GLUCAGON-LIKE PEPTIDE-1 ENHANCES GLUCOSE-TOLERANCE BOTH BY STIMULATION OF INSULIN RELEASE AND BY INCREASING INSULIN-INDEPENDENT GLUCOSE DISPOSAL

Glucagon-like peptide 1 [7-36 amide](GLP-1) has been shown to enhance insulin secretion in healthy and type II diabetic humans, and to increase glucose disposal in type I diabetic patients. To further define its action on glucose kinetics, we studied six healthy subjects who received either GLP-1 (45 pmol/ kg per h) or 150 mM saline on two mornings during which a modified intravenous glucose tolerance test was performed. Plasma insulin and glucose levels were analyzed using Bergman's minimal model of glucose kinetics to derive indices of insulin sensitivity (S-I) and glucose effectiveness at basal insulin (S-G), the latter a measure of glucose disposition independent of changes in insulin. In addition, basal insulin concentrations, the acute insulin response to glucose (AIR(g)), plasma glucagon levels, and the glucose disappearance constant (K-g) were measured on the days that subjects received GLP-1 or saline. Compared with saline infusions, GLP-1 increased the mean K-g from 1.61 +/- 0.20 to 2.65 +/- 0.25% /min (P = 0.022).The enhanced glucose disappearance seen with GLP-1 was in part the result of its insulinotropic effect, as indicated by a rise in AIR(g) from 240 +/- 48 to 400 +/- 78 pM (P = 0.013). However, there was also an increase in S-G from 1.77 +/- 0.11 to 2.65 +/- 0.33 x 10(-2).min(-1) (P = 0.038), which was accounted for primarily by insulin-independent processes, viz glucose effectiveness in the absence of insulin. There was no significant effect of GLP-1 on S-I or basal insulin, and glucagon levels were not different during the glucose tolerance tests with or without GLP-1. Thus, GLP-1 improves glucose tolerance both through its insulinotropic action and by increasing glucose effectiveness. These findings suggest that GLP-1 has direct effects on tissues involved in glucose disposition. Furthermore, this peptide may be useful for studying the process of insulin-independent glucose disposal, and pharmacologic analogues may be beneficial for treating patients with diabetes mellitus.