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2021 marks the 100th anniversary of the discovery of insulin, an event that forever changed the lives of people with diabetes mellitus. At present patients around the world experience the miracle of insulin therapy every day. A disease that used to kill children and teenagers in 2 years in 1920 has become a disease that can be controlled with a possibility to lead a long productive life. Over the past century, the great discovery of Banting, Best and Collip has forever changed the world and saved millions of lives. This review is devoted to the history of the development of insulin and its further improvement: from the moment of discovery to the present days. Various generations of insulin are considered: from animals to modern ultrashort and basal analogues. The article ends with a brief review of current trends in the development of new delivery methods and the development of new insulin molecules. Over the past century, insulin therapy has come a long way, which has significantly improved the quality of life of our patients. But research is actively continuing, including in the field of alternative methods of insulin delivery, which are more convenient for the patient, as well as in the development of «smart» molecules that will have a glucose-dependent effect.

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., (© National Institute of Public Health NIH – National Research Institute.)

The first insulin preparation injected in humans in 1922 was short-acting, extracted from animal pancreas, contaminated by impurities. Ever since the insulin extracted from animal pancreas has been continuously purified, until an unlimited synthesis of regular human insulin (RHI) became possible in the '80s using the recombinant-DNA (rDNA) technique. The rDNA technique then led to the designer insulins (analogs) in the early '90s. Rapid-acting insulin analogs were developed to accelerate the slow subcutaneous (sc) absorption of RHI, thus lowering the 2-h post-prandial plasma glucose (PP-PG) and risk for late hypoglycemia as comparing with RHI. The first rapid-acting analog was lispro (in 1996), soon followed by aspart and glulisine. Rapid-acting analogs are more convenient than RHI: they improve early PP-PG, and 24-h PG and A1C as long as basal insulin is also optimized; they lower the risk of late PP hypoglycemia and they allow a shorter time-interval between injection and meal. Today rapid-acting analogs are the gold standard prandial insulins. Recently, even faster analogs have become available (faster aspart, ultra-rapid lispro) or are being studied (Biochaperone lispro), making additional gains in lowering PP-PG. Rapid-acting analogs are recommended in all those with type 1 and type 2 diabetes who need prandial insulin replacement., Competing Interests: Declaration of competing interest The authors declare no conflict of interest in relation to this article. G.B.B. has received honoraria for lectures and advisory boards from Sanofi and Menarini; F.P. has received honoraria for lecturing and consultations from Sanofi, Lilly, Novo Nordisk, MSD; P. L. declares no conflict of interest; C.G.F. has received honoraria for lecturing and consultations from Sanofi, Lilly and travel grants from Menarini; D.R.O. has received honoraria for lectures and advisory board activities from Boehringer Ingelheim, Novo Nordisk, Roche Diagnostics and Sanofi., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Discovery of insulin. If the symptoms of diabetes have been known since Antiquity, it is at the end of the 19th century that several investigators searched for the active substance of the pancreas and endeavoured to produce extracts that lowered blood and urine glucose and decreased polyuria in pancreatectomized dogs. The breakthrough came 100 years ago when the team of Frederick Banting, Charles Best and James Collip, working in the Department of Physiology, headed by John MacLeod at the University of Toronto, managed to obtain pancreatic extracts that could be used to treat patients and rescue them from the edge of death by starvation, the only treatment then available. This achievement was quickly recognized by the Nobel Prize in Physiology or Medicine to Banting and MacLeod in 1923. The discovery has had important scientific, industrial and clinical developments still efficient nowadays., (© Société de Biologie, 2022.)

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., (© 2021 Diabetes UK.)

Background: While insulin has been central to the pathophysiology and treatment of patients with diabetes for the last 100 years, it has only been since 2007 that genetic variation in the INS gene has been recognised as a major cause of monogenic diabetes. Both dominant and recessive mutations in the INS gene are now recognised as important causes of neonatal diabetes and offer important insights into both the structure and function of insulin. It is also recognised that in rare cases, mutations in the INS gene can be found in patients with diabetes diagnosed outside the first year of life., Scope of Review: This review examines the genetics and clinical features of monogenic diabetes resulting from INS gene mutations from the first description in 2007 and includes information from 389 patients from 292 families diagnosed in Exeter with INS gene mutations. We discuss the implications for diagnosing and treating this subtype of monogenic diabetes., Major Conclusions: The dominant mutations in the INS gene typically affect the secondary structure of the insulin protein, usually by disrupting the 3 disulfide bonds in mature insulin. The resulting misfolded protein results in ER stress and beta-cell destruction. In contrast, recessive INS gene mutations typically result in no functional protein being produced due to reduced insulin biosynthesis or loss-of-function mutations in the insulin protein. There are clinical differences between the two genetic aetiologies, between the specific mutations, and within patients with identical mutations., (Copyright © 2021 The Author(s). Published by Elsevier GmbH.. All rights reserved.)

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., (© 2021 Wiley Periodicals LLC.)

Since the discovery of insulin 100 years ago, our knowledge and understanding of diabetes have grown exponentially. Specifically, with regards to the genetics underlying diabetes risk, our discoveries have paralleled developments in our understanding of the human genome and our ability to study genomics at scale; these advancements in genetics have both accompanied and led to those in diabetes treatment. This review will explore the timeline and history of gene discovery and how this has coincided with progress in the fields of genomics. Examples of genetic causes of monogenic diabetes are presented and the continuing expansion of allelic series in these genes and the challenges these now cause for diagnostic interpretation along with opportunities for patient stratification are discussed.

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 HbA 1c , over a mean 6.5 years of therapy. Intensive therapy in the DCCT, resulting in a mean HbA 1c 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 HbA 1c 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 HbA 1c 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 HbA 1c 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.

At 2:00 h on Oct 31, 1920, Frederick G Banting, a surgeon practising in London, ON, Canada, conceived an idea to isolate the internal secretion of the pancreas. The following week, he met with noted scientist John J R Macleod in Toronto, ON, Canada, and they developed a research plan. By August, 1921, Banting and his student assistant Charles H Best had prepared an effective extract from a canine pancreas. In January, 1922, biochemist James B Collip isolated insulin that was sufficiently pure for human use. On Oct 25, 1923, Banting and Macleod received the Nobel Prize in Physiology or Medicine for the discovery of insulin. Here, we recount the most relevant events before and after the fateful early morning of Oct 31, 1920, which culminated in the discovery and clinical use of insulin., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

In 1936, the journalist Hannah Lees published "Two Million Tightrope Walkers," drawing attention to the significant number of people in the United States estimated to have diabetes. Focusing on how people with diabetes should live, she emphasized the importance of recording the exact values of everything they ate and avoiding all "riotous living" lest they be unable to keep careful measurements of calories, insulin, and sleep. Employing two meanings of measured - as counted and as moderate - Lees was doing more than communicating how someone might control their disease; she was also calling for a "controlled and self-reliant citizenry." Indeed, Lees insisted that diabetics who followed a regime of measurement "make a good deal better citizens than the average." Drawing on the writings of Lees and other social commentators, I explore the link between biometrics, citizenship, and diabetes in the United States in the interwar years. In particular, I look at how this disease came to symbolize both the regimes of discipline thought to be necessary in a society moving to consumption as its economic motor, and the fears of what could happen if consumption ran amok. Biometrics, I argue, offered clinicians and patients a potent tool for measuring deviance and, potentially, for restoring a person to the "norm."

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.

Soon after the discovery of insulin in the early 1920s, the popular press celebrated the miraculous discovery. Although insulin had no curative effect on the chronic state of diabetes, it was frequently heralded as a "cure." This paper examines how the discovery of insulin intersected with the rise of diabetic technology and the transfer of medical technology to the home setting. By analyzing diabetic manuals written for patients and physicians, letters exchanged between patient and physician, medical journals, magazines and newspapers, I trace how patients learned about insulin and more significantly how patients adopted measurement technologies designed to allow better home administration of insulin. This included acquiring knowledge about nutritional content and scales, maintaining sterile glass syringes, sharpening needles, using chemistry to measure sugar in the urine, and recording various measurements into meaningful text for patient-physician dialogue. As diabetes was re-imagined as a chronic and controllable illness, patients and physicians alike grappled with the promises and limitations of new medical technologies. This historical perspective offers a lens for better understanding the process of implementing diabetic treatment plans that required home testing, measurement, and recording of medical data. Such processes centered the importance of patient-centered work and the value of diabetic technologies. Much of this discourse is outlined in diabetic manuals of the 1920s.

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.

The article aims to outline the historical development of treatment of diabetes in Czechoslovakia. Information has been obtained mainly from two Czech journals, Časopis lékařů českých (The Journal of Czech Physicians, published since 1862) and Praktický lékař (The General Practitioner, published since 1921). Until the discovery of insulin, the treatment of diabetes was based on the use of different diets and a great benefit was obtained by spa treatment. In 1923, imported insulin appeared on the market in Czechoslovakia; insulin injections or substances from which insulin was prepared. In the years 1923-1945, insulin was produced by five companies, then insulin and oral antidiabetics were manufactured just by one firm Léčiva (Pharmaceuticals).

The earliest description of diabetes was documented in the writings of Hindu scholars as long as in 1500 BC. In 1921 the Canadian scientists Fredrick G. Banting, Charles H. Best, J. J. R. Macleod and James B. Collip discovered insulin, a peptide (small protein hormone) which lowers blood sugar. They extracted insulin from the islets of animal pancreases. A year later, in January 1922, bovine insulin was first given to humans by injection. The co-discoverers, in particular James Collip, continued their work to purify the insulin extract to make it safer and more effective. In 1936, protamine, a low-weight protein, was used to develop a suspension. In 1951 the amorphous 'lente' insulins- semilente, lente and ultralente were developed. After several years of laboratory work during the years 1963-1966 human insulin was chemically synthesized. In 1975, fully synthetic insulin was synthesized. Since 1996, different insulin analogues have been introduced worldwide. Insulin therapy is undergoing a paradigm shift now a days and at this hour we need to focus on the cardinal principles of initiating, optimizing, and intensifying the treatment for achieving adequate control.

The Canadian Frederick Banting (1891-1941), in discovering the existence of insulin, was able to treat, for the first time, with efficiency, diabetic patients. This discovery and its application did not happen easily, in particular within his own team. In 1922, the Nobel Prize would reward this researcher, who died two decades later in an airplane crash., (Copyright 2010 Elsevier Masson SAS. All rights reserved.)

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.

This article traces insulin prices in Canada from 1922, just after its discovery at the University of Toronto, to 1984 when production fell out of Canadian control. Connaught Laboratories (part of the University of Toronto from 1914 to 1972) was the first to manufacture insulin and remained the sole Canadian producer. As a public trust, Connaught remained committed to providing insulin at the lowest possible price despite increasing economic pressures. This article analyzes the context surrounding the price of insulin preparations and how they fell from 1922 to 1942, remained unchanged until 1967, and rose during the 1970s.

Starting with the epoch-making discovery of proinsulin, C-peptide has played an important interdisciplinary role, both as part of the single-chain precursor molecule and as an individual entity. In the pioneering years, fundamental systematic experiments unravelled new biochemical mechanisms and chemical structures. After the first detection of C-peptide in human serum, it quickly became a most useful independent indicator of insulin biosynthesis and secretion, finding application in a rapidly growing number of clinical investigations. A prerequisite was the development of specific immuno assays for proinsulin and C-peptide. Further milestones were: the chemical synthesis of several C-peptides and the accomplishments in the synthesis of proinsulin; the detection of preproinsulin with its bearings on understanding protein biosynthesis; the pioneering role of insulin, proinsulin, C-peptide, and mini-C-peptides in the development of recombinant DNA technology; and the discovery of the enzymes for the endoproteolytic processing of proinsulin into insulin and C-peptide, completing the pathway of biosynthesis. Today, C-peptide continues to serve as a special diagnostic tool in Diabetology and related fields. Thus, its passive role is well established. Evidence for its active role in physiology and pathophysiology is more recent and is subject of the following contributions.

Before the discovery of insulin, one of the most common dietary treatments of diabetes mellitus was a high-fat, low-carbohydrate diet. A review of Frederick M. Allen's case histories shows that a 70% fat, 8% carbohydrate diet could eliminate glycosuria among hospitalized patients. A reconsideration of the role of the high-fat, low-carbohydrate diet for the treatment of diabetes mellitus is in order.

A fast development in therapy with insulin was observed after its discovery. Besides the widely used human regular insulin preparations, nowadays ultrashort and long-acting insulin analogues are also available for the patients. At present, the results of large clinical trials enable an evidence based diabetes care. It is well documented, that near-normoglycemia should be achieved by intensive conservative insulin treatment or pump therapy in type 1 diabetic patients. The beneficial effects of the good metabolic control could also be observed years later concerning late specific complications of diabetes. Similarly, as good as possible metabolic control should be aimed with antidiabetic treatment including insulin, if necessary, in type 2 diabetic patients. It is documented that the risk of cardiovascular complications is not increased in type 2 diabetic patients treated with insulin. Hypoglycemia and weight gain are the most important side effects of the insulin treatment. Recently, evidence based recommendations for treatment with ultrashort (insulin lispro, insulin aspart) and long-acting insulin analogues (glargine) can also be determined.

The discovery of insulin remains the greatest and one of the most controversial events in the history of endocrinology. Hypotheses about the possible existence of an internal secretion of the pancreas date from the early 1890s and were steadily modified with the development of the concept of an endocrine system. In the spring of 1922, after many false starts and dead ends, a team of researchers at the University of Toronto provided conclusive evidence of the existence of the internal secretion of insulin. The discovery process was fraught with personal and scientific rivalries more striking than fiction. The early use of insulin on starved, dying diabetic children awed everyone involved in the process. With the discovery of insulin, endocrinology moved into the mainstream of medical science., ((c) 2005 S. Karger AG, Basel.)