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Diabetes 54:1808-1815, 2005
© 2005 by the American Diabetes Association, Inc.

ß-Cell Secretory Products Activate {alpha}-Cell ATP-Dependent Potassium Channels to Inhibit Glucagon Release

Isobel Franklin1, Jesper Gromada2, Asllan Gjinovci1, Sten Theander1, and Claes B. Wollheim1

1 Department of Cell Physiology and Metabolism, University Medical Centre, Geneva, Switzerland
2 Lilly Research Laboratories, Hamburg, Germany

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

Address correspondencereprint requests to Dr. Claes B. Wollheim, Department of Cell PhysiologyMetabolism, University Medical Centre, 1211 Geneva 4, Switzerland. E-mail: claes.wollheim{at}medicine.unige.ch

Abbreviations: FACS, fluorescence-activated cell sorter; GLP-1, glucagon-like peptide 1; KATP channel, ATP-sensitive K+ channel; KRBH, Krebs-Ringer bicarbonate HEPES buffer; SUR, sulfonylurea receptor


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