[Evolution of insulin therapy: past, present, future].

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 «smart¼ molecules that will have a glucose-dependent effect.

Lydia Marie DeWitt and Mary Butler Kirkbride: Prototypical Circa-Early-1900s Women of Pathology and an Analysis of Their Contributions to the Discovery of Insulin.

CONTEXT.­: The year 2023 marks the centenary of the Nobel Prize honoring the discovery of insulin. Little-known experimental pathologists Lydia DeWitt, MD, at the University of Michigan and Mary Kirkbride, DSc [Hon], at Columbia University, both just beginning their academic careers, made independent contributions to the discovery that have never been critically examined. This happened at a time when it was exceedingly rare for women to work in pathology. OBJECTIVE.­: To explore the facilitative roles of DeWitt and Kirkbride in the discovery of insulin and to examine their trail-breaking careers in academic pathology. DESIGN.­: Available primary and secondary historical resources were reviewed. RESULTS.­: DeWitt made and tested pancreatic extracts from duct-ligated atrophic pancreas (ie, Frederick Banting's great idea to prevent digestion of its hypothetical internal secretion) 15 years before Banting; Banting was unaware of her work. His idea came from reading a paper by pathologist Moses Barron. Prior duct-ligation studies had sometimes been viewed with skepticism because histologic identification of islets in atrophic duct-ligated pancreata was imperfect; Kirkbride addressed this with histochemical staining, convincing Barron and, therefore, indirectly influencing and motivating Banting. The lives and convoluted careers of these 2 early-20th-century women are explored and compared with those of other contemporary women in pathology. A unifying pattern becomes clear: careers in experimental pathology and bacteriology were accepted but performing clinical work in anatomic pathology was not. CONCLUSIONS.­: Both DeWitt and Kirkbride are prototypical early-20th-century women in academic pathology whose careers were constrained by gender. However, Kirkbride made a unique and unrecognized contribution to the discovery of insulin.

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.

'I Was Only the Impresario - the Managing Director': J.J.R. Macleod and the Pragmatics of the Discovery and Development of Insulin.

On 7 November 1923, when J.J.R. Macleod announced that he would split his half of the Nobel Prize with J.B. Collip, following F.G. Banting splitting his half of the prize with C.H. Best, a reporter asked Macleod to assess his share in the discovery of insulin. "Oh, I was only the impresario - the managing director," he replied. Whether Macleod deserved the recognition with Banting of the Nobel Committee for the discovery of insulin, it is certainly clear that the discovery, and especially its efficient development into a remarkably effective diabetes treatment, would not have happened without Macleod's knowledge and laboratory research experience. Nor would it have happened without his leadership and, especially, without his acumen as the managing director, or impresario, of the insulin enterprise.

Résumé. Le 7 novembre 1923, lorsque J.J.R. Macleod annonça qu'il allait partager sa part du Prix Nobel avec J.B. Collip ­ imitant ainsi F.G. Banting, qui avait partagé la sienne avec C.H. Best ­, un journaliste demanda à Macleod d'évaluer sa contribution à la découverte de l'insuline. « Oh, je n'étais que l'impresario, le directeur général ¼, répondit-il. Que Macleod mérite ou non la récompense que le Comité du prix Nobel lui décerna conjointement avec Banting, il est certain que la découverte de l'insuline, qui déboucha sur un traitement remarquablement efficace du diabète, n'aurait pas eu lieu sans les connaissances et l'expérience de Macleod en matière de recherche en laboratoire. Elle n'aurait pas non plus eu lieu sans son leadership et, surtout, sans sa perspicacité en tant que directeur général ou impresario.

J.J.R. Macleod: Misunderstood, Misinterpreted, and Maligned.

After the discovery of insulin at the University of Toronto in 1921-22, Frederick Banting and Charles Best downplayed the contributions of physiology professor John James Rickard Macleod, the director of the laboratory where the discovery was made. Banting and Best, their allies, and to a lesser extent the university promoted a "fairy tale" version in which the two young investigators made the discovery on their own, creating the so-called "Banting and Best myth." Over the next 60 years, the myth prevailed and Macleod's reputation became increasingly tarnished, with both Banting and Best actively maligning their former mentor. While the publication of Michael Bliss' The Discovery of Insulin in 1982 placed Macleod's reputation on the road to recovery, there are still many lingering issues that have been raised, and Macleod remains misunderstood, misinterpreted, and maligned. This paper, using primary and secondary historical sources, addresses topics that have been repetitively raised by Macleod's detractors over the past century.

Résumé. Après la découverte de l'insuline à l'Université de Toronto en 1921­1922, Frederick Banting et Charles Best ont minimisé les contributions du professeur de physiologie John James Rickard Macleod, directeur du laboratoire où la découverte a été faite. En compagnie de leurs alliés et dans une certaine mesure de l'Université, Banting et Best ont propagé un conte de fée dans lequel les deux jeunes chercheurs auraient fait cette découverte par eux-mêmes, donnant ainsi naissance au « mythe Banting et Best ¼. Au cours des 60 années suivantes, ce mythe a prévalu et la réputation de Macleod a été ternie, Banting et Best s'employant à calomnier leur ancien mentor. Si la publication de The Discovery of Insulin (1982) par Michael Bliss a quelque peu rétabli la réputation de Macleod, celui-ci est encore largement incompris, mal interprété et dénigré. En s'appuyant sur des sources historiques premières et secondaires, cet article aborde les enjeux qui ont été soulevés de manière répétée par les détracteurs de Macleod au cours du XXe siècle.

Macleod Before Banting.

John James Rickard Macleod provided the facilities and support that enabled Frederick Banting and Charles Best to perform the experimental work that resulted in the discovery of insulin. This review considers Macleod's intellectual contribution to the initial discovery in light of his previously expressed opinions on glucose metabolism. He acknowledged the likely existence of an internal secretion from the pancreas and was aware of previous work in the area; however, seeking it was not among his research priorities. His advice in the immediate aftermath of the discovery does not appear to have made any essential contribution to the project, although he made its ultimate success possible. Instead, he gave Banting the chance he needed, gave him full credit for what he achieved, and promoted insulin tirelessly as a gift to the world.

Résumé. John James Rickard Macleod fournit les installations et le soutien qui ont permirent à Frederick Banting et Charles Best de découvrir l'insuline. Il contribua aussi intellectuellement au projet. Ce texte étudie cette contribution en analysant les idées de Macleod sur le métabolisme des glucides. Bien au fait des travaux antérieurs, le chercheur admettait l'existence probable d'une sécrétion interne du pancréas, mais l'étudier ne faisait pas partie de ses priorités de recherche. Si les conseils qu'il prodigua immédiatement après cette découverte ne semblent pas avoir été essentiels, ils contribuèrent néanmoins au succès du projet. En fait, Macleod offrit à Banting l'opportunité dont il avait besoin, lui attribua pleinement le mérite de la découverte et fit ensuite sans relâche la promotion des bienfaits de l'insuline.

La découverte de l'insuline 1921­1922 : un saut dans la recherche biomédicale.

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.

Title: La découverte de l'insuline 1921­1922 : un saut dans la recherche biomédicale. Abstract: Si les symptômes du diabète ont été décrits depuis l'Antiquité et caractérisés par la présence de sucre dans les urines et une soif intense, ce n'est qu'à la fin du xixe siècle que les travaux de plusieurs équipes aboutissent à rechercher la substance active de la sécrétion interne du pancréas dans des extraits susceptibles de diminuer le glucose dans le sang et les urines chez le chien diabétique. C'est à l'Université de Toronto, au Canada, il y a 100 ans, entre 1921 et 1922, que Frederick Banting, Charles Best et James Collip, travaillant dans le département de physiologie dirigé par John MacLeod, obtiennent des extraits pancréatiques suffisamment purifiés qui permettent de traiter de jeunes patients diabétiques. Cette découverte de l'insuline est très vite reconnue et saluée par l'attribution du Prix Nobel de Physiologie ou Médecine en 1923 à Frederick Banting et John MacLeod. Cette découverte a eu d'importantes retombées scientifiques, industrielles et cliniques, toujours d'actualité.

[The insulin receptor discovery is 50 years old - A review of achieved progress]. / Le récepteur de l'insuline a 50 ans ­ Revue des progrès accomplis.

The isolation of insulin from the pancreas and its purification to a degree permitting its safe administration to type 1 diabetic patients were accomplished 100 years ago at the University of Toronto by Banting, Best, Collip and McLeod and constitute undeniably one of the major medical therapeutic revolutions, recognized by the attribution of the 1923 Nobel Prize in Physiology or Medicine to Banting and McLeod. The clinical spin off was immediate as well as the internationalization of insulin's commercial production. The outcomes regarding basic research were much slower, in particular regarding the molecular mechanisms of insulin action on its target cells. It took almost a half-century before the determination of the tri-dimensional structure of insulin in 1969 and the characterization of its cell receptor in 1970-1971. The demonstration that the insulin receptor is in fact an enzyme named tyrosine kinase came in the years 1982-1985, and the crystal structure of the intracellular kinase domain 10 years later. The crystal structure of the first intracellular kinase substrate (IRS-1) in 1991 paved the way for the elucidation of the intracellular signalling pathways but it took 15 more years to obtain the complete crystal structure of the extracellular receptor domain (without insulin) in 2006. Since then, the determination of the structure of the whole insulin-receptor complex in both the inactive and activated states has made considerable progress, not least due to recent improvement in the resolution power of cryo-electron microscopy. I will here review the steps in the development of the concept of hormone receptor, and of our knowledge of the structure and molecular mechanism of activation of the insulin receptor.

Title: Le récepteur de l'insuline a 50 ans ­ Revue des progrès accomplis. Abstract: L'isolement de l'insuline du pancréas et sa purification à un degré suffisant pour permettre son administration à des patients atteints de diabète de type 1 furent accomplis il y a 100 ans à l'Université de Toronto par Banting, Best, Collip et McLeod et représentent sans conteste une des plus grandes révolutions thérapeutiques en médecine, reconnue par l'attribution du Prix Nobel de Physiologie ou Médecine en 1923 à Banting et McLeod. Les retombées cliniques furent rapides ainsi que l'internationalisation de sa production commerciale. Les retombées en matière de recherche fondamentale furent beaucoup plus lentes, en particulier en ce qui concerne les mécanismes moléculaires d'action de l'insuline sur ses cellules cibles. Presque un demi-siècle s'écoula avant la détermination de la structure tri-dimensionnelle de l'insuline en 1969 et la caractérisation de son récepteur cellulaire en 1970­1971. Le fait que le récepteur de l'insuline soit une enzyme appelée tyrosine kinase ne fut démontré que dans les années 1982­1985, et la structure cristallographique du domaine kinase intracellulaire fut déterminée dix ans plus tard. La structure cristallographique du premier substrat intracellulaire de la kinase (IRS-1) en 1991 ouvrira la voie à l'élucidation des voies de signalisation intracellulaires. Il faudra 15 ans de plus avant l'obtention de la structure cristallographique du domaine extracellulaire du récepteur (en l'absence d'insuline) en 2006. Depuis, la détermination de la structure du complexe insuline-récepteur dans les états inactif et activé a fait d'énormes progrès, en particulier grâce aux améliorations récentes dans les pouvoirs de résolution de la cryo-microscopie électronique. Je passerai ici en revue les étapes du développement du concept de récepteur hormonal, et de nos connaissances sur la structure et le mécanisme moléculaire d'activation du récepteur de l'insuline.

The continuum of insulin development viewed in the context of a collaborative process toward leveraging science to save lives: Following the trail of publications and patents one century after insulin's first use in humans.

Nearly 100 years ago, diabetes, a disease expected to reach global prevalence of at least 10% within the decade, was a fatal diagnosis. This year of 2022 marks a century since insulin, a lifesaving treatment for those living with diabetes, was purified, tested in humans, and brought to the bedside through widespread commercial production, thus saving countless lives. Insulin's arrival to the world stage was acknowledged with the 1923 Nobel Prize in Physiology or Medicine for "the discovery of insulin", the first among several Prizes awarded to honor scientific work on insulin. This initial awarding has been the subject of significant controversy since, as numerous other scientists paved the way towards the ultimate success, and priority for the true "discovery of insulin" has been argued for many other scientists. The intention and regulations around the Nobel Prize nomination and award process presented herein offer insight into the 1923 Nobel prize designation for the Toronto group, which distinguished itself in the accomplishment by their success in purifying insulin from pancreatic extract and in bringing insulin to worldwide production and the homes of those who needed it. However, a continuous, collaborative process involving contributors spanning centuries and continents was required for the development, rather than discovery, of insulin therapy and its benefits to humanity. This should be the story's enduring legacy. The prior 100 years have witnessed a series of significant innovations in insulin development and therapeutics, but both a cure for diabetes and equitable insulin access remain out of reach and require inspired attention and continuous diligent efforts.

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.

Insulin discovery: A pivotal point in medical history.

The discovery of insulin in 1921 - due to the efforts of the Canadian research team based in Toronto - has been a landmark achievement in the history of medicine. Lives of people with diabetes were changed forever, considering that in the pre-insulin era this was a deadly condition. Insulin, right after its discovery, became the first hormone to be purified for human use, the first to be unraveled in its amino acid sequence and to be synthetized by DNA-recombinant technique, the first to be modified in its amino acid sequence to modify its duration of action. As such the discovery of insulin represents a pivotal point in medical history. Since the early days of its production, insulin has been improved in its pharmacokinetic and pharmacodynamic properties in the attempt to faithfully reproduce diurnal physiologic plasma insulin fluctuations. The evolution of insulin molecule has been paralleled by evolution in the way the hormone is administered. Once-weekly insulins will be available soon, and glucose-responsive "smart" insulins start showing their potential in early clinical studies. The first century of insulin as therapy was marked by relentless search for better formulations, a search that has not stopped yet. New technologies may have, indeed, the potential to provide further improvement of safety and efficacy of insulin therapy and, therefore, contribute to improvement of the quality of life of people with 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.

One-hundred year evolution of prandial insulin preparations: From animal pancreas extracts to rapid-acting analogs.

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.

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.