-Cell Secretory Products Activate -Cell ATP-Dependent Potassium Channels to Inhibit Glucagon Release

Glucagon, secreted from islet -cells, mobilizes liver glucose. During hyperglycemia, glucagon secretion is inhibited by paracrine factors from other islet cells, but in type 1 and type 2 diabetic patients, this suppression is lost. We investigated the effects of -cell secretory products zinc and insulin on isolated rat -cells, intact islets, and perfused pancreata. Islet glucagon secretion was markedly zinc sensitive (IC50 2.7 mol/l) more than insulin release (IC50 10.7 mol/l). Glucose, the mitochondrial substrate pyruvate, and the ATP-sensitive K channel (KATP channel) inhibitor tolbutamide stimulated isolated -cell electrical activity and glucagon secretion. Zinc opened KATP channels and inhibited both electrical activity and pyruvate (but not arginine)stimulated glucagon secretion in -cells. Insulin transiently increased KATP channel activity, inhibited electrical activity and glucagon secretion in -cells, and inhibited pancreatic glucagon output. Insulin receptor and KATP channel subunit transcripts were more abundant in than -cells. Transcript for the glucagon-like peptide 1 (GLP-1) receptor was not detected in -cells nor did GLP-1 stimulate -cell glucagon release. -Cell secretory products zinc and insulin therefore inhibit glucagon secretion most probably by direct activation of KATP channels, thereby masking an -cell metabolism secretion coupling pathway similar to -cells. Diabetes 54:1808–1815, 2005