Milestones in diabetes

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.

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

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.

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

Several laboratories independently developed methods to chemically synthesize insulin.

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

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.

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

Glycated haemoglobin (HbA_1c), 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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Patients with diabetes were found to have an increased risk of severe COVID-19.