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.

La découverte de l'insuline.

The first therapeutic benefits of insulin were recorded after the injection of pancreatic extract, given on January 23, 1922 in Toronto to a 14-year-old teenager. Until then, type I diabetes was always fatal, within weeks or months; the fatal outcome being delayed only at the cost of a drastic low-calorie diet. In previous decades, the importance of the pancreas in the development of diabetes had been pointed out, but all attempts to use a pancreatic extract had failed. It is with the objective of "neutralizing" the destructive effects of pancreatic juice (proteolytic) that the isolation of insulin was carried out by a research team which was totally improbable since it was headed by an orthopedic surgeon, Frederick Banting and a 22-year-old stagiaire, Charles Best. Their work was carried out in the university physiology laboratory of John Macleod and their outcome was made possible thanks to the skills of James Collip who purified the insulin preparation. Scientific reality invites us to emphasize that, Banting works, based on a wrong hypothesis, drew towards an historical discovery. Very quickly recognized as of major importance for medicine, the discovery was greeted by the attribution of the Nobel Prize in 1923. For a hundred years, insulin has not ceased to be an essential drug for tens of millions of patients in the world, but it has been a motor for scientific research: innovation in galenic pharmacy and biopharmacy, in fundamental chemistry as a subject for the study of the structure, analysis and synthesis of proteins, and finally, as a motor for the development of biotechnologies, since insulin was the first drug prepared by DNA-recombinant technology, and marketed in 1982.

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.

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.

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.

Assessing the impact of diabetes on quality of life: what have the past 25 years taught us?

Over the past 25 years, there has been significant acknowledgement of the importance of assessing the impact of diabetes on quality of life. Yet, despite the development of several diabetes-specific quality of life measures, the challenges we faced in 1995 remain. There is little consensus on the definition of quality of life because of the complexity and subjectivity of the concept. General quality of life comprises several domains of life, and these are highly individualized. Assessing the impact of diabetes on these life domains adds to the complexity. While comprehensive diabetes-specific quality-of-life measures typically increase respondent burden, brief questionnaires may not capture all relevant/important domains. Today, the lack of resolution of these challenges may explain why the impact of diabetes on quality of life is not systematically assessed in research or clinical care. Few researchers report detailed rationales for assessment, there is often a mismatch between the concept of interest and the measure selected, and data are misinterpreted as assessing the impact of diabetes on quality of life when, in reality, related but distinct constructs have been assessed, such as diabetes distress, treatment satisfaction or health status. While significant efforts are being made to increase routine monitoring of psychological well-being and understand the lived experience, no guidelines currently recommend routine clinical assessment of diabetes-specific quality of life, and there is no consensus on which questionnaire(s) to use. The gaps identified in this review need urgent attention, starting with recognition that assessment of diabetes-specific quality of life is as important as biomedical markers, if we are to improve the lives of people with diabetes.

Looking back on 25 years of the PSAD study group.

The year 2020 marks the 25th anniversary of the Psychosocial Aspects of Diabetes (PSAD) study group of the European Association for the Study of Diabetes. At the time, psychosocial diabetes research in Europe was steadily growing, but not well recognized. By establishing an official European Association for the Study of Diabetes study group, PSAD, for which purpose some hurdles had to be overcome, diabetes psychology became more visible and accessible to the scientific diabetes community. Over the years the PSAD study group has been successful in promoting the quality of research in the field through scientific meetings, mentoring, postgraduate education and publications. Looking back we can conclude that starting the PSAD study group signified an important moment in time, where researchers were joining forces to further the quality of the science, raise awareness of the importance of psychosocial aspects and promote the dissemination of psychological interventions in diabetes care.

Trends in diabetes self-management education: where are we coming from and where are we going? A narrative review.

AIMS: To summarize the history, development and efficacy of diabetes self-management education on glycaemic control and mental health in adults and children or adolescents with type 1 diabetes and people with type 2 diabetes. A further aim was to review the status of implementation of diabetes self-management education into routine care and outline current gaps in implementation and research. METHODS: We searched PubMed and Google scholar for German- and English-language articles regarding diabetes self-management education, glycaemic control and mental health, and restricted this search to meta-analyses. RESULTS: Diabetes education has evolved from a compliance- and knowledge-oriented approach to an empowerment- and self-management-oriented approach. Diabetes self-management education seems to have a greater impact on glycaemic outcomes than on mental health outcomes, but the latter are rarely assessed. Technological development and digitalization can provide chances and challenges for diabetes self-management education. Digital solutions show promising results and great potential for improving the efficacy of diabetes self-management education further and providing ongoing support. The implementation of diabetes self-management education into routine clinical care frequently remains a challenge. CONCLUSION: Diabetes self-management education has been acknowledged as an essential part of diabetes therapy; however, current gaps regarding the efficacy of diabetes self-management education on mental health, and the need for education on the use of diabetes technology, are future avenues for research.

Motivation: key to a healthy lifestyle in people with diabetes? Current and emerging knowledge and applications.

AIM: Motivation to take up and maintain a healthy lifestyle is key to diabetes prevention and management. Motivations are driven by factors on the psychological, biological and environmental levels, which have each been studied extensively in various lines of research over the past 25 years. Here, we analyse and reflect on current and emerging knowledge on motivation in relation to lifestyle behaviours, with a focus on people with diabetes or obesity. Structured according to psychological, (neuro-)biological and broader environmental levels, we provide a scoping review of the literature and highlight frameworks used to structure motivational concepts. Results are then put in perspective of applicability in (clinical) practice. RESULTS: Over the past 25 years, research focusing on motivation has grown exponentially. Social-cognitive and self-determination theories have driven research on the key motivational concepts 'self-efficacy' and 'self-determination'. Neuro-cognitive research has provided insights in the processes that are involved across various layers of a complex cortical network of motivation, reward and cognitive control. On an environmental - more upstream - level, motivations are influenced by characteristics in the built, social, economic and policy environments at various scales, which have provided entry points for environmental approaches influencing behaviour. CONCLUSIONS: Current evidence shows that motivation is strongly related to a person's self-efficacy and capability to initiate and maintain healthy choices, and to a health climate that supports autonomous choices. Some approaches targeting motivations have been shown to be promising, but more research is warranted to sustainably reduce the burden of diabetes in individuals and populations.

State of the art: understanding and integration of the social context in diabetes care.

We review the past 25 years of research addressing challenges people living with diabetes experience in their daily lives related to social contexts, i.e. in their family, at work and in society at large, and identify research gaps. We found that young people with diabetes, as they develop through to adulthood, are exposed to considerable risks to their physical and mental health. Family-system interventions have had mixed outcomes. Research in this area would benefit from attention to ethnic/cultural diversity, and involving fathers and other family members. In adults with diabetes, social support relates to better diabetes outcomes. While family member involvement in care is likely to affect health and psychosocial outcomes of the person with diabetes, key elements and mediators of effective family interventions need to be identified. The challenges of diabetes management at work are under-researched; distress and intentional hyperglycaemia are common. When depression is comorbid with diabetes, there are increased work-related risks, e.g. unemployment, sickness absence and reduced income. Research to support people with diabetes at work should involve colleagues and employers to raise awareness and create supportive environments. Stigma and discrimination have been found to be more common than previously acknowledged, affecting self-care, well-being and access to health services. Guidance on stigma-reducing choice of language has been published recently. Resilience, defined as successful adaptation to adversity such as stigma and discrimination, requires studies relevant to the specific challenges of diabetes, whether at diagnosis or subsequently. The importance of the social context for living well with diabetes is now fully recognized, but understanding of many of the challenges, whether at home or work, is still limited, with much work needed to develop successful interventions.

Behaviour change in diabetes: behavioural science advancements to support the use of theory.

Behaviour is central to the management of diabetes, both for people living with diabetes and for healthcare professionals delivering evidence-based care. This review outlines the evolution of behavioural science and the application of theoretical models in diabetes care over the past 25 years. There has been a particular advancement in the development of tools and techniques to support researchers, healthcare professionals and policymakers in taking a theory-based approach, and to enhance the development, reporting and replication of successful interventions. Systematic guidance, theoretical frameworks and lists of behavioural techniques provide the tools to specify target behaviours, identify why ideal behaviours are not implemented, systematically develop theory-based interventions, describe intervention content using shared terminology, and evaluate their effects. Several examples from a range of diabetes-related behaviours (clinic attendance, self-monitoring of blood glucose, retinal screening, setting collaborative goals in diabetes) and populations (people with type 1 and type 2 diabetes, healthcare professionals) illustrate the potential for these approaches to be widely translated into diabetes care. The behavioural science approaches outlined in this review give healthcare professionals, researchers and policymakers the tools to deliver care and design interventions with an evidence-based understanding of behaviour. The challenge for the next 25 years is to refine the tools to increase their use and advocate for the role of theoretical models and behavioural science in the commissioning, funding and delivery of diabetes care.

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.

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.

Denis Burkitt and the origins of the dietary fibre hypothesis.

For more than 200 years the fibre in plant foods has been known by animal nutritionists to have significant effects on digestion. Its role in human nutrition began to be investigated towards the end of the 19th century. However, between 1966 and 1972, Denis Burkitt, a surgeon who had recently returned from Africa, brought together ideas from a range of disciplines together with observations from his own experience to propose a radical view of the role of fibre in human health. Burkitt came late to the fibre story but built on the work of three physicians (Peter Cleave, G. D. Campbell and Hugh Trowell), a surgeon (Neil Painter) and a biochemist (Alec Walker) to propose that diets low in fibre increase the risk of CHD, obesity, diabetes, dental caries, various vascular disorders and large bowel conditions such as cancer, appendicitis and diverticulosis. Simply grouping these diseases together as having a common cause was groundbreaking. Proposing fibre as the key stimulated much research but also controversy. Credit for the dietary fibre hypothesis is given largely to Burkitt who became known as the 'Fibre Man'. This paper sets out the story of the development of the fibre hypothesis, and the contribution to it of these individuals.

Food As Medicine: Diet, Diabetes Management, and the Patient in Twentieth Century Britain.

In classic accounts of the development of modern medicine in Europe and North America, the sick person is often portrayed as having a history of disappearance with the rise of the objectified body of the modern patient. To this account, sociologists and historians of medicine have added another for the period after 1950, in which the patient as subjective person "reappears" in medical discourse. However, despite histories of practice and identity revising narratives of disappearance, the patient's reappearance has largely escaped further assessment. Using an analysis of dietary management in twentieth-century British diabetes care, this article challenges accounts of this reappearance in three ways. Firstly, it argues that discursive interest in the social and psychological aspects of care emerged earlier than suggested. Secondly, it grounds such interest in reconfigured institutional arrangements that were initially designed to rationalize care and improve efficiency. Finally, it argues that patients regularly exceeded the efforts of even an expanded management regime to normalize and regulate life. Food planning, preparation, and consumption continued to sit at the nexus of competing demands that mediated medical efforts to cultivate governable selves and bodies.

Paul Bastenie et la recherche en diabétologie à l'ULB.

The present chapter deals with the contribution of Professor Paul A. Bastenie, as Chief of the Department of Medicine of the Saint-Pierre Hospital and Director of the Laboratory of Experimental Medicine at Brussels Free University, in the field of diabetes with emphasis on the role of insulin in glucose homeostasis. The knowledge and experimental work under consideration is covering the period from 1955 to 1974. They entail not only three treatises contributed by Bastenie but also fundamental and clinical investigations, such as those presented in eight doctoral dissertations submitted for aggregation examination at Brussels Free University. These theses are dealing with the measurement of glucose assimilation (V. Conard), the measurement of insulin activity in men (J.R.M. Franckson), the mechanisms of action of hypoglycemic drugs (R. Bellens), the study of energy metabolism in children (H. Loeb), the study of insulin secretion in vitro (W. Malaisse), the distribution of insulin in body fluids as influenced by the permeability and structure of blood capillaries (E. Rasio), the regulation of the extra-hepatic metabolism of ketone bodies in anesthetized dogs (E.O. Balasse) and the use of radioiodinated insulin as tracers in biology (H.A. Ooms).

Le présent article concerne la contribution du Professeur Paul A. Bastenie, en tant que Chef du Département de Médecine à l'Hôpital Saint-Pierre et de Directeur du Laboratoire de Médecine expérimentale à l'Université libre de Bruxelles, dans le domaine de la diabétologie, en particulier le rôle de l'insuline dans l'homéostasie glucidique. Le travail expérimental pris en considération couvre la période de 1955 à 1974. Il comporte non seulement trois traités contribués par Bastenie, mais également des investigations fondamentales et cliniques telles que celles présentées à l'Université libre de Bruxelles dans huit thèses d'agrégation de l'enseignement supérieur. Celles-ci concernent la mesure de l'assimilation de glucose (V. Conard), la mesure de l'activité de l'insuline chez l'homme (J.R.M. Franckson), les mécanismes d'action des drogues hypoglycémiantes (R. Bellens), le métabolisme énergétique de l'enfant (H. Loeb), la sécrétion insulinique in vitro (W. Malaisse), le passage capillaire de l'insuline (E. Rasio), le métabolisme extra-hépatique des corps cétoniques in vivo (E.O. Balasse) et l'emploi des insulines radioiodées comme traceurs en biologie (H.A. Ooms).

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.