Sir Frederick Grant Banting - the discoverer of insulin. On the 100th anniversary on the Nobel Prize.

Over the past thousands of years, diabetes has deprived people all over the world of their lives. Until 1922, mankind remained powerless. However, change came, with Frederick Banting (1891-1941), the discoverer of insulin. This breakthrough discovery was made not by a great scientist, but by a hard-working and persistent doctor. Perhaps Banting's conscientiousness and integrity stemmed from where he grew up? A small farm in the provinces certainly influenced his further development. A development that was not obvious, because as a child little Freddie had learning difficulties. Determination led him to medicine. It must not have been without surprise to Professor MacLeod (1876-1935) when, in his office at the University of Ontario, he heard from the 30-year-old doctor that he had an idea on how to save lives from an incurable disease. The opportunity Banting was given, he used effectively. Together with the help of his student Charles Best (1899-1978), he isolated insulin. The dissemination of insulin in Poland was very quickly taken up by Kazimierz Funk (1884-1967), the discoverer of thiamine and creator of the term 'vitamin'. As head of the Department of Biochemistry at the National Institute of Hygiene (PZH), he began producing insulin from bovine pancreases in 1924. He carried out this initiative using his private funds, equipping the laboratory with the appropriate equipment. Banting's remarkable feat was rewarded in 1923. Nobel Prize, which he shared with MacLeod. The fact that the actual co-discoverer of insulin, Charles Best, was not included in the award outraged Banting to such an extent that he decided not to accept the prize. After much persuasion, he changed his mind, but shared the financial reward with his faithful assistant. The discoverer's determination and behaviour in the face of success provides an invaluable lesson for today's doctors and scientists. By following the principles Banting espoused, we can honour his memory.

A century past the discovery of insulin: global progress and challenges for type 1 diabetes among children and adolescents in low-income and middle-income countries.

Type 1 diabetes is on the rise globally; however, the burden of mortality remains disproportionate in low-income and middle-income countries (LMICs). As 2021 marks 100 years since the discovery of insulin, we revisit progress, global burden of type 1 diabetes trends, and understanding of the pathogenesis and management practices related to the disease. Despite much progress, inequities in access and availability of insulin formulations persist and are reflected in differences in survival and morbidity patterns related to the disease. Some of these inequities have also been exacerbated by health-system challenges during the COVID-19 pandemic. There is a clear opportunity to improve access to insulin and related essential technologies for improved management of type 1 diabetes in LMICs, especially as a part of universal health coverage. These improvements will require concerted action and investments in human resources, community engagement, and education for the timely diagnosis and management of type 1 diabetes, as well as adequate health-care financing. Further research in LMICs, especially those in Africa, is needed to improve our understanding of the burden, risk factors, and implementation strategies for managing type 1 diabetes.

Insulin Centennial: Milestones influencing the development of insulin preparations since 1922.

During 1921 to 1922, a team effort by Banting, Macleod, Collip and Best isolated and purified insulin and demonstrated its life-giving properties, giving rise to the birth of insulin therapy. In the early years (1922-1950), priorities revolved around the manufacture of insulin to meet demand, improving purity to avoid allergic reactions, establishing insulin standards and increasing its duration of action to avoid multiple daily injections. Shortly after the emergence of insulin, Joslin and Allen advocated the need to achieve and maintain good glycaemic control to realize its full potential. Although this view was opposed by some during a dark period in the history of insulin, it was subsequently endorsed some 60 years later endorsed by the Diabetes Control and Complications Trial and United Kingdom Prospective Diabetes Study. Major scientific advances by the Nobel Laureates Sanger, Hodgkin, Yalow and Gilbert and also by Steiner have revolutionized the understanding of diabetes and facilitated major advances in insulin therapy. The more recent advent of recombinant technology over the last 40 years has provided the potential for unlimited source of insulin, and the ability to generate various insulin 'analogues', in an attempt to better replicate normal insulin secretory patterns. The emerging biosimilars now provide the opportunity to improve availability at a lower cost.

What Was Known About Childhood Diabetes Mellitus Before the Discovery of Insulin?

It has been widely reported by historians that physicians were aware of two distinct types of diabetes mellitus by the 1880s, and that these were both similar to and the direct forerunners of type 1, juvenile-onset and type 2, adult-onset diabetes. The writings of prominent specialist physicians practicing just prior to the discovery of insulin in 1921-1922 were reviewed and there is little evidence that experts believed that adult and childhood diabetes were different. In fact, more than a decade passed after the discovery of insulin before diabetes in children and adults even began to be distinguished. Childhood diabetes was exceedingly rare in the early 20th century and diabetes was believed to be primarily a chronic disease of adults. It is interesting to speculate about what might have happened if the first pancreatic extract tests had been performed on adult-onset diabetics with insulin-resistant diabetes mellitus. Clearly, the results would have been disappointing and the discovery of insulin delayed. This essay explores how the test subject decision was made. It is fortuitous that a 14 year old boy with what was unequivocally type 1 diabetes was selected to be the first insulin recipient, and the rest is history.

CELEBRATING 100 YEARS OF INSULIN USE.

The year 2022 marked the one-hundredth anniversary of the first application of insulin. November 14th, the birth date of one of its main discoverers, Frederick Banting, was designated as World Diabetes Day. This paper comprises a narrative review of the history of the discovery of diabetes and insulin, progress in insulin development, important breakthroughs in insulin production and delivery, and a short commentary regarding potential future developments in insulin treatment. Diabetes, as one of the earliest recorded illnesses in medical writings, has been a focus of research for almost the entire written human history. Groundbreaking discoveries during the early 20th century have resulted in type 1 diabetes mellitus becoming a treatable, chronic condition. The relationship between good glycemic control and reduced occurrence of diabetes complications was established, which has enticed further development and refinements in insulin treatment, ranging from the purification and increased quality of insulin itself, as well as various inventions in its administration. Despite great achievements in insulin therapy so far, future research aims to avoid the need for subcutaneous administration and to create non-invasive means of insulin application.

The discovery of insulin in Toronto: beginning a 100 year journey of research and clinical achievement.

There has been a great deal of controversy regarding priority of discovery of insulin. Indeed, many scientists made important and, in some cases, seminal contributions to identifying the endocrine role of the pancreas and the potential for pancreatic extracts to have a glucose-lowering effect. The purpose of this article is to describe the early experiences with respect to research leading to the discovery of insulin in Toronto (ON, Canada). The experiments conducted at the University of Toronto resulted in the first demonstration that a pancreatic extract could be prepared that would consistently lower glucose, reverse ketosis and arrest the catabolic effects of type 1 diabetes. The remarkably rapid commercial production of insulin soon followed. The Toronto story begins on 17 May 1921, when Frederick Banting and Charles Best began their summer research project in the laboratory of John James Rickard Macleod, and we are now celebrating the 100th anniversary of this landmark achievement. The article herein outlines the steps leading up to the discovery of insulin and provides an overview of some of the key developments in insulin therapy over the past 100 years.

Realising the long-term promise of insulin therapy: the DCCT/EDIC study.

The introduction of insulin in the treatment of juvenile-onset, now type 1, diabetes mellitus transformed a rapidly fatal disease into a chronic degenerative one. During the insulin-treatment era, long-term microvascular and cardiovascular complications proved to be the bane of existence for people with type 1 diabetes, leading to blindness, kidney failure, amputations, cardiovascular disease (CVD) and premature mortality. The nascent understanding of the link between non-physiologically regulated glucose levels and these complications led to the development of new treatment tools in the 1970s and 1980s that facilitated the delivery of insulin to achieve glucose levels closer to non-diabetic levels. These therapeutic advances set the stage for definitive testing of the glucose hypothesis. The Diabetes Control and Complications Trial (DCCT), supported by the National Institute of Diabetes Digestive and Kidney Diseases, National Institutes of Health (NIH), definitively established the benefits and risks of intensive therapy that substantially lowered mean blood glucose levels, measured by HbA1c, over a mean 6.5 years of therapy. Intensive therapy in the DCCT, resulting in a mean HbA1c of ~7% (53 mmol/mol), reduced the development and progression of early microvascular and neurological complications associated with diabetes by 34-76% compared with the conventional-treatment group, which maintained an HbA1c of ~9% (75 mmol/mol). Intensive therapy was also associated with weight gain and a threefold increased risk for hypoglycaemia. At the end of the DCCT, a long-term observational follow-up study, the Epidemiology of Diabetes Interventions and Complications (EDIC) study, commenced. Despite the convergence of HbA1c levels between the two groups during EDIC, owing to the adoption of intensive therapy by the original DCCT conventional-treatment group and the return of all participants to their own healthcare providers for diabetes care, the development and progression of complications continued to be substantially less in the original intensive-treatment group vs the conventional-treatment group; this phenomenon was termed 'metabolic memory'. The DCCT demonstrated a major reduction in early-stage complications with intensive therapy and the metabolic memory phenomenon during EDIC contributed to a substantially lower burden of advanced complications over time. These included a 57% lower risk of CVD events and 33% lower rate of mortality in the original intensive-treatment group compared with the conventional-treatment group. DCCT/EDIC has ushered in the intensive-treatment era, which has been universally adopted and includes the goal of achieving HbA1c levels less than 7% (53 mmol/mol) for most patients. Although the challenge of making intensive therapy (with the aim of achieving normoglycaemia) as widely accessible and safe as possible remains, continuing improvements in insulin therapy 100 years after its introduction promise a brighter future for people with type 1 diabetes.

100th anniversary of the discovery of insulin perspective: insulin and adipose tissue fatty acid metabolism.

Insulin inhibits systemic nonesterified fatty acid (NEFA) flux to a greater degree than glucose or any other metabolite. This remarkable effect is mainly due to insulin-mediated inhibition of intracellular triglyceride (TG) lipolysis in adipose tissues and is essential to prevent diabetic ketoacidosis, but also to limit the potential lipotoxic effects of NEFA in lean tissues that contribute to the development of diabetes complications. Insulin also regulates adipose tissue fatty acid esterification, glycerol and TG synthesis, lipogenesis, and possibly oxidation, contributing to the trapping of dietary fatty acids in the postprandial state. Excess NEFA flux at a given insulin level has been used to define in vivo adipose tissue insulin resistance. Adipose tissue insulin resistance defined in this fashion has been associated with several dysmetabolic features and complications of diabetes, but the mechanistic significance of this concept is not fully understood. This review focusses on the in vivo regulation of adipose tissue fatty acid metabolism by insulin and the mechanistic significance of the current definition of adipose tissue insulin resistance. One hundred years after the discovery of insulin and despite decades of investigations, much is still to be understood about the multifaceted in vivo actions of this hormone on adipose tissue fatty acid metabolism.

Winner's curse: The sad aftermath of the discovery of insulin.

Every young researcher dreams of making a great discovery, but few achieve it. If they do, success does not guarantee happiness. There is little satisfaction in discovering something if others get the credit, and those who achieve fame must face the 'winner's curse' of living up to their reputation. Few discoveries have been more dramatic than the isolation of insulin which, as Michael Bliss said, resembled a secular miracle. And yet, as he also pointed out, this great discovery brought little happiness to those who made it. Some were sidelined, and Banting and Best were saddled with the winner's curse. Here, we look at the ways in which a great discovery can haunt its discoverers.

100 years of physiology, discrimination and wonder.

There has been 100 years of research detailing the role of insulin in glucose, protein and free fatty acid metabolism. We explore the learnings though evolution and changes in management with an understanding of how it has impacted the care of people with diabetes. The discrimination endured is described and recent advances to empower and counter this are highlighted.

A comprehensive account of insulin and LDL receptor activity over the years: A highlight on their signaling and functional role.

Insulin receptor (IR) was discovered in 1970. Shortcomings in IR transcribed signals were found pro-diabetic, which could also inter-relate obesity and atherosclerosis in a time-dependent manner. Low-density lipoprotein receptor (LDLR) was discovered in 1974. Later studies showed that insulin could modulate LDLR expression and activity. Repression of LDLR transcription in the absence or inactivity of insulin showed a direct cause of atherosclerosis. Leptin receptor (OB-R) was found in 1995 and its resistance became responsible for developing obesity. The three interlinked pathologies namely, diabetes, atherosclerosis, and obesity were later on marked as metabolic syndrome-X (MSX). In 2012, the IR-LDLR inter-association was identified. In 2019, the proficiency of signal transmission from this IR-LDLR receptor complex was reported. LDLR was found to mimic IR-generated signaling path when it remains bound to IR in IR-DLR interlocked state. This was the first time LDLR was found sending messages besides its LDL-clearing activity from blood vessels.

Experiences of First Insulin-Treated Patients (1922-1923).

BACKGROUND: Historical description of first insulin trials just after its discovery. AREAS OF UNCERTAINTY: The review includes first initiatives of insulin treatment. The probability of other trials, not reported to the Insulin Committee of the University of Toronto and conducted in the years 1922 and 1923, is quite low. DATA SOURCES: (1) Archival Collections, University of Toronto: Insulin Discovery and Early Developments of Insulin (University of Toronto Libraries digital special collection, with a particular section entitled "From a Patient's Point of View" containing letters, patient charts, newspaper clippings, and photographs). (2) Thomas Fisher Rare Book Library: Academy of Medicine Collection, F. G. Banting Papers, C. H. Best Papers, J. B.Collip Papers, W. R. Feasby Papers, E. Hugues Papers, J. J. R. Macleod Papers. (3) National Library of Medicine: PubMed search for the topic of history of insulin, History of Medicine-on syllabus archive. (4) Selected Journals for History of Medicine: Bulletin of the History of Medicine, Journal of the History of Medicine and Allied Sciences, Medical History. (5) Selected books: The Discovery of Insulin (M. Bliss); Diabetes, Its Medical and Cultural History (D. von Engelhardt); H. C. Hagedorn and Danish Insulin (T.Deckert), Continuing Quest (W. A. Tomkins). THERAPEUTIC ADVANCES: This historical review shows the quick progress from impure pancreatic extract to the selective isoelectric precipitation of the hormone, which made possible the introduction of insulin in the clinic. CONCLUSIONS: The coordination between the Departments of Physiology (Connaught Laboratories) and Medicine (Toronto General Hospital) was essential for the discovery and implementation of insulin therapy. The Insulin Committee was decisive for the negotiation with the pharmaceutical industry, the purification, grand-scale production, patents' achievement, and provision of licenses to expert clinicians and prestigious health centers. At the end of the year 1923, insulin treatment was already extended to Europe (mainly Scandinavia, Great Britain, and Spain). Insulin discovery and treatment changed the clinical spectrum of diabetes.

Hundred Years of Insulin Therapy: Purified Early Insulins.

BACKGROUND: The discovery of insulin has changed dramatically the outcome of patients with type 1 diabetes, giving them the possibility to survive. This is of particular concern due to the fact that type 1 diabetes most frequently occurs in children who were destined to die in ketoacidosis coma. AREAS OF UNCERTAINTY: From insulin discovery to the availability of human insulin and human insulin analogs to be used in diabetes therapy, a series of problems have arisen as the difficulty of insulin purifications, the animal insulin used by the first researches were in fact contaminated by proteins, fats, and other impurities, and the presence of side effects such as allergy, antibodies generation, and lipoatrophy. DATA SOURCE LITERATURE: Data strictly related to the argument have been searched in Pub Med and used. RESULTS: Starting from insulin discovery in 1921 to nowadays, significant efforts have been made by a series of researches to purify animal insulin, discover the molecular structure of human insulin, and develop methods to synthetize human insulin and then insulin analogs. CONCLUSIONS: The history of insulin discovery here reported is fascinating; insulin is a hormone, a product of biotechnology, a field of research that saved and save the life of many diabetic patients.

Insulin: Almost a Century of Lifesaving.

The identification and purification of insulin in 1922 changed life for individuals with type 1 diabetes mellitus (T1DM). Its discovery was, to a certain extent, serendipitous. Although medical researchers suspected that some type of hormone was responsible for carbohydrate metabolism, by the end of the 19th century they had made little progress. When World War I broke out, efforts stalled. A somewhat cantankerous group of Canadian researchers led by Frederick Grant Banting, a surgeon, are credited with insulin's discovery. Their initial research was discredited and criticized for poor technique. Regardless, they persevered, and in January 1922 they successfully treated their first patient. A mere nine months later, collaboration between the University of Toronto and Eli Lilly Company made insulin available in North America. Derived from beef and pork pancreases, the 40 unit/mL product little resembled today's more refined human insulin. While insulin is indispensable to individuals with T1DM, it is also used or being studied for several different conditions. Some researchers have dubbed Alzheimer's disease "type 3 diabetes" because of similar aberrations in the blood-brain barrier and protein deposits.