ENTERAL ENHANCEMENT OF GLUCOSE DISPOSITION BY BOTH INSULIN-DEPENDENT AND INSULIN-INDEPENDENT PROCESSES - A PHYSIOLOGICAL-ROLE OF GLUCAGON-LIKE PEPTIDE-I

Glucagon-like peptide I(GLP-I)(7-36) amide is secreted by intestinal L-cells in response to food ingestion. GLP-I is a potent insulin secretagogue and also inhibits glucagon release. In addition, when given to humans in pharmacological amounts, GLP-I increases glucose disposal independent of its effects on islet hormone secretion. To test the hypothesis that this extrapancreatic effect of GLP-I on glucose disposition is present at physiological levels of GLP-I, we performed intravenous glucose tolerance tests (IVGTTs) 1 h after the following interventions: I) the ingestion of 50 g fat to stimulate GLP-I secretion or the ingestion of water as a control and 2) infusion of GLP-I to attain physiological levels or a control infusion of saline. The results of the IVGTTs were analyzed using the minimal model technique to determine the insulin sensitivity index (S-I) and indexes of insulin-independent glucose disposition, glucose effectiveness at basal insulin (S-G), and glucose effectiveness at zero insulin (GEZI), as well as the glucose disappearance constant (k(g)) and the acute insulin response to glucose (AIR(g)). These parameters were compared between conditions of elevated circulating GLP-I and control conditions. After ingestion of fat and infusion of synthetic hormone, plasma GLP-I increased to similar levels; GLP-I did not change with water ingestion or saline infusion. Elevated levels of GLP-I, whether from fat ingestion or exogenous infusion, caused increased glucose disappearance (k fat versus water 2.67 +/- 0.2 vs. 1.72 +/- 0.2, P < 0.001; GLP-I versus saline 2.42 +/- 0.2 vs. 1.96 +/- 0.2 %/min, P = 0.045), insulin secretion (AIR(g) : fat versus water 427 +/- 50 vs. 284 +/- 41, P = 0,001; GLP-I versus saline 376 +/- 65 vs. 258 +/- 16 pmol/l, P = 0.03), and glucose effectiveness (S-G : fat versus water 2.5 +/- 0.1 vs. 1.8 +/- 0.2, P = 0,001; GLP-I versus saline 2.5 +/- 0.2 vs. 1.8 +/- 0.2 %/min, P = 0.014; GEZI : fat versus water 1.9 +/- 0.2 vs. 1.3 +/- 0.2 %/min, P = 0.003; GLP-I versus saline 1.9 +/- 0.2 vs. 1.3 +/- 0.2, P = 0.006) but no difference in insulin sensitivity. These results suggest that GLP-I, released after meals, promotes glucose assimilation both by augmenting insulin secretion and through a separate effect to increase glucose uptake and/or inhibit hepatic glucose output.