The Nobel Prize of Physiology or Medicine, 1923: controversies on the discovery of the antidiabetic hormone.

AIMS: To analyze the main contributions to the discovery of the antidiabetic hormone in the period between 1889, the year in which Oskar Minkowski demonstrated that complete pancreatectomy in dogs caused diabetes, and the year 1923, the date in which the clinical use of insulin was consolidated. A main objective has been to review the controversies that followed the Nobel Prize and to outline the role of the priority rule in Science. METHODS: We have considered the priority rule defined by Robert Merton in 1957, which takes into account the date of acceptance of the report of a discovery in an accredited scientific journal and/or the granting of a patent, complemented by the criteria set out by Ronald Vale and Anthony Hyman (2016) regarding the transfer of information to the scientific community and its validation by it. The awarding of the Nobel Prize in Physiology or Medicine in October 1923 has represented a frame of reference. The claims and disputes regarding the prioritization of the contributions of the main researchers in the organotherapy of diabetes have been analyzed through the study of their scientific production and the debate generated in academic institutions. MAIN RESULTS AND CONCLUSIONS: (1) According to the criteria of Merton, Vale and Hyman, the priority of the discovery of the antidiabetic hormone corresponds to the investigations developed in Europe by E. Gley (1900), GL Zülzer (1908) and NC Paulescu (1920). (2) The active principle of the pancreatic extracts developed by Zülzer (acomatol), Paulescu (pancreina) and Banting and Best (insulin) was the same. (3) JB Collip succeeded in isolating the active ingredient from the pancreatic extract in January 1922, eliminating impurities to the point of enabling its use in the clinic. (4) In 1972, the Nobel Foundation modified the purpose of the 1923 Physiology or Medicine award to Banting and Macleod by introducing a new wording: "the credit for having produced the pancreatic hormone in a practical available form" (instead of "for the discovery of insulin").

On the occasion of the centennial of insulin therapy (1922-2022), II-Organotherapy of diabetes mellitus (1906-1923): Acomatol. Pancreina. Insulin.

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 Preußischen Staates (Berlin, DE); Landesamt für Bürger-und Ordnungsangelegenheiten (LABO) (Berlin, DE); Arhivele Academiei Române si 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.

Pancreatic Extracts for the Treatment of Diabetes (1889-1914): Acomatol.

BACKGROUND: Historical review on the early development of organotherapy for diabetes [pancreatic extracts (PE)] and its relationship with the social and political circumstances. AREAS OF UNCERTAINTY: The diagnosis of diabetes relied only in the presence of glycosuria and cardinal symptoms. Blood glucose determinations were not regularly available, requiring large volumes for sampling. Micromethods for glycemia were developed just in the last years of the investigated period. Hypoglycemia remains undiscovered. Isolation and purification of PE were difficult tasks due to the unknown chemical structure of the antidiabetic hormone. DATA SOURCES: (1) Berliner Medizinhistoriches Museum der Charité (Humboldt University). (2) GeDenKort Charité-Wissenschaft in Verantwortung. (3) Geheim Staatsarchiv Preußischer Kulturbesitz. (4) Archival Collections, University of Toronto: Thomas Fisher Rare Book Library. Academy of Medicine Collection, F. G. Banting Papers, C. H. Best Papers, J. J. R. Macleod Papers. (5) National Library of Medicine: Pubmed search for the topic of history of insulin. History of Medicine-on syllabus archive. (6) Selected books: The Discovery of Insulin (M. Bliss); Diabetes, Its Medical and Cultural History (D. von Engelhardt); Brown-Séquard (M. J. Aminoff); Diabetes: The Biography (R. Tattersall); The Endocrine Organs (E. Schäfer); The Internal Secretions (E. Gley); Health, race and German politics between national unification and Nazism, 1870-1945 (P. Weindling). THERAPEUTIC ADVANCES: Demonstration that diabetes is a pancreatic disease. The outstanding progress of medical physiology led to the birth of endocrinology and the key concepts of homeostasis. Experimental scientists designed new procedures for complete pancreatectomy and elaboration of PE containing the antidiabetic principle. Organotherapy achieved complete success in the treatment of myxedema and partial success in the treatment of experimental and clinical diabetes. CONCLUSIONS: The organotherapy of diabetes was an obliged step to facilitate the identification of the antidiabetic hormone. Organotherapy of diabetes was a paradigm for the integration of basic and applied knowledge about hormone action and development of endocrine pharmacology.

Giuseppe Moscati (1880-1927): a holistic approach to medicine.

Giuseppe Moscati was a physician, medical school professor and a pioneer in the field of biochemistry and Italian studies on diabetes. He was declared a Catholic saint in 1987. In order to respond better to both the physical and spiritual needs of his patients, he developed his own holistic approach to healthcare involving meticulous drug regimens, meditation and discipline.

Development of the Clinic of Endocrinology, diabetes and metabolic disorders.

The Clinic of Endocrinology, diabetes and metabolic disorders was founded in 1975 by Prof d-r Alexandar Plashevski. Healthcare, educational and scientific activities in the Clinic of Endocrinology are performed in its departments. The Department for hospitalized diabetic and endocrine patients consists of the metabolic and endocrine intensive care unit, the department for diagnosis and treatment of diabetics and endocrine patients, day hospital, the department for education of diabetic patients, and the national center for insulin pump therapy. The Center for Diabetes was established in 1972 by Prof d-r Dimitar Arsov. In 1975, Prof d-r Alexandar Plasheski broadened the activities of the Center for Diabetes. It was dislocated in 1980, with new accommodation outside the clinic. Since then the Center has consisted of several organized units: two specialist outpatient clinics for diabetic patients, biochemical and endocrine laboratory, sub-departments for: diabetic foot, cardiovascular diagnosis, ophthalmology, and urgent interventions. The Department of Endocrinology and Metabolic Disorders for outclinic endocrine patients was established in 1980, and it integrates the following sub-departments: thyrology, andrology, reproductive endocrinology, obesity and lipid disorders and sub-department for osteoporosis. The educational staff of the Clinic of Endocrinology organizes theoretical and practical education about Clinical Investigation and Internal Medicine with credit transfer system course of study of the Medical Faculty, Faculty of Stomatology, postgraduate studies, specializations and sub-specializations. Symposiums, 3 congresses, schools for diabetes and osteoporosis and continuous medical education were also organized. The Clinic of Endocrinology was initiator, organizer, founder and the seat of several medical associations.

Neem (Azadirachta indica): prehistory to contemporary medicinal uses to humankind.

The divine tree neem (Azadirachta indica) is mainly cultivated in the Indian subcontinent. Neem has been used extensively by humankind to treat various ailments before the availability of written records which recorded the beginning of history. The world health organization estimates that 80% of the population living in the developing countries relies exclusively on traditional medicine for their primary health care. More than half of the world's population still relies entirely on plants for medicines, and plants supply the active ingredients of most traditional medical products. The review shows the neem has been used by humankind to treat various ailments from prehistory to contemporary.

[Historical review of Antidiabetic Drugs' discovery].

Early in the ancient Egyptian period 3, 500 years ago, people began to record the symptoms of diuresis related to Diabetes Mellitus. Thereafter, the cognition of Diabetes Mellitus in people evolved several times, that is: from simple symptom-recording to realizing that the essential pathogenesis is the kidney, and then recognizing that the root cause is the pancreas; from the cognition of islet cells to the separation and purification of insulin; from recognizing that sulfonamides have a hyperglycemic action to the appearance of dimethyldiguanide and the improvement of the method of Insulin's injection method. Reviewing this historical process can benefit a better realization and prevention and cure of Diabetes Mellitus.

[On contribution of Liu Wan-su's San xiao lun (treatise on three diabetic syndromes) to the diagnosis and treatment of diabetes].

Liu Wan-su's San xiao lun is the earliest existing book solely dealing with the subject of diabetes in traditional Chinese medicine. Its main contribution to the diagnosis and treatment of diabetes is the thorough presentation of pathogenesis. It points out the cause of diabetes is the vacuity of kidney, spleen and stomach while the clinical manifestation shows repletion heat of heart. Its main emphasis is on the common pathogenesis of the three diabetic syndromes rather than their pattern differentiation. Thus, the treatment principle is enriching the yin of kidney and spleen and draining the heart fire with cold and damp drugs. The maneuver in the book is flexible and plays a pivotal role in the theoretical development of diabetes in TCM.

Antidiabetic drugs used in Europe prior to the discovery of insulin.

Many therapeutic agents had been used for the treatment of diabetes mellitus before insulin was discovered and several hundred plants have shown some extent of antidiabetic activity. This study tries to explore which agents were most widely used in Europe in the pre-insulin era. According to the scientific literature and the proprietary drug industry around 1900, more than 100 agents were considered to have hypoglycemic activity. Most of them seem to have been used only occasionally while some others were recommended and marketed to a large extent. Among the medicinal plants, Syzygium cumini (syn. S. jambolanum, Eugenia jambolana), Vaccinum myrtillus and Phaseolus sp. were most common, and other frequently used agents were opium, opium alkaloids, other alkaloids like quinine or Belladonna alkaloids, salicylates, alkaline substances like sodium (bi)carbonate and even strong poisons like arsenic or uranium salts. Syzygium jambolanum seed powder seems to be one of the most intensively studied antidiabetic agents of plant origin.

Kidney and urinary therapeutics in early medieval monastic medicine.

This study will explore a few recipes in relation to what monastic medicine considered kidney disorders. Technical terms, such as strangury, cause us difficulties in interpreting early medieval monastic medicine. The action described can vary considerably. For example, he has action for urination problems that center in the verb: (in translation) "dries out", "quietens", "expels", "moves", "provoking", and treating "retention of urine". Sometimes the term "diuretic" is used. The Lorsch monastic book of medical recipes, written around 800, employed the words "deuritica" and "diureticon" but most of monastic accounts simply say something similar to that in Reichenau Monastery's recipe book, 9th or 10th century: "urinam movet/moves the urine"; "urinam provocat/stimulates urination"; "ad difficultate urine/difficulty in urination". In order to examine the relationship between diagnosis and therapy, let us turn to a disease that is difficult even for modern medicine, diabetes. An examination of several early medieval monastic accounts reveals that they could have effectively treated diabetes.

A history of diabetes: from antiquity to discovering insulin.

This article, the first of a three-part series, gives a historical account of events for diabetes, dating from antiquity and its first recording in the Ebers Papyrus--an Egyptian document circa 1500 BC. This article describes initial thoughts that diabetes was linked to an alimentary complaint, and concludes with the discovery of it being a chronic systemic disease. It highlights the discoveries and also includes details of the failed attempts to locate the cause and identify a solution to the ancient mysterious disease which became known to all as diabetes mellitus. Early remedies and treatments are included. The article tells how for many centuries individuals suffered from the debilitating complaint with very little offered in terms of treatment or relief. Eventually the pancreas was identified as the causative organ and, some time later, animal experimentation resulted in the abstraction of the substance insulin. The article concludes with Frederick Banting and John Macleod being awarded the Nobel Prize in 1923 for their revolutionary discovery of insulin.

A comparative study of Prameha Roga from the Brihatrayee.

The study of this Prameha Roga reveals the rich knowledge of the Ayurveda developed since the time immemorial. Although descriptions of this disease are scattered in different classics of Ayurveda but here importance has been given to Brihatrayee. The aim and object of this paper review the well documented concept of the Ayurveda about the Prameha Roga as the trend of diabetes is increasing day by day in the society and is very difficult to prevent and manage owing to its complexity. The Ayurvedic concept of this Roga information on the subject regarding classification, characteristics, features etc. has been also made in this paper. This article highlights the wisdom of ancient Indian literature and some historical view of the disease i.e. Prameha Roga or Diabetes Mellitus.

Glimpses of the history of insulin.

The discovery of the insulin which took place at Toronto, Canada in 1921-22 is one of the most important medical discoveries of the modern age. For this miracle, Prof. John James Macleod and Frederic Grant Banting were Jointly awarded the Nobel Prize in 1923 for Physiology or Medicine. Frederick Sanger a British biochemist discovered the structure of insulin in 1958 and was awarded Nobel prize for chemistry. Diabetes mellitus is called Madhumeha in ancient Indian Ayurvedic medicine. Egyptians and Greeks knew about it. Greek physician Aretaeus of Capadocia first suggested the term "Diabetes" and described it. Though insulin was discovered about 80 years ago research interest in it still continues unabated. This paper also gives case details of the first patient on whom Insulin was first tried and chronology of research on pancreas and Insulin.

Screening of Madhumehaghna (anti diabetic) plants in Vrihattrayee.

The three texts written by Charak, Sushrut and Vagbhat are considered as Vrihattrayee because of their original contributions to the basic tenants of Ayurveda and innovative uses of plants and medicine. But despite the possibility of exploring efficacious for mulations from among these classics, not much attempts have been made in this direction, due to the fact that now most of them are not in vogue in practice by majority of Ayurvedic physicians. As such, a glossary of plants as described in those texts for the management of prameha including diabetes has been collected which would be useful for studying these drugs from different angles.

Yugi's pramegam and diebetes mellitus: an analogue.

Yugimahamuni was one among the greatest siddhars and has matchless contribution towards enrichment of Siddha system. In his Vaidya Chinthamani-800, he has written clearly about 4448 names of the diseases, its signs, symptoms and prognosis. Under the heading - "Meganoikal," he has elaborated twenty varieties of the urinary disorders based on the physical characters of urine. But the general signs and symptoms of 'Meganoikal' described by Yugi clearly indicate that many of these characteristics are of diabetic in nature. Under the sub-heading 'avasthaikal', Yugi accurately described certain sufferings experienced by the patients of 'Meganoikal'. It is quite interesting to note that those ten types of sufferings he has listed out, starting from obesity ending in Tuberculosis are comparable with the acute and long term complications of diabetics, and hence this analogue.