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. Inaddition, 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: 1) 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 wellas 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_g: 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/1, 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 suggestthat 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.