The Role of α-Cells in Islet Function and Glucose Homeostasis in Health and Type 2 Diabetes

Pancreatic alpha-cells are the major source of glucagon, a hormone that counteracts the hypoglycemic action of insulin and strongly contributes to the correction of acute hypoglycemia. The mechanisms by which glucose controls glucagon secretion are hotly debated, and it is still unclear to what extent this control results from a direct action of glucose on alpha-cells or is indirectly mediated by beta- and/or delta-cells. Besides its hyperglycemic action, glucagon has many other effects, in particular on lipid and amino acid metabolism. Counterintuitively, glucagon seems also required for an optimal insulin secretion in response to glucose by acting on its cognate receptor and, even more importantly, on GLP-1 receptors. Patients with diabetes mellitus display two main alterations of glucagon secretion: a relative hyperglucagonemia that aggravates hyperglycemia, and an impaired glucagon response to hypoglycemia. Under metabolic stress states, such as diabetes, pancreatic acells also secrete GLP-1, a glucose-lowering hormone, whereas the gut can produce glucagon. The contribution of extrapancreatic glucagon to the abnormal glucose homeostasis is unclear. Here, I review the possible mechanisms of control of glucagon secretion and the role of alpha-cells on islet function in healthy state. I discuss the possible causes of the abnormal glucagonemia in diabetes, with particular emphasis on type 2 diabetes, and I briefly comment the current antidiabetic therapies affecting alpha-cells. (C) 2020 Elsevier Ltd. All rights reserved.