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 blood glucose control in insulin-deficient states, GLP-I [GLP-I(7-36) amide; 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 turnover rates of glucose (6-³H-glucose), alanine (U-¹⁴C-alanine), and urea (¹⁵N₂-urea) starting 22 h after the last subcutaneous dose of exogenous 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 significantly reduce the preexisting diabetic hyperglucagonemia. Since in the utilized model functioning pancreatic β-cells are lacking, GLPI 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 infusion of GLP-I and was most likely caused by a decrease of elevated glucose production since overall glucose turnover decreased with no alteration in glucose metabolic clearance. Alanine turnover was significantly reduced, obviously reflecting a decline in alanine production in relation to changed muscle glucose uptake under conditions of lower glycemia and overall glucose turnover. There was, however, neither an effect of GLPI on alanine conversion into circulating glucose nor an effect on urea production rate, indicating unchanged gluconeogenesis from amino acid precursors. We conclude that the blood glucose–lowering effect of GLP-I in an animal model of insulinopenia was shown to be due to a reduction in hepatic glucose output, possibly secondary to reduction in glucagon concentrations leading to decreased glycogenolysis. Whether GLP-I might be therapeutically useful in clinical insulin-deficient diabetes needs to be verified.