Frederick Banting Research Articles

100 Years since the Discovery of Insulin, from Its Discovery to the Insulins of the Future.

The term diabetes first emerged in the 3rd century BC, in a reference by Demetrius of Apamea, who described the disease as a dropsy in which any liquid ingested is eliminated in the form of urine. However, the great discovery that revolutionized this field came from the Canadian doctor Frederick Banting, who together with his student and assistant Charles Best, managed to isolate insulin and treat a patient with diabetes on 23 January 1922. This patient was Leonard Thompson, and the results obtained from him were surprising. His glycosuria and ketonuria disappeared and his blood glucose returned to normal. He received daily injections and lived 13 more years. Advances in the treatment of diabetes have been numerous in the 100 years since its discovery. In this review, we recapitulate the most important events that have occurred, and where research is progressing today.

The History of Diabetes Mellitus

Diabetes mellitus, an incessant metabolic disorder caused by increased blood glucose levels, has a rich and complex history spanning paradise. The first famous reference to diabetes dates back to ancient Egypt, where the condition was defined in healing texts around 1500 BCE. However, it was not just before the 19th century that important progress had been made in understanding and directing diabetes. In 1889, two German physicians, Joseph von Mering, and Oskar Minkowski, fashioned an important finding by professing that the removal of organ meat in dogs caused diabetes-like manifestations. This led to the identification of organ meat as an insulin source. In 1921, a Canadian group led by Frederick Banting and Charles Best released insulin, a birth control method that is critical for regulating glucose levels. This finding was obvious at a critical juncture in diabetes administration, as insulin injections have become a lifesaving situation for things associated with type 1 diabetes

November 14 — World Diabetes Day

Today, there are about half a billion people with diabetes all over the world, and almost a third of them do not even know about their diagnosis. Expressing serious concern about this state of affairs, in 1991 the International Diabetes Federation proposed that November 14 should be considered World Diabetes Day. It was on this day that the Canadian doctor and scientist Frederick Banting, a Nobel laureate, was born. Together with his colleagues, he discovered insulin and gave millions of patients hope for salvation. This initiative was supported by the World Health Organization, and on this day, for almost thirty years, doctors around the world have urged not to remain indifferent and unsympathetic to those suffering from this terrible disease. Since 2007, World Diabetes Day has been observed under the auspices of the United Nations (UN); this day was proclaimed by the UN General Assembly in a special resolution in 2006.

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

Abstract.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.

Macleod Before Banting

Abstract.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.

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.

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. To explore the facilitative roles of DeWitt and Kirkbride in the discovery of insulin and to examine their trail-breaking careers in academic pathology. Available primary and secondary historical resources were reviewed. 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. 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.

KATP Channels and the Metabolic Regulation of Insulin Secretion in Health and Disease: The 2022 Banting Medal for Scientific Achievement Award Lecture.

Diabetes is characterized by elevation of plasma glucose due to an insufficiency of the hormone insulin and is associated with both inadequate insulin secretion and impaired insulin action. The Banting Medal for Scientific Achievement Commemorates the work of Sir Frederick Banting, a member of the team that first used insulin to treat a patient with diabetes almost exactly one hundred years ago on 11 January 1922. This article is based on my Banting lecture of 2022 and concerns the mechanism of glucose-stimulated insulin secretion from pancreatic β-cells, with an emphasis on the metabolic regulation of the KATP channel. This channel plays a central role in insulin release. Its closure in response to metabolically generated changes in the intracellular concentrations of ATP and MgADP stimulates β-cell electrical activity and insulin granule exocytosis. Activating mutations in KATP channel genes that impair the ability of the channel to respond to ATP give rise to neonatal diabetes. Impaired KATP channel regulation may also play a role in type 2 diabetes. I conjecture that KATP channel closure in response to glucose is reduced because of impaired glucose metabolism, which fails to generate a sufficient increase in ATP. Consequently, glucose-stimulated β-cell electrical activity is less. As ATP is also required for insulin granule exocytosis, both reduced exocytosis and less β-cell electrical activity may contribute to the reduction in insulin secretion. I emphasize that what follows is not a definitive review of the topic but a personal account of the contribution of my team to the field that is based on my Banting lecture.

Topology of cell-free DNA from tumour cells influences its immunogenicity in macrophages and dendritic cells in vitro

Abstract Activation of DNA-sensing pathways can induce an anti-tumour immune response, but the mechanisms by which tumour-derived cell-free DNA (cfDNA) activates pro-inflammatory signaling is not well-understood. In particular, the topological features of cfDNA that contribute to DNA sensor activation in phagocytes are unknown. As such, we investigated how tumour-derived cfDNA topology influences DNA sensor activation in macrophages and dendritic cells. We treated a murine colon adenocarcinoma cell line (MC38) with chemotherapy (topotecan or staurosporine) for varying durations to induce cfDNA release. We then harvested cfDNA, separated the protected (membrane-bound) and accessible (non-membranous) fractions, and quantified nuclear and mitochondrial cfDNA abundance. The cfDNA fractions were then added to murine RAW 264.7 macrophages or bone marrow-derived dendritic cells (BMDCs), and a panel of inflammatory markers was measured by RT-qPCR. We found that accessible cfDNA from MC38 cells treated with chemotherapy for 48h increased Il6expression in RAW 264.7, but other inflammatory markers were not elevated. Interestingly, both nuclear and mitochondrial cfDNA abundance directly correlated with Il6expression. Surprisingly, cfDNA did not induce pro-inflammatory signalling in BMDCs. These results demonstrate that tumour-derived cfDNA immunogenicity depends on its mechanistic origins, abundance, and the immune cell type to which it is exposed. We are currently examining the impact of other cfDNA biophysical properties on macrophage activation, as well as elucidating the DNA sensing pathways responsible for inducing Il6expression. Our findings will help uncover the role of cfDNA in mediating anti-tumour immunity. E.Z. Malkin is supported by the Frederick Banting and Charles Best Canada Graduate Scholarship (FRN: FBD-175873) through CIHR. S.V. Bratman is supported by the Gattuso-Slaight Personalized Cancer Medicine Fund at the Princess Margaret Cancer Centre and the Dr. Mariano Elia Chair in Head and Neck Cancer Research at University Health Network and the University of Toronto.

[The unknown face of Sir Frederick Banting].

[The unknown face of Sir Frederick Banting].

100 Years of Insulin in Australia

Abstract: In 1921, Frederick Banting and his colleagues in Toronto, Canada, first used insulin for managing type 1 diabetes. Insulin transformed the disease from a death sentence to a chronic condition requiring life-long management. News of the development spread fast, and Australia became an early therapeutic adoptor and manufacturer of insulin; the same year Australian physicians were experimenting with insulin. An estimated 1.8 million Australians live with diabetes; it remains a significant health problem for First Nations Australians. In this witness seminar, the achievements of the first 100 years of insulin are celebrated.

I-European research, the cradle of the discovery of the antidiabetic hormone: the pioneer roles and the relevance of Oskar Minkowski and Eugène Gley

AimsThe introduction of hormonal treatment in severe diabetes in 1922 represented a clinical and social impact similar to that of antibiotic therapy. In October 1923, the Assembly of the Karolinska Institute decided to award the Nobel Prize in Physiology or Medicine to the Canadian Frederick Grant Banting and the Scottish John James Rickard Macleod, researchers at the University of Toronto (UT), for "the discovery of insulin a year before". A few weeks later, European and American researchers protested the decision. The controversy remains to this day.MethodsWe have conducted a comprehensive review of primary and critical sources focused on theorganotherapy of animal and human diabetes mellitus since 1889, when Oskar Minkowski demonstrated the induction of experimental diabetes by total pancreatectomy in the dog, until the spring of 1923, when the Nobel Foundation had already received all the nominations for the award in Physiology or Medicine.ResultsThe in-depth analysis of all these sources revealed that Europe was the cradle of the discovery of the antidiabetic hormone. The discovery involved multiple research steps headed by a long list of key investigators, mainly European.ConclusionMarcel Eugène Émile Gley was the first to demonstrate the presence of the “antidiabetic principle” in extracts from “sclerosed” pancreas. The French physiologist pioneered the successful reduction of glycosuria and diabetic symptoms by the parenteral administration of pancreatic extracts to depancreatized dogs in experiments developed between 1890 and 1905, antedating insulin in two decades.

November 14 — World Diabetes Day

Today, there are about half a billion diabetic patients worldwide, and almost a third of them do not even know about their diagnosis. Expressing serious concern about this state of affairs, in 1991 the International Diabetes Federation proposed November 14 to be designated as World Diabetes Day. It was on this day that the Canadian doctor, scientist and a Nobel laureate Frederick Banting was born. Together with his colleagues, he discovered insulin and gave millions of patients hope for salvation. This initiative was supported by the World Health Organization, and for almost thirty years now, doctors around the world have been calling not to remain indifferent on this day to patients with this terrible disease. Since 2007, World Diabetes Day has been held under the auspices of the United Nations (UN); this day was proclaimed by the UN General Assembly in a special resolution in 2006.

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.

Management of Type 1 Diabetes in Children in the Outpatient Setting.

Pediatricians should be aware of diabetes treatment advances, which can lead to optimal control of type I diabetes in the outpatient setting.After completing this article, readers should be able to: Provide a concise summary of the epidemiology, pathophysiology, and initial presentation of type 1 diabetes in children.Highlight routine diabetes management and screening recommendations.Review the available insulin preparations used in pediatric type 1 diabetes management.Illustrate contemporary diabetes technology and its role in improving diabetes care.The year 2021 marked the hundredth anniversary of the discovery of insulin by Frederick Banting and Charles Best. (1) This landmark discovery transformed type 1 diabetes from a fatal to a chronic disease. During the past hundred years, type 1 diabetes management has evolved tremendously. Currently, we live in an exciting era of diabetes care that not only provides children with reliable lifesaving insulin but, with recent advancements in insulin delivery and blood glucose monitoring, also promotes a return to normal childhood activities with a hope for reduced long-term complications.Management of type 1 diabetes in outpatient settings is a complex yet rewarding process. The advancements in diabetes technology and the availability of new preparations of insulin have made optimal control of type 1 diabetes in children a feasible task. In this article, we provide a comprehensive review of the current cutting-edge approaches to children with type 1 diabetes. Furthermore, we explore and discuss the available insulin delivery systems and how they may improve outcomes for children with type 1 diabetes.The incidence of type 1 diabetes seems to be steadily increasing, (2)(3) with a prevalence among youth in the United States estimated to be 1.54 to 1.93 per 100,000 younger than 20 years. (4)(5) The prevalence of this disease is disproportionately higher among non-Hispanic white individuals compared with all other ethnic groups. Native Americans have the lowest incidence of type 1 diabetes. (4) The peak incidence of diagnosis is bimodal, with a peak between 5 and 9 years of age and another peak between 10 and 14 years of age. (6)(7)It is essential to differentiate between the different types of diabetes in children. Although type 1 diabetes continues to be the most common form of diabetes in children, there has been an increase in the incidence of type 2 diabetes as well. This increase has been associated with the rise of prevalence of obesity among youth in the United States and worldwide. Note, though, that the presence of obesity in a child with new-onset diabetes is not sufficient to determine the presence of type 2 diabetes over type 1. Therefore, measuring diabetes autoantibodies is frequently necessary to make that differentiation (Table 1).One form of diabetes mellitus that is often overlooked is monogenic diabetes, or maturity-onset diabetes of the young (MODY), which is a group of genetic forms of diabetes that vary in severity from normal variance with no need for treatment to progressive forms that require insulin treatment similar to type 1 diabetes. In their analysis from the SEARCH for Diabetes in Youth study, Pihoker et al (10) found that 1.2% of children with diabetes have MODY. (11) When a child presents with new-onset diabetes, a clinician should suspect MODY in the presence of negative diabetes antibodies and a strong family history of diabetes mellitus.Type 1 diabetes results from insulin insufficiency due to β-cell destruction from an autoimmune process occurring in genetically susceptible individuals exposed to environmental and immunologic factors. (12) The progression toward overt type 1 diabetes typically goes through 3 consecutive stages: the first stage is manifested by the presence of 2 or more autoantibodies in a presymptomatic and normoglycemic individual; the second stage comprises the presence of autoantibodies with glucose intolerance in a presymptomatic patient; and the third stage begins when the patient starts experiencing the typical symptoms of diabetes mellitus (polyuria, polydipsia, weight loss, and development of diabetic ketoacidosis [DKA]). (13)(14)The 4 main autoantibodies found in patients with type 1 diabetes are glutamic acid decarboxylase, tyrosine phosphatase, insulin, and zinc transporter 8 antibodies. The presence of 2 or more of these antibodies in a patient with a genetic propensity for type 1 diabetes places the lifelong risk of developing symptomatic type 1 diabetes close to 100%; the 5- and 10-year risk is approximately 44% and approximately 70%, respectively. (15)Although preventable, approximately one-third of children with new-onset diabetes present with DKA in the United States. (16)(17) This high incidence identifies an area for needed improvement in the identification and management of children with new-onset diabetes. (18)Typical clinical symptoms associated with type 1 diabetes are polyuria, polydipsia, and nocturia. New onset of recurrent bed-wetting is not uncommon in young children with type 1 diabetes. Weight loss is frequently seen at the time of new-onset type 1 diabetes diagnosis. If unrecognized, these symptoms can rapidly progress to abdominal pain, recurrent emesis, dehydration, weakness, and lethargy, (19) which are all symptoms of DKA.In the clinic setting, when new-onset diabetes mellitus is suspected in a child, the presence of 1 or more of the following laboratory findings confirms the diagnosis: A random plasma glucose level greater than or equal to 200 mg/dL (≥11.1 mmol/L) in the presence of classic symptoms of type 1 diabetes as described previously herein.A fasting glucose level greater than or equal to 126 mg/dL (≥7.0 mmol/L).A 2-hour glucose level greater than or equal to 200 mg/dL (≥11.1 mmol/L) after a 1.75–g/kg of glucose load (maximum of 75 g).A glycohemoglobin level greater than or equal to 6.5%.If the child presents with symptoms suggestive of DKA, additional laboratory test results should be obtained. Cashen and Petersen (19) detailed the diagnostic criteria and management of DKA in a review article.Once the diagnosis of new-onset diabetes mellitus is established, insulin therapy should be started. Delay in initiating insulin therapy may lead to progression to DKA.For non–critically ill children with new-onset type 1 diabetes, there is a debate about whether inpatient diabetes management is required. Many experts argue that inpatient management for new-onset diabetes is not cost-effective and does not lead to better long-term metabolic outcomes. (20)(21) Despite that argument, many countries around the world, and many centers in the United States, opt to admit patients with new-onset diabetes to provide extensive and multidisciplinary diabetes education, to monitor for adverse reactions to treatment, and to ensure that the patients and their families are comfortable with starting the diabetes management journey at home.Regardless of the setting of initial diabetes education, the diabetes treatment team should include an expert in pediatric diabetes (pediatrician or endocrinologist), a diabetes educator with expertise in pediatric-onset diabetes, a dietitian, a social worker, and a mental health specialist to help the child and the family cope with the psychological burden of this chronic disease.At this time, due to the nature of the disease, intensive insulin therapy is the only treatment for patients with type 1 diabetes. This is established through a daily multiple-injection regimen or via a continuous subcutaneous insulin infusion device (insulin pump).Although common practice is to use insulin in the form of basal (insulin that is administered regardless of the patient’s feeding status) and prandial (ie, administered before or around meals/snacks) insulin for the management of type 1 diabetes in children, note that insulin therapy should be individualized and titrated based on the need of the child, the child’s lifestyle, and the child’s blood glucose patterns throughout the day. (22)Throughout the past century, insulin preparations have advanced tremendously from purified extract from the pancreas in 1921 to modified insulin analogues using recombinant DNA technology today. (23)Exogenous insulin preparations are broadly divided into 2 categories: rapid-acting/short-acting insulin analogues and basal insulin analogues. In each of these categories, the advancements in genetic engineering and recombinant DNA technology have allowed for the invention of different types of insulin products that vary in onset of action, peak, and length of effect (Table 2). (23)These forms of insulin differ from each other by small alterations in the amino acid structure of the insulin molecule. In 1982, regular recombinant human insulin (Humulin®; Eli Lilly and Co, Indianapolis, IN) was the first genetically engineered medication ever approved by the Food and Drug Administration (FDA). (22) This was followed by Novolin® R (Novo Nordisk Inc, Plainsboro, NJ) in 1991. To improve the insulin absorption process when administered subcutaneously, newer insulin analogues were produced: lispro (Humalog®; Eli Lilly and Co) was approved by the FDA in 1996, aspart (NovoLog®; Novo Nordisk Inc) in 2000, and glulisine (Apidra®; sanofi-aventis US, Bridgewater, NJ) in 2004. (1) These analogues are more rapidly absorbed, metabolized, and excreted than human regular insulin, providing a more ideal way to dose insulin with meals for patients with diabetes. Recently, ultra-rapid-acting insulin preparations were introduced to the market. In January 2020, Fiasp® (Novo Nordisk Inc), an ultra-rapid-acting insulin aspart, was approved by the FDA for use in children as young as 2 years old. The intent of the ultra-rapid-acting insulin is to make it easier for patients with diabetes to administer insulin for carbohydrate coverage right before, while, or even within 20 minutes after eating. (23)These forms of insulin are designed to be administered once a day to maintain steady glucose levels throughout the day. Similar to short-acting insulin, forms of long-acting insulin differ in their amino acid structures. In the United States, glargine (Lantus® [sanofi-aventis US] and Basaglar® [Eli Lilly and Co]) and determir (Levemir®; Novo Nordisk Inc) are long-acting insulin forms approved for use in children for diabetes management. In 2016, the FDA approved use of the ultra-long-acting insulin degludec (Tresiba®; Novo Nordisk Inc) in children.Before embarking on the different ways to manage type 1 diabetes in children at home, it is critical to mention the tremendous social and psychological impact of this disease on children and their families on starting the journey of self-management.The optimal method to manage type 1 diabetes at home differs significantly among patients based on their age, eating habits, lifestyles, parental level of education, socioeconomic status, and many other factors. However, it is established that the constant gold standard is to deliver an intensive insulin regimen via multiple daily injections or a continuous insulin infusion device (insulin pump). (22)To determine the total daily dose of insulin, the patient's age, weight, and pubertal status are considered. The usual initial total daily insulin dose is 0.5 to 1.0 U/kg.To maintain insulin replacement as close to physiologic as possible, a combination of long- and short-acting insulin preparations is usually needed. A ratio of 40% to 50% of long-acting insulin and 50% to 60% of short-acting insulin is widely acceptable as an initial dosing regimen. In most scenarios, long-acting insulin is administered once a day. Short- or rapid-acting insulin preparations are typically administered preprandially to prevent hyperglycemia after eating. The timing of insulin administration is adjusted based on the child's eating habits and the pattern of their glucose trends associated with food. In certain situations, rapid-acting insulin is given between meals in patients with significant hyperglycemia or an illness. The dose of short-acting insulin is calculated based on insulin-to-carbohydrate ratios, or fixed insulin doses based on the amount of carbohydrates the child eats with every meal. To provide flexibility, insulin doses are tailored to the child's carbohydrate intake with every meal, hence carbohydrate counting with insulin-to-carbohydrate ratios is generally the preferred method when the patient and/or the family can apply these skills after inpatient or outpatient education. Preprandial or between-meal hyperglycemia is treated with correction doses of short-acting insulin. This is usually calculated based on a glucose target and correction factor or on a sliding scale.Insulin doses are adjusted frequently after diagnosis depending on glucose level patterns. Many diabetes centers invest time and effort to educate patients and families on monitoring patterns of hypoglycemia and hyperglycemia and on self-adjusting insulin doses. Avenues of communication with the diabetes management teams are open for questions and concerns from families of children with diabetes.To clarify the process outlined previously herein, we provide a practical example. A 10-year-old boy presents with a 2-week history of polyuria, polydipsia, and weight loss. At presentation he is found to have a random glucose level of 285 mg/dL (15.8 mmol/L) and a glycohemoglobin level of 8.9%. The remainder of his evaluation ruled out DKA. After discussing the diagnosis of diabetes mellitus with the child and his family, the diabetes team, in coordination with the child’s family and primary care provider, decided to admit him to the hospital for diabetes management and education. The child's weight is 32 kg and he is prepubertal. The diabetes treatment team decided to start him on a daily multiple-injection insulin regimen.Because the boy is prepubertal and appeared well-hydrated, his initial total daily dose of insulin is calculated based on 0.7 U/kg (a value of 0.5–1.0 U/kg per day); the decision to choose the initial dose depends on the setting (whether the child is observed in the hospital or at home), the age of the child, and pubertal status. Typically, lower doses are chosen in younger, lean, and prepubertal children. Total daily dose = 32 × 0.7 = 22.4 U per day (rounded to 22 U daily)Dose of long-acting insulin = 22 × 50% = 11 U to be administered at bedtime dailyFor short-acting insulin dose, the team decided to calculate based on a carbohydrate ratio and correction factors as follows: ○ To estimate the insulin-to-carbohydrate ratio, the

GWAS and ExWAS of blood mitochondrial DNA copy number identifies 71 loci and highlights a potential causal role in dementia.

Mitochondrial DNA copy number (mtDNA-CN) is an accessible blood-based measurement believed to capture underlying mitochondrial (MT) function. The specific biological processes underpinning its regulation, and whether those processes are causative for disease, is an area of active investigation. We developed a novel method for array-based mtDNA-CN estimation suitable for biobank-scale studies, called 'automatic mitochondrial copy (AutoMitoC).' We applied AutoMitoC to 395,781 UKBiobank study participants and performed genome- and exome-wide association studies, identifying novel common and rare genetic determinants. Finally, we performed two-sample Mendelian randomization to assess whether genetically low mtDNA-CN influenced select MT phenotypes. Overall, genetic analyses identified 71 loci for mtDNA-CN, which implicated several genes involved in rare mtDNA depletion disorders, deoxynucleoside triphosphate (dNTP) metabolism, and the MT central dogma. Rare variant analysis identified SAMHD1 mutation carriers as having higher mtDNA-CN (beta = 0.23 SDs; 95% CI, 0.18-0.29; p=2.6 × 10-19), a potential therapeutic target for patients with mtDNA depletion disorders, but at increased risk of breast cancer (OR = 1.91; 95% CI, 1.52-2.40; p=2.7 × 10-8). Finally, Mendelian randomization analyses suggest a causal effect of low mtDNA-CN on dementia risk (OR = 1.94 per 1 SD decrease in mtDNA-CN; 95% CI, 1.55-2.32; p=7.5 × 10-4). Altogether, our genetic findings indicate that mtDNA-CN is a complex biomarker reflecting specific MT processes related to mtDNA regulation, and that these processes are causally related to human diseases. No funds supported this specific investigation. Awards and positions supporting authors include: Canadian Institutes of Health Research (CIHR) Frederick Banting and Charles Best Canada Graduate Scholarships Doctoral Award (MC, PM); CIHR Post-Doctoral Fellowship Award (RM); Wellcome Trust Grant number: 099313/B/12/A; Crasnow Travel Scholarship; Bongani Mayosi UCT-PHRI Scholarship 2019/2020 (TM); Wellcome Trust Health Research Board Irish Clinical Academic Training (ICAT) Programme Grant Number: 203930/B/16/Z (CJ); European Research Council COSIP Grant Number: 640580 (MO); E.J. Moran Campbell Internal Career Research Award (MP); CISCO Professorship in Integrated Health Systems and Canada Research Chair in Genetic and Molecular Epidemiology (GP).

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.

Book Review

Making excellence a habit: The secret to building a world class healthcare system in India, V. Mohan (Penguin Random House India Pvt. Ltd, Gurugram, India) 2021. 240 pages. Price: 699.00 ISBN: 978-0-670-09453-0 ‘Nothing in this world can take the place of persistence. Talent will not; nothing is more common than unsuccessful people with talent. Genius will not; unrewarded genius is almost a proverb. Education will not; the world is full of educated derelicts. Persistence and determination alone are omnipotent. The slogan “press on” has solved and always will solve the problems of the human race’. This quote from the 30th American President, Calvin Coolidge, can perfectly depict the character and exemplary life of Dr Mohan. The story begins with how Dr Mohan brought India’s name onto the world stage. It was in June 2018 when Dr Viswanathan Mohan was awarded Dr Harold Rifkin Award for Distinguished International service in the cause of diabetes. The book starts with the initial dreams of the author in the summer of 1968. A delightful childhood was well described as an inquisitive youngster with his love for poetry and English literature. It is humbling to read about Dr Mohan’s father, Prof Viswanathan, known as the ‘Father of Diabetology’ in India, and how he motivated Dr Mohan to take up medicine. It was thrilling to know about a 14 yr old discussing ‘research’ in India. Reading about the ‘red fort’ and the reference to ‘Psycho’ movie transported me to that time and reference to it provides a glimpse into Dr. Mohan’s psyche as a first year MBBS student. Verily, the first year of MBBS can be really intimidating and disenchanting. A poem on anatomy composed by Dr Mohan was really piquant and captured his state of mind very well. The story of Dr Frederick Banting and Charles Best was fascinating, and it is engrossing to read how this story motivated Dr Mohan to work harder. He was driven to win the Physiology University Examination and was willing to go to great lengths to achieve this goal. There was a burning desire in his heart to attain success. Thus, the Herculean task of reading 17 physiology books and accomplishing this mammoth feat demonstrated extraordinary grit of Dr Mohan. Indeed, there is a fine line between genius and insanity, and it is said that, ‘there is no great genius without some touch of madness’. However, tasting failure despite the hard work and having the patience to accept it is another life lesson altogether. The advice given by his father, ‘to focus on research’, which had the potential to change the world was well followed. The story of finding true love and life partner, Dr Rema during MBBS, was truly heart-touching. Only a medical student could think of ‘wooing’ a girl by offering her the ‘carefully prepared notes’. Reading about a family full of inspirational doctors is awe-inspiring. Walking home to save the 50 paisa bus fare and collecting money to buy books illustrated Dr Mohan’s passion for learning. The determination, grit, and resilience of character are also visible later in his life when several landmark studies are discussed which elucidated the unique profile of south Asians for increased susceptibility to type 2 diabetes mellitus. Getting funding from Wellcome Trust UK and fellowships from the UK and Germany was not achieved easily. The inspirational words of Dr Rema, ‘a bright future awaits us’, encouraged him to be the best version of himself. It acted as the force required for the inception and start of the Diabetes clinic in Chennai – beginning from a single clinic to 52 branches spread across the country. It just demonstrates the power of determination, hard work, and the attitude to grab every opportunity in life. Focus and resilience are the two secrets of success. Dr Rema is a shining example of an embodiment of such marvellous grit. She supervised a Ph.D. thesis while battling breast cancer. Life is indeed for those who dare. Reading about the motivational lessons from Dr Mohan’s childhood which left an indelible mark on his psyche and made him what he is today, was really thought-provoking. Father Whyte’s motivational words, ‘If you think you can, you will’, built a foundation for his success. Dr Mohan’s exceptional passion for research is admirable. He burnt the midnight oil to read about innumerable articles on diabetes, and this gave him an extra edge. As the saying goes, he regularly remembered to ‘sharpen his axe’ to learn and grow. Writing a DSC thesis during flight time seemed like an out-of-this-world idea indeed! Dr Mohan popularized the concept of ‘diabetes nurse educators’. However, life is not always a bed of roses. Dr Mohan harnessed the power of failure. Despite the closure of some of his national and international centres, he sprang back after every failure. This just demonstrated his mettle and power of positive thinking. He was also ingenious with out-of-the-box ideas, one such being ‘Expo on Diabetes’. Thus, ‘Diabetes 2000’ was planned, which was an instant hit. Despite being mocked by some people for having such unconventional ideas, he always remained undeterred. He firmly believed in avoiding naysayers. CURES and ICMR-INDIAB Study, which involved the collection of large-scale epidemiological data are some other examples. Similarly, Chunampet Rural Development Project was a mega success and won him international acclaim and coverage on Discovery channel. There is no substitute for hard work, and to achieve greatness, one has to make a lot of sacrifices. Although being a workaholic, Dr Mohan was always a devoted family man and deeply loved and cared for his family. He speaks fondly of his daughter Anju and talks about how he made sure he spent his holidays with family and spent quality time with them. He had singlehandedly mastered the art of time management. When people were catching up on their sleep during flights, he was working on flights. Reducing stress and learning to laugh are also an important part of success. Undeniably, a journey of a thousand miles begins with a single step. The first step is the most difficult one, after that there will be a snowball effect. Dr Mohan has a deep and intense spiritual craving to help people. Thousands of those who could not afford treatment were helped through free charitable clinics. He orchestrated the exemplary act of establishment of a DIRECT Charitable Trust, which provides lifelong free treatment. His acumen for research and skills were honed by international mentors and stalwarts in the medical field like Dr Podolsky. As a medical student, he was able to do outstanding world-class research on Diabetes. Even former US President Bill Clinton appreciated his efforts to combat and manage diabetes in a commendable fashion. Dr Mohan is a deeply spiritual person and believes in a strong mind–body connection. He talks about how he has been influenced by several spiritual Gurus who have guided him throughout his career. He strongly believes that positive reinforcement and spirituality can help in winning over even chronic ailments. The willpower and faith could move mountains. There are certain surreal events in our lives that cannot be explained by any logic. One such occurrence was the prediction by Dr Rema that Dr Mohan would be awarded the Padma Shri. Lo and behold, it did occur after her death! The vigorous shaking of garlands on pictures of Dr Rema and Bhagwan Sri Sathya Sai Baba just before the announcement of the Padma Shri Award was indeed like a divine connection. Dr Mohan wears multiple hats with panache - a doctor, a researcher, a teacher, an administrator, a philanthropist and a motivational speaker. Dr Mohan’s inspirational life has innumerable lessons for everyone to emulate and be inspired. The book ‘Making excellence a habit’ is a time capsule and beautifully teaches the basic qualities anyone needs for success. Doctors like him are one of the stalwarts in the world capable of bringing change, and his success story is something everyone should read.

La découverte de l’insuline 1921–1922 : 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.

Frederick Banting's observations leading to the potential for islet neogenesis without transplantation.

On 31 October 1920, Sir Frederick Banting, while preparing for a medical student lecture on diabetes, a topic that he knew little about, learned how pancreatic stones resulted in the formation of new islets of Langerhans. He then scribbled down a potential research study of tying off the ducts of the pancreas and collecting the secretions to improve diabetes. These secretions became known as insulin. A century later, 60 different oral medications and 20 different insulins are available for the treatment of diabetes, yet none stimulate new islet formation. One hundred years later, after the discovery of insulin, more than a dozen research teams from around the world have demonstrated that similar studies to Banting's pancreatic ligation studies have resulted in upregulation of the REG gene. There are now more than 200 publications on the role of Reg gene proteins and shorter Reg peptides in initiating new islet formation islet from exocrine pancreatic ducts and protecting against inflammation to islets resulting in islet death. Human data through Phase 2b in both type 1 and 2 diabetes patients with diabetes for an average of 20 years have demonstrated that the use of a shorter bioactive Reg peptide can generate new endogenous insulin production, resulting in significant reductions in hemoglobin A1C and increases in stimulated C‐peptide. The observations of Frederick Banting, one century ago, may now lead to the generation of therapeutics that form new islets without the need for transplantation.