GLUCAGON-LIKE PEPTIDE-1(7-36)-AMIDE CONFERS GLUCOSE SENSITIVITY TO PREVIOUSLY GLUCOSE-INCOMPETENT BETA-CELLS IN DIABETIC RATS - IN-VIVO ANDIN-VITRO STUDIES

The effects of glucagon-like peptide-1(7-36)-amide (GLP-1) on cAMP con tent and insulin release were studied in islets isolated from diabetic rats (nO-STZ model) which exhibited impaired glucose-induced insulin release. We first examined the possibility of re-activating the insuli n response to glucose in the beta-cells of the diabetic rats using GLP -1 in vitro. In static incubation experiments, GLP-1 amplified cAMP ac cumulation (by 170%) and glucose-induced insulin release (by 140%) in the diabetic islets to the same extent as in control islets. Using a p erifusion procedure, GLP-1 amplified the insulin response to 16.7 mM g lucose by diabetic islets and generated a clear biphasic pattern of in sulin release. The incremental insulin response to glucose in the pres ence of GLP-1, although lower than corresponding control values (1.56 +/- 0.37 and 4.53 +/- 0.60 pg/min per ng islet DNA in diabetic and con trol islets respectively), became similar to that of control islets ex posed to 16.7 mM glucose alone (1.09 +/- 0.15 pg/min per ng islet DNA) . Since in vitro GLP-1 was found to exert positive effects on the gluc ose competence of the residual beta-cells in the n0-STZ model, we inve stigated the therapeutic effect of in vivo GLP-1 administration on glu cose tolerance and glucose-induced insulin release by n0-STZ rats. An infusion of GLP-1 (10 ng/min per kg; i.v.) in n0-STZ rats enhanced sig nificantly (P<0.01) basal plasma insulin levels, and, when combined wi th an i.v. glucose tolerance and insulin secretion test, it was found to improve (P<0.05) glucose tolerance and the insulinogenic index, as compared with the respective values of these parameters before GLP-1 t reatment.