INFLUENCE OF GLUCAGON-LIKE PEPTIDE-1 ON BETA-CELL RESPONSIVENESS

The postulated incretin factor glucagon-like peptide-1 (GLP-1) causes a glucose-dependent increase in insulin secretion from perifused rat islets. In the presence of 6 mM glucose the response to 10 nM GLP-1 is characterized by a large initial spike of secretion, followed by a brief, slowly rising phase. However, after 30-40 min of stimulation, this phase subsides to prestimulatory secretory rates. Raising the glucose level to 8 mM, however, amplifies and sustains the stimulatory effect of 10 nM GLP-1. The response to GLP-1 (10 nM) in the presence of 8 mM glucose is abolished by the metabolic inhibitor mannoheptulose (15 mM), and reduced by the calcium channel antagonist nitrendipine (5 muM), or the protein kinase C inhibitor of staurosporine (20 nM). A significant synergistic effect of GLP-1 (10 nM) and 10 muM carbachol, acholinergic agonist, on insulin secretion was observed in the presence of 6 mM glucose. In the presence of either 6 or 8 mM glucose, GLP-1 (10 nM) has no significant effect on glucose usage or on inositol phosphate generation in [H-3]inositol prelabeled islets. The results support the concept that GLP-1 may function as an important physiologic incretin factor, particularly when accompanied by agonists that activate phosphoinositide hydrolysis.