GLP-1(7-36) amide stimulates insulin secretion in rat islets: studies on the mode of action.
Previously it has been shown that glucagon-like peptide (GLP)-1(7-36)amide stimulates insulin secretion from tumoral RIN m5F cells by activation of adenylate cyclase. However, its mechanism in normal islets is not established. We therefore examined the effects of GLP-1(7-36)amide in isolated, overnight cultured, normal rat islets. GLP-1(7-36)amide (greater than or equal to 10(-9) M) stimulated insulin secretion by augmenting both the efficacy and potency of glucose over a wide dose-range of glucose (3.3-16.7 mM). The first 15 min of GLP-1(7-36)amide-stimulated insulin secretion was independent on extracellular Ca2+, whereas a sustained insulin secretion was seen only in the presence of extracellular Ca2+. Concurrently with this, GLP-1(7-36)amide sustainely stimulated 45Ca(2+)-efflux from prelabelled islets only in the presence of extracellular Ca2+, whereas after removal of extracellular Ca2+, the peptide stimulated only a slight 45Ca(2+)-efflux during the first 15 min. GLP-1(7-36)amide also stimulated 86Rb(+)-efflux from prelabelled islets, but in contrast to 45Ca(2+)-efflux, the 86Rb(+)-efflux was not reduced by removal of extracellular Ca2+. GLP-1(7-36)amide had no influence on 3H-efflux from myo-[2-3H]-inositol prelabelled islets. Moreover, the inhibitor of protein kinase C (PKC), staurosporine, did not affect GLP-1(7-36)amide-stimulated insulin secretion. The results show that the first phase of GLP-1(7-36)amide-stimulated insulin secretion is independent on extracellular Ca2+, whereas the sustained phase of GLP-1(7-36)amide-stimulated insulin secretion requires extracellular Ca2+. In contrast, phosphoinositide hydrolysis and PKC are not involved in the signal transduction pathway stimulated by GLP-1(7-36)amide in normal islets.
Fridolf
T
T
Department of Pharmacology, Lund University, Sweden.
Ahrén
B
B
D000470:Alkaloids / Q000494:pharmacology; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D005934:Glucagon; D052216:Glucagon-Like Peptide 1; D004763:Glucagon-Like Peptides; D005947:Glucose / Q000494:pharmacology; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D010446:Peptide Fragments / Q000494:pharmacology*; D010455:Peptides / Q000494:pharmacology*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors; D051381:Rats; D011919:Rats, Inbred Strains; D019311:Staurosporine
D000470:Alkaloids; D007328:Insulin; D010446:Peptide Fragments; D010455:Peptides; C055453:glucagon-like peptide 1 (7-36)amide; D004763:Glucagon-Like Peptides; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D011493:Protein Kinase C; D019311:Staurosporine; D005947:Glucose