Milestones | 17 June 2021

Milestones in diabetes

  • Foreword

    Frederick Banting declared that “insulin is not a cure for diabetes; it is a treatment” in his 1923 Nobel lecture. The year 2021 marks 100 years since the discovery of insulin, which revolutionized the management of patients with type 1 diabetes. The past 100 years have seen seismic shifts in our understanding of the pathogenesis of the different types of diabetes, leading to advances in patient care. In this Nature Milestones in Diabetes, we highlight some of these key discoveries, which lay a path to the elusive goal of finding a cure for diabetes. Read more.

  • Milestone 1 1922

    A history of insulin: initial discovery to first use in the treatment of T1D

    In the early 1920s, Banting, Best, Macleod and Collip identified and purified a pancreatic extract — insulin. Subsequently, insulin was successfully used to regulate glucose levels in patients with type 1 diabetes, revolutionizing the treatment of these patients. Read more.

    By Claire Greenhill

    Video

    The discovery of insulin

    Nearly 100 years since insulin was first used in the treatment of diabetes, Professor Chantal Mathieu, Professor of Medicine at the Katholieke Universiteit Leuven, Belgium, takes us through the history, development and future of this life saving drug.

    Please visit YouTube to view this video.

  • 1923

    Nobel Prize in Physiology or Medicine

    Frederick Banting and John Macleod were awarded the Nobel Prize in Physiology or Medicine for their role in the discovery of insulin. Banting and Macleod went on to share the prize money with Charles Best and James Bertram Collip.

  • 1958

    Nobel Prize in Chemistry

    Frederick Sanger was awarded a share of the Nobel Prize in Chemistry for his work determining the structure of proteins, particularly insulin. He had determined the amino acid sequence of insulin.

    Related article: The Nobel Prize: Frederick Sanger facts

  • Milestone 2 1965

    Islet pathology in diabetes

    Early autopsy studies of individuals who died at onset of type 1 diabetes have helped inform us of the pathological changes occurring in the pancreas. In type 1 diabetes, a progressive and immune-mediated deterioration of β-cells occurs within pancreatic islets, eventually leading to an almost complete absence of insulin secretion. In type 2 diabetes, β-cell number is reduced owing to increased β-cell apoptosis. Read more.

    By Shimona Starling

  • 1967

    Proinsulin identified

    Proinsulin, the precursor of insulin, was identified by Donald F. Steiner and colleagues at the University of Chicago. This, together with subsequent works, showed that insulin is derived from a larger prohormone, through processing inside insulin-secreting cells.

  • 1969

    X-ray crystallography of insulin

    Nobel Prize-winning chemist Dorothy Hodgkin and colleagues used X-ray crystallography to create a 3D electron density map of insulin.

    Related article: Structure of Rhombohedral 2 Zinc Insulin Crystals

  • 1971

    Glycated haemoglobin

    Glycated haemoglobin (HbA1c), a form of haemoglobin that is chemically linked to glucose, was identified as a stable indicator of diabetes status.

    Related article: Hemoglobin Components in Patients with Diabetes Mellitus

  • Milestone 3 1974

    The genetic underpinnings of T1D

    Nerup et al. demonstrated that the types of HLA protein present on white blood cells associate with type 1 diabetes as well as with the occurrence of anti-pancreatic autoantibodies in patients, thereby pinpointing that the HLA system genes contribute to the heritability of type 1 diabetes. Read more.

    By Anna Kriebs

  • 1977

    Nobel Prize in Physiology or Medicine

    Rosalyn Yalow was awarded a share in the Nobel Prize in Physiology or Medicine for her work on developing radioimmunoassays of peptide hormones. The radioimmunoassay enabled Yalow and her colleagues to track insulin in a patient, leading to the demonstration that type 2 diabetes was caused by the body being unable to use insulin effectively, rather than a lack of insulin.

    Related article: The Nobel Prize: Rosalyn Yalow facts

  • Milestone 4 1978

    Animal models of T1D

    The BB rat and the non-obese diabetic (NOD) mouse, two animal models of type 1 diabetes, spontaneously develop the disease. These models have enabled the study of mechanisms underlying type 1 diabetes onset and progression and the development of therapeutic interventions. Read more.

    By Aline Lueckgen

  • Milestone 5 1978

    A pioneering study of diabetes complications

    A ground-breaking longitudinal study, conducted by the Belgian physician Jean Pirart over a period of more than 30 years, established a clear link between poor glycaemic control and degenerative complications such as neuropathy, retinopathy and nephropathy in patients with diabetes. Read more.

    By Heather Wood

  • Milestone 6 1979

    Insulin gets an upgrade

    Concerns about the immunogenicity of animal-derived insulin led to a search for alternative methods of insulin production. The first successful generation of fully synthetic human insulin was reported in 1979 and the product was approved by the FDA just 3 years later, providing a less immunogenic form of insulin for the millions of people around the world who need it. Read more.

    By Sarah Lemprière

  • Milestone 7 1982

    Autoantibodies emerge on the scene

    The 1970s and 1980s saw the discovery of islet cell antibodies and their various targets, providing evidence of type 1 diabetes as an autoimmune disease, as well as spurring on research into disease prevention and the development of antibody assays that remain in use today. Read more.

    By Jessica McHugh

  • 1984

    Nobel Prize in Chemistry

    Bruce Merrifield was awarded the Nobel Prize in Chemistry for his development of a methodology for chemical synthesis on a solid matrix, which included work on insulin.

    Related article: The Nobel Prize: Bruce Merrifield facts

  • Milestone 8 1986

    Cytokines directly implicated in T1D

    A study published in Science showed a direct role for the cytokine IL-1 in mediating β-cell death, heralding a new understanding of the mechanisms involved in insulitis and providing a new approach for targeted therapies. Read more.

    By Joanna Clarke

  • Milestone 9 1987

    Illuminating the incretin effect

    In 1987, the laboratories of Habener and Holst established intestinal GLP1(7–37) as a key regulator of pancreatic insulin secretion. These studies laid the foundations for further exploration of the role of GLP1 in glucose homeostasis, which ultimately led to the development of incretin-based therapies for the treatment of type 2 diabetes. Read more.

    By Sarah Crunkhorn

  • Milestone 10 1988

    GLUT4 traffic control

    Insulin is essential for glucose homeostasis, and one of its key functions is to drive glucose uptake into adipocytes and myocytes. Owing to work in the late 1980s, we now know that the insulin-stimulated glucose uptake in these tissues relies on the expression of a unique glucose transporter, GLUT4, whose intracellular trafficking is regulated by insulin signalling. Read more.

    By Paulina Strzyz

  • 1988

    Insulin analogues

    The first insulin analogues were developed in 1988. These analogues are absorbed much faster than previous forms of insulin, which enables patients to achieve an insulin plasma profile that more closely reflects the profile in people without diabetes.

    Related article: Monomeric insulins obtained by protein engineering and their medical implications

  • Milestone 11 1992

    The discovery of monogenic diabetes

    In the early 1990s, genetic linkage analysis studies identified a new form of diabetes, known as monogenic diabetes, in which single gene mutations that interfere with β-cell function lead to disease. This discovery is considered an important landmark in the field owing to its profound implications for the clinical care and prognosis of patients. Read more.

    By Deepitha Maennich

  • Milestone 12 1993

    TNF short-circuits the insulin receptor

    Key studies in the 1990s from Gökhan Hotamisligil, Bruce Spiegelman and colleagues showed how the pro-inflammatory cytokine TNF drives insulin resistance and provided key insight into the mechanisms of obesity-associated diabetes. Read more.

    By Yvonne Bordon

  • Milestone 13 1993

    Findings from DCCT — glycaemic control prevents diabetes complications

    The publication of the results of the Diabetes Control and Complications Trial marked a change in the treatment of diabetes. This trial demonstrated that intensive therapy — aimed at achieving glycaemic control as close to the non-diabetic range as safely possible — substantially reduced the complications of diabetes. From this point on, intensive therapy became the new standard therapy for patients with insulin-dependent diabetes. Read more.

    By Megan Cully

  • Milestone 14 1995

    Role of bariatric surgery in T2D

    In 1995, Pories et al. reported the remarkable remission of type 2 diabetes in a cohort of individuals with obesity undergoing bariatric surgery. Bariatric surgery remains one of the most effective treatment options for this disease. Read more.

    By Isobel Leake

  • Milestone 15 1997

    Better living (not) through chemistry

    In 1997, the Da Qing IGT and Diabetes Study reported a statistically significant reduction in incident type 2 diabetes following a 6-year behavioural intervention of diet and/or exercise compared with placebo in individuals with impaired glucose tolerance. Read more.

    By Jennifer Sargent

  • Milestone 16 2000

    Genetics of T2D

    In 2000, a ground-breaking genetic association study was published that confirmed PPARG as a type 2 diabetes susceptibility gene. The field has now advanced so far that >550 type 2 diabetes risk signals have been identified. The valuable knowledge gained from these genetic factors has been used to inform disease mechanisms and research into therapeutics and might be used to form the basis of future precision medicine approaches. Read more.

    By Shimona Starling

  • Milestone 17 2002

    Anti-CD3: the agonist and the ecstasy

    Immunomodulating CD3-specific antibodies were shown for the first time to slow the loss of β-cell function in patients with type 1 diabetes. Read more.

    By Zoltan Fehervari

  • Milestone 18 2006

    Towards a stem cell therapy for diabetes

    Transplantation of insulin-producing pancreatic β-cells to replenish diminishing populations in patients with type 1 diabetes might provide the ultimate therapy or even cure for the disease. This milestone study reported, for the first time, the generation of hormone-expressing endocrine pancreatic cells from differentiating human embryonic stem cells in vitro. Some of these cells expressed β-cell markers and synthesized and secreted insulin, although they showed a minimum response to glucose. Read more.

    By Anna Melidoni

  • Milestone 19 2007

    Islet inflammation in T2D

    A 2007 study by Marc Donath and colleagues showed that insulitis is a pathological feature of type 2 diabetes, as well as type 1 diabetes, paving the way for further exploration of inflammasome activation and anti-inflammatory therapies in type 2 diabetes. Read more.

    By Kirsty Minton

  • Milestone 20 2012

    Treg cells to the rescue: the first clinical studies

    The first clinical trials using regulatory T cells in children and adults with diabetes were reported in 2012 and 2014, respectively. These trials showed that the approach is safe and tolerable, with promising first indications of efficacy. Read more.

    By Alexandra Flemming

  • Milestone 21 2014

    Technology will set you free

    A paper published in 2014 provided the first demonstration of the use of a bihormonal closed-loop system under free-living conditions in adults and adolescents with type 1 diabetes. Read more.

    By Jennifer Sargent

    Video

    The artificial pancreas: a bridge to a cure

    Tight control of blood glucose levels is vital for people with diabetes to lead healthy lives. But this challenge is no small undertaking, requiring careful monitoring of the diet and blood glucose levels, and regular insulin injections. One solution might be the development of the artificial pancreas; a device that monitors blood glucose levels and administers insulin automatically. Dr Helen Murphy, Clinical Professor in Medicine at Norwich Medical School, University of East Anglia, UK, takes us through her work with such devices — could they represent a bridge to a cure for people with diabetes?

    Please visit YouTube to view this video.

  • 2016

    Islet transplantation

    A phase III trial reported improved glucose control, improved hypoglycaemia awareness and fewer severe hypoglycaemic events in patients with type 1 diabetes following a transplant of purified human pancreatic islets.

    Related article: Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia

  • 2016

    T2D in sub-Saharan Africa

    The protocol for one of the first large studies to assess the prevalence of type 2 diabetes in sub-Saharan Africa, as well as the environmental and genetic determinants of the disease, was published in 2016. The study is part of the Human Heredity and Health in Africa (H3Africa) initiative.

    Related article: H3Africa multi-centre study of the prevalence and environmental and genetic determinants of type 2 diabetes in sub-Saharan Africa: study protocol

    Video

    Diabetes in sub-Saharan Africa

    It is estimated that over 19 million adults in Africa have diabetes, an enormous problem that Professor Jean Claude Mbanya, Professor of Medicine and Endocrinology at the University of Yaoundé I, Cameroon, understands too well. Here he takes us through the unique challenges and pitfalls of treating patients with diabetes in sub-Saharan Africa.

    Please visit YouTube to view this video.

  • Milestone 22 2017

    Incretin drugs for glycaemic control

    Incretin drugs, which include glucagon-like peptide 1 receptor agonists (GLP1RAs) and dipeptidyl peptidase 4 inhibitors, exploit the effects of GLP1 on insulin production to improve glycaemic control. In addition to their proven benefits in the treatment of hyperglycaemia, clinical studies have shown that GLP1RAs promote weight loss, and can improve cardiovascular and kidney outcomes in patients with type 2 diabetes, expanding the therapeutic potential of these agents. Read more.

    By Monica Wang

  • Milestone 23 2019

    An infectious cause for T1D?

    In 2002, clinical centres across the USA and Europe began recruiting young children to study the environmental causes of type 1 diabetes (T1D) — the TEDDY study. From this cohort, a paper by Vehik et al. in 2019 pinpointed a role for prolonged enteroviral B infection in T1D development in young children, representing a major advance in our understanding of the links between the virome and T1D. Read more.

    By Lucy Bird

  • Milestone 24 2019

    Getting to the heart of the matter

    2019 saw the publication of meta-analyses demonstrating beneficial effects for cardiovascular and renal outcomes in patients with type 2 diabetes given glucose-lowering therapies — sodium–glucose co-transporter 2 inhibitors and glucagon-like peptide 1 receptor agonists. Read more.

    By Jennifer Sargent