EXPRESSION AND FUNCTIONAL-ACTIVITY OF GLUCAGON, GLUCAGON-LIKE PEPTIDE-I, AND GLUCOSE-DEPENDENT INSULINOTROPIC PEPTIDE RECEPTORS IN RAT PANCREATIC-ISLET CELLS

Rat pancreatic alpha- and beta-cells are critically dependent on hormo nal signals generating cyclic AMP (cAMP) as a synergistic messenger fo r nutrient-induced hormone release, Several peptides of the glucagon-s ecretin family have been proposed as physiological Ligands for cAIMP p roduction in beta-cells, but their relative importance for islet funct ion is still unknown. The present study shows expression at the RNA le vel in beta-cells of receptors for glucagon, glucose-dependent insulin otropic polypeptide (GIP), and glucagon-like peptide I(7-36) amide (GL P-I), while RNA from islet alpha-cells hybridized only with GIP recept or cDNA, Western blots confirmed that GLP-I receptors were expressed i n beta-cells and not in or-cells, Receptor activity, measured as cellu lar cAIMP production after exposing islet beta-cells for 15 min to a r ange of peptide concentrations, was already detected using 10 pmol/l G LP-I and 50 pmol/l GIP but required 1 nmol/l glucagon, EC(50) values o f GLP-I- and GIP-induced cAMP formation were comparable (0.2 nmol/l) a nd 45-fold lower than the EC(50) of glucagon (9 nmol/l), Maximal stimu lation of cAMP production was comparable for the three peptides, In pu rified alpha-cells, 1 nmol/l GLP-I failed to increase cAMP levels, whi le 10 pmol/l to 10 nmol/l GIP exerted similar stimulatory effects as i n beta-cells In conclusion, these data show that stimulation of glucag on, GLP-I, and GIP receptors in rat beta-cells causes cAMP production required for insulin release, while adenylate cyclase in alpha-cells i s positively regulated by GIP.