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

Glucagon is secreted from pancreatic -cells to activate gluconeogenesis and other pathways that raise blood glucose during hypoglycemia. Glucose-dependent regulation of glucagon secretion involves both -cell-intrinsic mechanisms and paracrine control through insulin and somatostatin. In type-2 diabetes (T2D) inadequately high glucagon levels contribute to hyperglycemia. To understand these disease-associated changes at the cellular level, and to isolate intrinsic and paracrine effects, we analyzed glucagon granule exocytosis and membrane excitability in isolated -cells from 56 non-diabetic (ND) and 15 T2D human donors. High resolution imaging showed that glucagon granule exocytosis had a U-shaped sensitivity to glucose, with the slowest rate around 7 mM glucose, and accelerated rates at 10 mM glucose. Exocytosis was reduced in T2D -cells, but their glucose sensitivity remained intact and there were no changes in voltage-dependent ion currents or granule trafficking. Instead, -cells from T2D donors were markedly insensitive to somatostatin and insulin, which rapidly inhibited exocytosis and electrical activity in ND cells. Thus, intrinsic mechanisms do not inhibit glucagon secretion at hyperglycemia, and elevated glucagon levels in human T2D reflect an insensitivity of -cells to paracrine inhibition.