered orally. which pancreatic juice is poured. Over time the fistula closes Organotherapy of hypothyroidism with thyroid extracts rep- and excretion is exhausted. If the dog with a subcutaneous resented one of the most important triumphs of hormone pancreatic autotransplantation has the pancreatic remnant replacement therapy and scientific medicine. in the abdomen removed, glycosuria does not occur. If the Several research teams tested the administration of pan- graft is removed, severe glycosuria develops within hours creatic extracts from various animal sources in experimental and persists until death in a profound state of cachexia [55]. diabetes and in isolated cases in the clinic, mainly in Great The liquid poured from the small fistula is analysed with Britain, using commercial pancreatic extracts administered the following protocol: (1) Addition of a few drops of the orally or parenterally, with unsatisfactory results, published liquid to a paste of cooked starch and heating over the flame in 1893 [62–68]. In 1894, P. Watson Williams treated with of a Bunsen burner; in a few seconds the saccharisation pancreatic extracts a 15-year-old boy in the Bristol Royal process takes place, and the addition of the Fehling solu- Infirmary during approximately a month, without suc- tion shows its reducing capacity. (2) Stirring in a test tube cess. Then, pieces of sheep pancreas were subcutaneous a few drops of the liquid with a small volume of olive oil; a implanted. The procedure triggered a diabetic coma and persistent emulsion is instantly generated and after several the boy died three days later. The case was reported as hours the mixture becomes acidic. (3) Introduction of small an overt failure (“we must guard against attributing a too fragments of muscle tissue into the fistula fluid and heating important position to the pancreas as a factor in diabetes of the mixture in an oven at 40 °C; after two hours digestion mellitus”) [69]. of the tissue takes place; the process is continued by add- Leonidas Sobolev (1876–1919), a collaborator of L. ing half the volume of water and boiling it; the albumin is P. Pavlov, observed that ligation of the pancreatic duct in digested and the clean filtrate is precipitated by the addition the rabbit induced hyperplasia of the islets of Langerhans, of special reagents for peptones [56]. a procedure that facilitated the anatomical isolation of the Hédon’s textbook Physiologie normale et pathologique islets and the study of their properties without the presence du pancréas comprises his most relevant contributions to of digestive ferments, facilitating the organotherapy of dia- experimental diabetes, which expand on the descriptions of betes. To this end, he suggested the use of embryonic or his research published in 1891–1892 [57]. early-aged islets, comparatively more developed than acinar Joseph H. Pratt praised Hédon’s contributions to experi- tissue [70]. mental diabetes at the 64th Annual Meeting of the American Between 1902 and 1904, John Rennie and Thomas Fraser, Medical Association, held in 1910 in Saint Louis. In his researchers at the University of Aberdeen, administered pan- words: “Hédon has asserted that the internal secretion of the creatic extracts from bony fishes (teleosts) and cartilaginous pancreas will remain a hypothesis until it is possible to iso- skeleton fishes (elasmobranchs) for months to five patients late from the gland a substance, the injection of which will with diabetes (clinically severe in four of them). In teleost check completely the diabetes of a depancreatized dog” [58]. fish, in particular, the islets of Langerhans are located inde- Emmanuel Charles Èdouard Hédon was nominated four pendently of the exocrine pancreas. The islets were macer- times for the Nobel Prize in Physiology or Medicine (three ated in a mortar with a weakly acidic (acetic) solution at in 1926 and one in 1932) [59]. 40 °C and then filtered before daily oral administration of 13 Acta Diabetologica (2022) 59:1635–1651 1645 4 g in three doses. The experience did not generate relevant Murray. He was also the first to understand and publish the results. One patient was additionally treated hypodermi- physiological role of the parathyroid glands, as well as inves- cally with three daily doses of 1.5 g, also without significant tigating the relationship between the adrenal glands and the results (the patient died in diabetic coma) [71]. autonomic nervous system. A worthy follower of Claude Bernard, his treatise on internal secretions is considered a most important document (Fig. 12). Marcel Eugène Émile Gley (1857–1930) Many researchers and historians consider Gley to be a cofounder of organotherapy and endocrinology [1]. His Eugène Gley was born in Espinal (France). He received critical spirit regarding experimentation with organ extracts his medical training at the universities of Montpellier and earned him antipathy among surgeons and clinical endo- Nancy, where he defended his doctoral thesis in 1881. He crinologists of his time who overindulged in organ trans- entered the Collège de France, under the direction of Jules plantation or administration of glandular extracts with little Marey, in 1880. Between 1886 and 1893 he was director scientific rigour [73]. of the clinical laboratory at the Hotêl Dieu. He obtained Between 1881 and 1929 he published 524 papers [74]. He the post of professeur agrégé de Phisiologie at the Faculty was particularly interested in physiology and organotherapy, of Medicine in Paris (Sorbonne) and in 1908 the chair of mainly of the endocrine glands. Eugène Gley received a total General Biology at the Collège de France. He collaborated of fifty-one nominations for the Nobel Prize in Physiology for many years with the Société Française de Biologie or Medicine (1921, 1925, 1926, 1928 and 1931), eleven of (vice-president in 1897 and secretary in 1899), publishing them in 1921 [75]. numerous works in its official journal (Comptes Rendus des A group of selected works carried out by E. Gley qualifies Séances et Mémoires de la Société de Biologie) (Fig. 11). him as undisputed authority on the induction of experimental A member of the French Academy of Medicine since 1903, diabetes and a pioneering scientist in therapeutic trials with he became its president in 1927. Shortly before his sudden pancreatic extracts in the pancreatectomised animal, which death in Paris on 25 October 1930, he received the Osiris he initiated in 1890 with positive results. Within hours, prize in Physiology from the Institut de France [72]. pancreatectomised dogs developed glycosuria, ketonuria In 1890, Gley demonstrated that thyroidectomised ani- and azoturia, only in case of complete glandular ablation. mals could survive if treated with aqueous extract of thyroid Coincidental observations were confirmed in other animal gland, anticipating its introduction into the clinic by G.B. species (pigs, cats, rabbits, frogs, turtles…). Shortly after Fig. 11  Eugène Gley. For many years he collaborated with the Société de Biologie (Paris) and its journal, C.R. Soc. Biol. Wellcome Collection Library, London, reference 127,961. Probable date: 1925 13 1646 Acta Diabetologica (2022) 59:1635–1651 surgery, the animals became voracious and showed polyuria the active principle of the islets of Langerhans, capable of and polydipsia. A dog weighing 7 kg excreted over 1000 ml preventing experimental diabetes, Gley reproduced the pre- of urine per day as opposed to 200–400 ml previously. In vious experiments of Minkowski and Bernard. To eliminate addition to glucose, the urine of animals with experimen- the exocrine function of the gland, he ligated the accessory tal diabetes contained high concentrations of acetoacetic pancreatic duct and injected into Wirsüng's canal mixtures acid, hydroxybutyric acid and acetone [76]. Several weeks of olive oil and glycerine, or sodium carbonate and glycer- later, the dogs developed serious malnutrition in associa- ine, or gelatine and melted tallow at 40 °C. To check that tion to muscle weakness, important weight and hair loss, the product penetrated the entire gland, he used gelatine and died of marasmus [77]. Gley found that the regulatory coloured blue or tallow coloured violet. He waited for the function of the pancreatic antidiabetic principle extended to time required for the 'degeneration' of the acinar tissue to the liver. Pancreatic glycosuria did not occur if the animal take place and prepared aqueous extracts of the 'sclerosed was hepatectomised at the same operative time (experiments pancreas. On December 16, 1892, Gley administered the with frogs). J. Thirolox and É. Gley performed subcutane- aqueous extract of "degenerated pancreas" intraperitoneally ous autotransplantations in 12 previously pancreatectomised to a dog pancreatectomised in two stages (Hédon's proce- dogs, following the procedure described by Hédon. The sur- dure), which reduced the daily absolute glycosuria from viving animals developed transient glycosuria (4–5 days) 115.5 to 38.6 g, an experiment he described in detail in 1900 and the "tumour" generated by the autotransplantation (Fig. 13) [78]. increased considerably in size. Graft exeresis led to the rapid Statement and sealed letter from E. Gley to the Société onset of marked hyperglycaemia and within a few weeks the de Biologie de France. animals died with diabetic cachexia, as reported by Hédon. When the first experiences of the University of Toronto These experiments convinced Gley, definitively, that dia- research team led by J.J.R. Macleod were published, claim- betes was indeed a pancreatic disease and not a liver disease, ing that extracts from pancreatic glands ("degenerated", as Claude Bernard thought. To demonstrate the existence of foetal and adult) reduced hyperglycaemia and glycosuria Fig. 12  Gley’s treatise “The Internal Secretions (their Physiology and as being of historical interest. The photograph of the French professor applications to Pathology)”, translated into English in 1917 by Mau- comes from the Institute of Physiology of the University of Barcelona rice Fishberg, professor at New York University, has been described [1]. Probable date: 1919 13 Acta Diabetologica (2022) 59:1635–1651 1647 in dogs with post-pancreatectomy diabetes, as well as gly- isolate the active principle of these extracts from the internal caemia in healthy rabbits, the French physiologist, on 23 secretion of the pancreas, and to study its mode of action". December 1922, staged one of the most eccentric acts in Gley concluded the paper by stating that these experiments the history of science before the Assembly of the Société had been conceived at least twelve years earlier and had de Biologie. Gley asked to make public a document he had to be interrupted in 1900–1901 because of other commit- submitted to the Society's secretariat on 20 February 1905. ments. However, in the doctoral thesis defended by J. Lafon, The short paper was entitled: “Sur la sécrétion interne du in 1906, directed by Gley, both supported the theory that the pancréas et son utilisation thérapeutique”. In this paper, internal secretion of the pancreas is essential for hepatic gly- Gley summarised the experiments he started in 1890 with cogen synthesis and in experiments conducted in 1909 and "extracts of degenerated pancreas", obtained by occluding 1910, Gley reproduced similar investigations by administer- the excretory ducts of the gland. He added that parenteral ing intraperitoneal injections of the extract; he observed in injections of these extracts reduced urinary excretion in pan- pancreatectomised dogs a reduction of urinary glucose from createctomised dogs, improving their clinical condition. In 14.0 to 2.3 g/L (Fig. 14) [80]. his letter, Gley claimed that the "sclerosed pancreas" pro- Although in the documentation so extravagantly delivered vides the active principle, since the extract injected into by Gley in 1905 the protocol is not sufficiently detailed (a diabetic dogs by total removal of the pancreas significantly frequent circumstance in those years), it is plausible to admit decreased the amount of sugar eliminated. At the same time, that his final results (considerable decrease in glycosuria the features of diabetes were corrected. "I've been inject- and substantial improvement of diabetic symptoms) were ing these pancreatic extracts into the veins of the peripheral correct [81]. circulation and the portal vein. It will be important to try to Fig. 13  E. Gley published in 1900 series of experiments performed in his laboratory since 1892 describing in detail the metabolic actions of the pancreatic extract [“Diabète Pancreatique Expérimental: Essais de Traitement”] [79] 13 1648 Acta Diabetologica (2022) 59:1635–1651 J.J.R. Macleod gave credit to Gley's research. In his book The role of the priority rule in science Carbohydrate metabolism and insulin, published in 1926, he wrote the following about Gley's scientific activities in Robert K. Merton, founding father of the Sociology of Sci- relation to the antidiabetic hormone of the pancreas [82]: ences, defined the Priority Rule as the credit given to the individual or group of individuals who first made the dis- “At the meeting of the Société de Biologie, held in Paris on covery, documented by an original publication or filing the 23rd December, 1922, to commemorate the centenary of the birth of Pasteur, Professor E. Gley requested that an envelope, successful application for a patent [83, 84]. deposited by him in February, 1905, be opened and read the Already in the seventeenth century, the Royal Society of inside document entitled “Sur la sécrétion interne du pancréas London, and later on, the Academy of Sciences of Paris et son utilisation thérapeutique”. In this communication, after and other scientific societies accepted, as an alternative to referring to his earlier researches in which it was shown that the destruction of the pancreas in situ does not lead to diabe- the Priority Rule, a signed and dated document showing an tes, Gley states that it is probable, as indicated by the words original description, sealed in an envelope and deposited in of Laguesse, that this was because the islets of Langerhans the secretary, to be read in a future meeting of the institu- remained intact. tion [1, 85]. (…) He therefore prepared extracts from sclerosed remains of pancreas, and found them to diminish considerably the sugar This was the case of Eugène Gley with his sealed letter in the urine of depancreatised dogs, and to alleviate all the deposited by him in the Secretary of the Society of Biol- other diabetic symptoms. Gley then indicate his intentions ogy in Paris on February 20, 1905. In this communication to isolate the active antidiabetic principle, to study its mode Gley stated that since 1891 he had carried out multiples of action and to see whether the extracts could be used on man, either subcutaneously or by mouth. Because of other experiments comprising: a) induction of diabetes after com- researches, these problems were laid aside. Previous to plete pancreatectomy, b) development of pancreatic extracts depositing this sealed package, Gley had contributed valuable from sclerosed remains of the gland, and c) administration of observations concerning the effects on depancreatised dogs of these extracts to pancreatectomised dogs. The extracts were extracts of the entire pancreas prepared in various ways.” able to reduce the amount of sugar excreted and alleviated diabetic symptoms. Fig. 14  E. Gley: Detail, enlarged, of the text of the sealed letter "Sur la sécrétion interne du pancréas et son utilisation thérapeutique" (1905). Gley's photograph, date unknown, is from the Wellcome Collection Library (date unknown; author, Lafayette Ltd., public domain) 13 Acta Diabetologica (2022) 59:1635–1651 1649 European research, the cradle References of the discovery of the antidiabetic hormone 1. de Leiva-Hidalgo A (2022) Organotherapy of diabetes mellitus (1889–1923). 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