A Novel Regulator of the Pancreatic Islet Physiology
Miniglucagon, the COOH-terminal (19-29) fragment processed from glucagon, is a potent and efficient inhibitor of insulin secretion from the MIN 6 β-cell line. Using the rat isolated-perfused pancreas, we investigated the inhibitory effect of miniglucagon on insulin secretion and evaluated the existence of an inhibitory tone exerted by this peptide inside the islet. Miniglucagon dose-dependently inhibited insulin secretion stimulated by 8.3 mol/l glucose, with no change in the perfusion flow rate. A concentration of 1 nmol/l miniglucagon had a significant inhibitory effect on a 1 nmol/l glucagon-like peptide 1 (7-36) amide-potentiated insulin secretion. A decrease in extracellular glucose concentration simultaneously stimulated glucagon and miniglucagon secretion from pancreatic α-cells. Using confocal and electron microscopy analysis, we observed that miniglucagon is colocalized with glucagon in mature secretory granules of α-cells. Perfusion of an anti-miniglucagon antiserum directed against the biologically active moiety of the peptide resulted in a more pronounced effect of a glucose challenge on insulin secretion, indicating that miniglucagon exerts a local inhibitory tone on β-cells. We concluded that miniglucagon is a novel local regulator of the pancreatic islet physiology and that any abnormal inhibitory tone exerted by this peptide on the β-cell would result in an impaired insulin secretion, as observed in type 2 diabetes.
Address correspondence and reprint requests to Dominique Bataille, the Institut National de la Santé et de la Recherche Médicale U 376, CHU Arnaud-de-Villeneuve, 34295 Montpellier, France. E-mail:.
Received for publication 11 July 2001 and accepted in revised form 7 November 2001.
AUC, area under the curve; FITC, fluorescein isothiocyanate; GLP-1, glucagon-like peptide 1; HPLC, high-performance liquid chromatography; KRB, Krebs-Ringer bicarbonate; MGE, miniglucagon-generating endopeptidase; PBS, phosphate-buffered saline; tGLP-1, GLP-1 (7-36) amide.