Diabetes

2021 marks the centenary of the discovery of insulin. Since that landmark discovery, huge advances have taken place in our understanding of the pathogenesis of type 1 diabetes and type 2 diabetes, as well as improvements in the treatment of patients with diabetes. This Milestone timeline highlights some of the key advances that have occurred in diabetes research over the past 100 years — from the development of synthetic insulin to new drug classes and technologies for the management of diabetes.

More than 7,000 clinical trials are currently ongoing involving new drugs for type 2 diabetes mellitus (T2DM). This Review summarizes the novel drugs in development for T2DM that improve insulin sensitivity, stimulate insulin secretion or the incretin axis, or suppress hepatic glucose production.

This Review examines the evidence that β-cells are active participants in the dialogue with the immune system during the development of type 1 diabetes mellitus. The authors suggest that therapies targeting β-cell health, vitality and function might prove essential, in combination with immunotherapy, to change the course of events leading to β-cell destruction.

This Review highlights the research advances, advantages and challenges in several different strategies for generating functional β-cells for therapeutic use in diabetes mellitus. In addition, scalable bioengineering processes are also discussed for the realization of the therapeutic potential of derived β-cells.

Metabolically-mature human islet-like organoids generated from induced pluripotent stem cells are able to recapitulate insulin-responsive pancreatic islet function and avoid immunologic cell death in diabetic mouse transplantation models.

A genome-wide association study combined with single-cell epigenomics identifies risk loci for type 1 diabetes.

Clustering of patients with prediabetes using simple clinical features reveals six distinct groups with differing risk of developing type 2 diabetes and its associated complications.

The randomized-controlled trial ADVICE4U demonstrates non-inferiority of an automated AI-based decision support system compared with advice from expert physicians for optimal insulin dosing in youths with type 1 diabetes.

The authors consider the inflammatory basis of type 1 and type 2 diabetes. In particular, they focus on the role of IL-1β in both diseases and discuss the feasibility of targeting innate immune mechanisms in the clinic.

Using data from 74,629 individuals from 4 independent surveys, Bonnefond et al. report a much stronger burden of pathogenic genetic variants of MODY genes among people diagnosed with type 2 diabetes than has previously been reported.

It is 100 years since the famous experiments that identified insulin and showed that this protein could be used to treat people with type 1 diabetes mellitus. This Review charts the developments in insulin research over the past century and highlights future directions for this field.

Decades of scientific accomplishment have transformed diabetes treatment; this Review describes key milestones in our understanding of the insulin molecule and looks to the future of insulin therapy.

A large-scale genetic analysis of type 1 diabetes identifies new susceptibility variants, highlights potential regulatory mechanisms and provides genetic support for therapeutic targets for immune intervention.

Insulin resistance and lower muscle strength in relation to mass are hallmarks of type 2 diabetes. Here, the authors report alterations in muscle stem cells from individuals with type 2 diabetes that may contribute to these phenotypes through VPS39 mediated effects on autophagy and epigenetics.

The editing of primary human islets could provide insight into diabetes pathogenesis. Here the authors use CRISPR-Cas9 to target regulatory elements associated with T2D susceptibility.

Sex differences in fasting glucose and insulin have been identified, but the genetic loci underlying these differences have not. Here, the authors perform a meta-analysis of genome-wide association studies to detect sex-specific and sex-dimorphic loci associated with fasting glucose and insulin.

Hypothalamic inflammation is involved in the pathogenesis of diabetes. The underlying mechanisms are unclear. Here, the authors show that astrocytic PDK2 ablation or inhibition attenuates hypothalamic inflammation in mouse models of diabetes.

The early identification of metabolic disorders could improve or prevent overt disease. Here the authors show that the circulating concentration of hyocholic acid (HCA) species is decreased in the context of obesity and diabetes and increased after gastric bypass surgery in humans, and further that serum HCA species are predictive of metabolic outcomes in healthy individuals.

The soluble bioactive form of the transmembrane protein fibronectin type III domain containing 4 (sFNDC4) has anti-inflammatory effects and improves insulin sensitivity. Here the authors show that liver derived sFNDC4 signals through adipose tissue GPCR GPR116 to promote insulin-mediated glucose uptake.

Type 2 diabetes (T2D) is prevalent in populations worldwide, however, mostly studied in European and mixed-ancestry populations. Here, the authors perform a genome-wide association study for T2D in over 5,000 sub-Saharan Africans and identify a locus, ZRANB3, that is specific for this population.

Type 1 as well as type 2 diabetes are characterized by a loss of insulin-producing β-cells. Here the authors show that the FDA-approved drug neratinib has beneficial effects on β-cell survival, insulin secretion, and glycemic control in mouse models of diabetes.

The insulin inhibitory receptor (inceptor) is identified as a negative regulator of insulin and IGF1 signalling that could be targeted for β-cell regeneration in treatments for diabetes.

Chen et al. show that a prior history of hyperglycaemia can induce persistent DNA methylation changes at key CpGs to facilitate metabolic memory (the effect of early metabolic control on risk of developing diabetic complications later in life) and trigger diabetic complications, through modifying enhancer activity at myeloid and other cells.

Yu et al. report a preparation that enables transplantation of pancreatic islets underneath the skin and achieves long-term euglycaemia in several preclinical models of type 1 diabetes, thus providing a simple method that might enable a more widespread adoption of islet transplantation in the clinic.

The CTLA-4–Ig fusion protein (abatacept) can have beneficial effects in autoimmune disease. Walker and colleagues show in mouse and human type 1 diabetes that abatacept targets pathogenic follicular helper T cells, and the frequencies of these cells at baseline can be used to stratify treatment responses in patients.

In a study of children with high genetic risk aged 2 years or older, a risk score integrating pancreatic islet autoantibodies, genetic factors and family history is highly predictive of type 1 diabetes in the subsequent 8 years.

A deep neural network applied to smartphone-based vascular imaging can detect diabetes, opening new possibilities for non-invasive diagnosis.

Analysis of known viruses in stool samples from young children with high genetic risk for type 1 diabetes shows that sustained enterovirus B (EV-B) infections, rather than independent, short-duration EV-B infections, might be involved in the development of islet autoimmunity, but not type 1 diabetes.

This Primer by Umpierrez and colleagues reviews the epidemiology, pathophysiology, diagnosis and management of diabetic ketoacidosis, the most common acute hyperglycaemic emergency in people with diabetes mellitus. Additionally, the authors also discuss different strategies that can be implemented to prevent recurrent diabetic ketoacidosis episodes.

This Review summarizes the physiological functions, pharmacology and clinical studies of G protein-coupled receptors that are specific for lipid metabolite ligands. The challenges associated with the clinical development of therapeutics for type 2 diabetes mellitus that target these G protein-coupled receptors are also discussed.

This Review highlights the evidence from clinical trials that diet-induced weight loss interventions can be used to treat type 2 diabetes mellitus. The composition of the diet and the importance of physical exercise programmes are discussed. Lifestyle interventions for prevention of type 2 diabetes mellitus are also considered.

This Review highlights the landmark T1DM and T2DM trials that inform the current guidelines for HbA_1c targets, which remain contentious. In addition, the Review discusses individualized HbA_1c targets, examines the limitations of HbA_1c and considers alternatives for monitoring glycaemic control.

Dipeptidyl peptidase 4 inhibitors are now widely used in the treatment of patients with type 2 diabetes mellitus. This Review discusses the use of the five main dipeptidyl peptidase 4 inhibitors for this purpose, highlighting their benefits and risks.

Sodium–glucose cotransporter type 2 inhibitors (SGLT2is) are used for the treatment of type 2 diabetes mellitus. This Review provides an in-depth overview of the role of SGLT2is as glucose-lowering agents and as cardiovascular and renal protective agents.

The pathophysiology of coronavirus disease 19 (COVID-19) and diabetes mellitus are interlinked, and diabetes mellitus is associated with severe COVID-19 outcomes. This Review highlights new advances in diabetes mellitus and COVID-19, considering disease mechanisms and clinical management of patients with diabetes mellitus in the ongoing pandemic.

This Review focuses on the current understanding of the molecular and cellular pathology of diabetic retinopathy. The primary focus is on the cellular signalling between the neuronal and vascular retina that promotes formation of the inner blood–retinal barrier of the retinal vasculature as an important point of intervention.

This article discusses the latest advances in the mechanisms of diabetic sensorimotor peripheral neuropathy (DSPN) and painful DSPN, originating both from the periphery and the central nervous system, and outlines the emerging diagnostics and treatments.

A meta-analysis of genome-wide association study data from 77,418 individuals of East Asian ancestry with type 2 diabetes identifies novel variants associated with increased risk of type 2 diabetes.