β-Cell secretory products activate α-cell ATP-dependent potassium channels to inhibit glucagon release

Glucagon, secreted from islet alpha-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 beta-cell secretory products zinc and insulin on isolated rat a-cells, intact islets, and perfused pancreata. Islet glucagon secretion was markedly zinc sensitive (IC50 = 2.7 mu mol/l) more than insulin release (IC50 = 10.7 mu mol/l). Glucose, the mitochondrial substrate pyruvate, and the ATP-sensitive K+ channel (K-ATP channel) inhibitor tolbutamide stimulated isolated alpha-cell electrical activity and glucagon secretion. Zinc opened K-ATP channels and inhibited both electrical activity and pyruvate (but not arginine) stimulated glucagon secretion in alpha-cells. Insulin transiently increased K-ATP channel activity, inhibited electrical activity and glucagon secretion in alpha-cells, and inhibited pancreatic glucagon output. Insulin receptor and K-ATP channel subunit transcripts were more abundant in alpha- than beta-cells. Transcript for the glucagon-like peptide 1 (GLP-1) receptor was not detected in alpha-cells nor did GLP-1 stimulate a-cell glucagon release. beta-Cell secretory products zinc and insulin therefore inhibit glucagon secretion most probably by direct activation of K-ATP channels, thereby masking an alpha-cell metabolism secretion coupling pathway similar to beta-cells.