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 the organotherapy 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 nominations 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.

Aims The general objective has been the historiographical investigation of the organotherapy of diabetes mellitus between 1906 and 1923 in its scientific, social and political dimensions, with special emphasis on the most relevant contributions of researchers and institutions and on the controversies generated on the priority of the "discovery" of antidiabetic hormone. Methods We have analyzed the experimental procedures and determination of biological parameters used by researchers during the investigated period (1906–1923): pancreatic ablation techniques, induction of acinar atrophy with preservation of pancreatic islets, preparation of pancreatic extracts (PE) with antidiabetic activity, clinical chemistry procedures (glycemia, glycosuria, ketonemia, ketonuria, etc.). The field investigation has included on-site and online visits to cities, towns, buildings, laboratories, universities, museums and research centers where the reported events took place, obtaining documents, photographic images, audiovisual recordings, as well as personal interviews complementary to the documentation consulted (primary sources, critical bibliography, reference works). The documentary archival sources have been classified according to theme, including those consulted in situ with those extracted online and digitized copies received mainly by email. Among the many archives contacted, those listed below have been most useful and have been consulted on site and on repeated visits: National Library of Medicine-Historical Archives (Bethesda, MD, USA); Archives, University of Toronto and Thomas Fisher Rare Books Library (Toronto, Ontario, Canada); Francis A. County Library of Medicine, Harvard University (Boston, Mass, USA); Zentralbibliothek der Humboldt-Universität (Berlin, DE), Geheimarchiv des Preuβischen Staates (Berlin, DE); Landesamt für Bürger—und Ordnungsangelegenheiten (LABO) (Berlin, DE); Arhivele Academiei Române şi Universitǎții Carol Davila (Bucharest, RO). Main results and conclusions A) The European researchers Zülzer (Z Exp Path Ther 23:307–318, 1908) and Paulescu (CR Seances Soc Biol Fil 85:558, 1921) meet the requirements of the priority rule in the discovery of the antidiabetic hormone. B) Factors of socioeconomic and political nature related with the First World War and the inter-war period delayed the process of purification of the antidiabetic hormone in Europe. C) The Canadian scientist J. Collip, University of Alberta, temporarily assimilated to the University of Toronto, and the American chemist and researcher G. Walden, with the expert collaboration of Eli Lilly & Co., were the main authors of the purification process of the antidiabetic hormone. D) The scientific evidence, reflected in the heuristics of this research, allows to assert that the basic investigation carried out by the Department of Physiology of the University of Toronto, directed by the Scottish J. Macleod, in conjunction with the clinical research undertaken by the Department of Medicine of the University of Toronto (W. Campbell, A. Fletcher, D. Graham) made it possible in record time the successful treatment of patients with what was until then a deadly disease.

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Nel 2021, le celebrazioni per il 100° anniversario della scoperta dell’insulina sono state numerose, sottolineando, in particolare, il ruolo di Banting e Best. A seguito di una revisione sull’organoterapia del diabete mellito sperimentale ed umano abbiamo concluso che le ricerche effettuate in Europa tra il 1889 e il 1921 sono state decisive per la scoperta dell’ormone antidiabetico. Conformemente alle premesse della “regola di priorità”, tre ricercatori europei furono i pionieri nella scoperta: E. Gley (Parigi, 1905), G. Zülzer (Berlino, acomatol, 1908) e N. Paulescu (Bucarest, pancreina, 1920). Le circostanze socioeconomiche e politiche della Prima Guerra Mondiale e del periodo interbellico hanno influenzato in modo critico il ritardo della ricerca europea nel processo di purificazione degli estratti pancreatici. I ricercatori dell’Università di Toronto non hanno scoperto l’ormone antidiabetico. Il loro risultato principale è stato la purificazione dell’estratto pancreatico, che ha reso possibile l’introduzione dell’insulina nella pratica clinica nel 1922. Grazie alle ricerche di storici della medicina (soprattutto M. Bliss) è stato possibile smontare il mito di Banting e Best, ancora accettato da molte istituzioni e associazioni di diabete. PAROLE CHIAVE ormone antidiabetico; scoperta dell’insulina; centenario dell’insulina; acomatol; pancreina.