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 x kg(-1) x 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-(3)H-glucose), alanine (U-(14)C-alanine), and urea ((15)N(2)-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 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 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 GLP-I 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.

Glucagon-like peptide-1 has no insulin-like effects in insulin-dependent diabetic dogs maintained normoglycemic and normoinsulinemic.

A pharmacological concentration of glucagon-like peptide-1 (GLP-1) in the insulin-deficient state clearly decreases the blood glucose level. Therefore, this study was designed to evaluate a putatively relevant effect of the gastrointestinal peptide as an adjuvant to insulin replacement therapy. GLP-1 (GLP-1(7-36) amide 10 pmol x kg(-1) x min(-1)) was infused intravenously over 8 hours in nine fasting, C-peptide-negative diabetic dogs. The animals were under normoglycemic control by glucose-controlled insulin infusion (GCII) during the night before and during GLP-1 administration. During the paired control tests, the animals received saline infusion instead of GLP-1. In addition to the insulin infusion rates required to maintain normoglycemia, hormones, metabolites, and the turnover rates for glucose (6-3H-glucose), alanine (U-14C-alanine), and urea (15N2-urea) were measured during the final 2 hours of GLP-1 administration. Circulating plasma GLP-1 levels increased from 3+/-1 to 17+/-7 pmol/L. There was no significant difference in the insulin infusion rate between the experimental and control groups (0.43+/-0.05 v. 0.40+/-0.05 mU x kg(-1) x h(-1), average over the entire interval). Glycemia was maintained at a practically identical level (4.9+/-0.3 v. 4.8+/-0.4 mmol/L). Also, the concentration of plasma insulin-which was not hyperinsulinemic--and pancreatic glucagon remained unaltered. We found no appreciable effect of GLP-1 on glucose production and metabolic clearance, alanine turnover and the formation of glucose from alanine (1.8+/-0.2 v. 1.4+/-0.2 micromol x kg(-1) x min(-1), or the urea production rate as a measure of overall amino acid catabolism (4.1+/-0.4 v. 4.1+/-0.4 micromol x kg(-1) x min(-1)). Thus, no conclusive adjuvant effect of GLP-1 was ascertained in insulin-treated diabetic dogs under normoglycemic control.