Human Beta Cells Produce and Release Serotonin to Inhibit Glucagon Secretion from Alpha Cells

In the pancreatic islet, serotonin is an autocrine signal increasing beta cell mass during metabolic challenges such as those associated with pregnancy or high-fat diet. It is still unclear whether serotonin is relevant for regular islet physiology and hormone secretion. Here, we show that human beta cells produce and secrete serotonin when stimulated with increases in glucose concentration. Serotonin secretion from beta cells decreases cyclic AMP (cAMP) levels in neighboring alpha cells via 5-HT1F receptors and inhibits glucagon secretion. Without serotonergic input, alpha cells lose their ability to regulate glucagon secretion in response to changes in glucose concentration, suggesting that diminished serotonergic control of alpha cells can cause glucose blindness and the uncontrolled glucagon secretion associated with diabetes. Supporting this model, pharmacological activation of 5-HT1F receptors reduces glucagon secretion and has hypoglycemic effects in diabetic mice. Thus, modulation of serotonin signaling in the islet represents a drug intervention opportunity. [Display omitted] •Human beta cells release serotonin to regulate glucagon secretion•Serotonin lowers cAMP in alpha cells via 5-HT1F receptors•5-HT1F receptor activation reduces hyperglycemia in diabetic mice•Serotonin is a bona fide paracrine signal in the human islet Almaça et al. found that serotonin is a paracrine signal released by human pancreatic beta cells to regulate glucagon secretion. Without serotonergic control, alpha cells do not respond appropriately to changes in glucose concentration. Targeting serotonin receptors in alpha cells could be used to reduce glucagon secretion in diabetes.