Paracrine control of α-cell glucagon exocytosis is compromised in human type-2 diabetes

Glucagon is released from pancreatic alpha -cells to activate pathways that raise blood glucose. Its secretion is regulated by alpha -cell-intrinsic glucose sensing and paracrine control through insulin and somatostatin. To understand the inadequately high glucagon levels that contribute to hyperglycemia in type-2 diabetes (T2D), we analyzed granule behavior, exocytosis and membrane excitability in alpha -cells of 68 non-diabetic and 21 T2D human donors. We report that exocytosis is moderately reduced in alpha -cells of T2D donors, without changes in voltage-dependent ion currents or granule trafficking. Dispersed alpha -cells have a non-physiological V-shaped dose response to glucose, with maximal exocytosis at hyperglycemia. Within intact islets, hyperglycemia instead inhibits alpha -cell exocytosis, but not in T2D or when paracrine inhibition by insulin or somatostatin is blocked. Surface expression of somatostatin-receptor-2 is reduced in T2D, suggesting a mechanism for the observed somatostatin resistance. Thus, elevated glucagon in human T2D may reflect alpha -cell insensitivity to paracrine inhibition at hyperglycemia. Glucagon is elevated Type-2 diabetes, which contributes to poor glucose control in patients with the disease. Here the authors report that secretion of the hormone is controlled by paracrine inhibition, and that resistance of alpha -cells to somatostatin can explain hyperglucagonemia in type-2 diabetes.