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Pancreatic beta-cell glucose metabolism is coupled to insulin secretion. Here the authors set out to characterize changes in beta-cell metabolism in hyperglycemia which may contribute to insufficient insulin secretion in type 2 diabetes and, using a multi-omics approach, find that mitochondrial metabolism is perturbed.

Impaired glucagon secretion in patients with diabetes causes hypoglycemia. Here the authors show that therapeutic concentrations of insulin inhibit alpha-cell glucagon secretion by stimulating delta-cell insulin receptor and the release of somatostatin. Blocking somatostatin secretion or action ameliorates this effect.

Prior hypoglycemia alters the paracrine interaction between islet α and δ cells, leading to impaired counter-regulatory glucagon secretion through somatostatin hypersecretion, increasing the risk of recurrent hypoglycemia.

K_ATPchannels have a key role in the regulation of blood glucose homeostasis. This Review outlines their role in the regulation of insulin and glucagon release, which decrease and increase blood glucose levels respectively, under both physiological conditions and in disease states such as diabetes mellitus and hyperinsulinism.

MacDonald and Rorsman discuss the physiological role of glucagon, regulation and dysregulation of its secretion from alpha cells, and the potential of glucagon as a therapeutic target for diabetes and associated metabolic diseases.

Somatostatin is secreted by delta cells and inhibits insulin and glucagon secretion. Here Vergari et al. demonstrate a mechanism for somatostatin secretion that is dependent on decreased extracellular potassium and increased intracellular sodium levels, and is altered in islets from patients with diabetes.

Insulin secretion depends on action potential firing in pancreatic islet beta-cells, but the underlying mechanism is unclear. Here, the authors show that activation of the mechanosensor ion channel PIEZO1 plays a central role in beta-cell electrical activity and insulin release.

Impaired somatostatin secretion owing to loss of β- to δ-cell electrical coupling underlies defective counter-regulatory glucagon secretion in type-1 diabetes.

Deriving functional pancreatic cell types from human stem cells may have important clinical applications. Building on previous work, here the authors generate stem cell-derived alpha cells via a polyhormonal intermediate, which have a gene expression pattern similar to human islet alpha cells and behave as such when transplanted into mice.

Glutamate is best known for its function in nervous transmission, where it is secreted from nerve terminals and acts as an extracellular excitatory neurotransmitter. There is now evidence that glutamate also has an intracellular function. It has been found to be involved in preparing secretory granules for release from the insulin-secreting β-cells of the pancreas.

Chronic hyperglycemia impairs insulin secretion from pancreatic beta cells in diabetes. Here, the authors reveal that a glucose metabolite is responsible and show lowering glucose metabolism during hyperglycemia prevents loss of beta-cell function.

Coding variants in peptidylglycine α-amidating monooxygenase (PAM) associated with type 2 diabetes risk negatively impact overall PAM activity via defects in expression and catalytic function, resulting in reduced insulin content and altered dynamics of insulin secretion.

The rare loss-of-function allele p.Arg138* in SLC30A8 (encoding ZnT8) mediates protection against type 2 diabetes (T2D) through promoting better insulin secretion and enhanced glucose responsiveness, suggesting ZnT8 as a target for T2D treatment.

Diabetes is characterized by prolonged hyperglycaemia and tissue damage in pancreatic islets. Here, Brereton et al. show that chronic high glucose levels lead to glycogen accumulation in β-cells, associated with reduced autophagy, impaired metabolism, insulin granule depletion and apoptosis.

Glucagon secretion is promoted during hypoglycemia and inhibited by increased glucose levels. Here, Basco et al. show that glucokinase suppresses glucose-regulated glucagon secretion by modulating the intracellular ATP/ADP ratio and the closure of K_ATP channels in α-cells.

In patients with diabetes, insulin release from pancreatic β-cells is reduced due to altered islet structure and function. Here, Brereton et al. show that elevated blood glucose underlies these changes and is sufficient to reversibly alter β-cell identity in a mouse model of β-cell dysfunction.

Steviol glycosides are sweet-tasting compounds isolated from a South American shrub and are increasingly used as sweeteners in foods and beverages. Philippaertet al. demonstrate that steviol glycosides potentiate Ca²⁺-dependent TRPM5 activity and promote glucose-induced insulin secretion and glucose tolerance.

The δ-cells of the pancreatic islets secrete somatostatin, which inhibits insulin and glucagon secretion. In this Review, the authors summarize the cellular physiology of somatostatin secretion, how this might go wrong in diabetes mellitus and potential therapeutic targets.

The authors of this Perspective summarize the state of human islet research and compare available islet procurement methods, proposing strategies to increase collaboration and standardization to accelerate discoveries on diabetes.

Veprik et al. show that Acetyl-CoA-carboxylase 1 (ACC1), an enzyme that couples glucose metabolism to lipogenesis, is involved in glucagon secretion and regulates S-acylation of critical glucose-sensing proteins. Loss of ACC1 in pancreatic alpha-cells negatively affects both size and number, as well as glucagon content, while in gut enteroendocrine cells leads to reduced release of glucagon-like peptide 1.