Glucagon, secreted from pancreatic islet cells, stimulates gluconeogenesis and liver glycogen breakdown. The mechanism regulating
glucagon release is debated, and variously attributed to neuronal control, paracrine control by neighbouring cells, or to an intrinsic glucose sensing by the cells themselves. We examined hormone
secretion and Ca2 responses of and cells within intact rodent and human islets. Glucose-dependent suppression of glucagon release persisted when paracrine GABA or Zn2 signalling was blocked, but was reversed by low concentrations (120 M) of the ATP-sensitive K (KATP) channel opener diazoxide, which had no effect on insulin release or cell responses. This effect was prevented by the KATP channel blocker tolbutamide (100 M). Higher diazoxide concentrations (30 M) decreased glucagon and insulin secretion, and - and -cell Ca2 responses, in parallel. In the absence of glucose, tolbutamide at low concentrations (<1 M) stimulated glucagon secretion, whereas high concentrations (>10 M) were inhibitory. In the presence of a maximally inhibitory concentration of tolbutamide (0.5 mM), glucose had no additional suppressive effect. Downstream of the KATP channel, inhibition of voltage-gated Na (TTX) and N-type Ca2
channels (-conotoxin), but not L-type Ca2 channels (nifedipine), prevented glucagon secretion. Both the N-type Ca2 channels and -cell exocytosis were inactivated at depolarised membrane potentials. Rodent and human glucagon secretion is regulated by an -cell KATP channel-dependent mechanism. We propose that elevated glucose reduces electrical activity and exocytosis via depolarisation-induced inactivation of ion channels involved in action potential firing and secretion.