BLOOD-GLUCOSE LOWERING AND GLUCAGONOSTATIC EFFECTS OF GLUCAGON-LIKE PEPTIDE-I IN INSULIN-DEPRIVED DIABETIC DOGS

To establish potential effects of glucagon-like peptide I (GLP-I) on b lood glucose control in insulin-deficient states, GLP-I [GLP-I(7-36) a mide; 10 pmol.kg(-1).min(-1)] was infused intravenously in six fasting , canine C-peptide-negative, chronically diabetic dogs for 8 h. Blood samples were saved for the analysis of hormones, metabolites, and turn over rates of glucose (6-H-3-glucose), alanine (U-C-14-alanine), and u rea (N-15(2)-urea) starting 22 h after the last subcutaneous dose of e xogenous insulin. Circulating plasma GLP-I levels rose under infusion from 2.9 +/- 0.8 to 41.4 +/- 10.1 pmol/l. This was efficient to signif icantly reduce the preexisting diabetic hyperglucagonemia. Since in th e utilized model functioning pancreatic beta-cells are lacking, GLP-I had no insulinogenic effect. Compared with control experiments in the same animals receiving saline infusion, glycemia dropped from 20.8 +/- 1.9 to 16.2 +/- 1.0 mmol/l (P < 0.05). This was in parallel to the in fusion of GLP-I and was most likely caused by a decrease of elevated g lucose production since overall glucose turnover decreased with no alt eration in glucose metabolic clearance. Alanine turnover was significa ntly reduced, obviously reflecting a decline in alanine production in relation to changed muscle glucose uptake under conditions of lower gl ycemia and overall glucose turnover. There was, however, neither an ef fect of GLP-I on alanine conversion into circulating glucose nor an ef fect on urea production rate, indicating unchanged gluconeogenesis fro m amino acid precursors. We conclude that the blood glucose-lowering e ffect of GLP-I in an animal model of insulinopenia was shown to be due to a reduction in hepatic glucose output, possibly secondary to reduc tion in glucagon concentrations leading to decreased glycogenolysis. w hether GLP-I might be therapeutically useful in clinical insulin-defic ient diabetes needs to be verified.