Glucagon: celebrating 100 years

This Review highlights mechanisms of glucagon secretion from pancreatic α-cells, including paracrine actions in islets and α-cell–β-cell crosstalk. Dysregulated glucagon secretion in metabolic diseases is also considered and the clinical potential of targeting glucagon is discussed.

In type 1 diabetes, the immune system destroys pancreatic β-cells but not neighbouring α-cells. Here, the authors describe the key differences between β-cells and α-cells that could account for their differential autoimmune vulnerability, and how these differences could result in the preferential endurance and survival of α-cells over β-cells.

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.

Within the pancreatic islets of Langerhans, endocrine cells are heterogeneous in terms of transcriptional profile, protein expression and the regulation of hormone release. This Review describes how endocrine cell heterogeneity, particularly of β-cells, affects the regulation of hormone secretion within pancreatic islets.

In 1923, Kimball and Murlin published work that identified a substance in pancreatic extracts that caused hyperglycaemia, which they named glucagon. A century later, we now know the importance of this hormone in human physiology and disease, and drugs targeting the glucagon receptor family have been developed to treat metabolic diseases.

In a recent issue of Cell Reports, Xi et al. reported on their studies of an anti-glucagon receptor antibody in several mouse models of insulin-deficient diabetes mellitus, in which they show substantial increase in β-cell mass from enhanced replication and transdifferentiation of glucagon-expressing α-cells to insulin-expressing β-cells.

Glucagon-like peptide 1 (GLP1) analogues are licensed options for obesity, but new treatments are required to obtain better weight loss and to directly address other co-morbidities, such as non-alcoholic fatty liver disease. Research published in 2022 shows that co-agonist combinations of GLP1 with other hormones provide clinically important advances.

In this study, Juan-Mateu et al. discover microexons that modulate insulin secretion in the pancreas in response to glucose levels in beta cell lines and mouse islets. Human genetic variants modulating these islet microexons are associated with type 2 diabetes risk.

Elevated hepatic alanine catabolism is shown to promote hyperglycaemia and reduce skeletal muscle protein synthesis, thereby linking sarcopenia with hyperglycaemia in the context of type 2 diabetes.

Based on preclinical studies, gamma aminobutyric acid (GABA) and immunization for the enzyme that produces GABA glutamate decarboxylase (GAD) could be a potential therapy for type 1 diabetes. Here the authors report that in a placebo-controlled, double blind trial in children with new onset type 1 diabetes oral GABA plus GAD did not preserve beta-cell function measured as fasting/meal-stimulated c-peptide levels.

The Ca²⁺ modulated pulsatile glucagon and insulin secretions by pancreatic α and β cells are critical in glucose homeostasis. Here the authors show that the Ca²⁺ oscillations of α and β cells are phase-locked, and that the oscillation pattern is tuned by paracrine interactions between α and β cells.

Insufficient glucagon signalling results in hyperaminoacidemia, which drives adaptive proliferation of glucagon-producing α cells. Here the authors report that the amino acid sensitive calcium sensing receptor (CaSR) is necessary for α cell proliferation via Gq signalling during hyperaminoacidemia.

Cell therapy to replace β-cells is a potential therapeutic avenue to treat diabetes, but the production of insulin-secreting replacement cells requires reliable tools to assess islet cellular identity. Here the authors use single-cell transcriptomics meta-analysis to construct gene sets that describe the identity of human α-, β-, γ- and δ-cells.

How pancreatic islets of Langerhans are built during development is incompletely understood. Here the authors find that Synaptotagmin-13 mediates remodeling of cell-matrix adhesion to regulate endocrine cell egression and islet morphogenesis.

Glucagon-like peptide-1 receptor (GLP1R) agonists are used to treat type 2 diabetes (T2D), and polyagonists targeting multiple hormone receptors are investigated as potential therapeutics for T2D. Here the authors report that IBI362 (LY3305677), a balanced once-weekly GLP-1 and glucagon receptor dual agonist, showed favourable safety and tolerability in Chinese patients with type 2 diabetes in a randomized controlled phase 1b clinical trial.

Disordered hepatic glucagon response contributes to hyperglycemia in diabetes via gluconeogenesis. Here the authors report that the mitochondrial β-oxidation enzyme HADHA promotes β-hydroxybutyrate production, which negatively regulates hepatic gluconeogenesis during glucagon challenge by targeting HDAC7 in mice.

During hypoglycemia, glucagon secretion is part of the mechanism needed to restore normal blood glucose levels. Here, Strembitska et al. report that sensing of hypoglycemia by AgRP neurons requires Agpat5, an enzyme which prevents fatty acids from entering the mitochondria for ATP production, ensuring correct neuronal activation and glucagon secretion.