GLP-1(32–36)amide, a novel pentapeptide cleavage product of GLP-1, modulates whole body glucose metabolism in dogs

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We have previously demonstrated in human subjects who under euglycemic clamp conditions GLP-1(9–36)amide infusions inhibit endogenous glucose production without substantial insulinotropic effects. An earlier report indicates that GLP-1(9–36)amide is cleaved to a nonapeptide, GLP-1(28–36)amide and a pentapeptide GLP-1(32–36)amide (LVKGR amide). Here we study the effects of the pentapeptide on whole body glucose disposal during hyperglycemic clamp studies. Five dogs underwent indwelling catheterizations. Following recovery, the dogs underwent a 180min hyperglycemic clamp (basal glucose +98mg/dl) in a cross-over design. Saline or pentapeptide (30pmolkg−1min−1) was infused during the last 120min after commencement of the hyperglycemic clamp in a primed continuous manner. During the last 30min of the pentapeptide infusion, glucose utilization (M) significantly increased to 21.4±2.9mgkg−1min−1compared to M of 14.3±1.1mgkg−1min−1 during the saline infusion (P=0.026, paired t-test; P=0.062, Mann–Whitney U test). During this interval, no significant differences in insulin (26.6±3.2 vs. 23.7±2.5μU/ml, P=NS) or glucagon secretion (34.0±2.1 vs. 31.7±1.8pg/ml, P=NS) were observed. These findings demonstrate that under hyperglycemic clamp studies the pentapeptide modulates glucose metabolism by a stimulation of whole-body glucose disposal. Further, the findings suggest that the metabolic benefits previously observed during GLP-1(9–36)amide infusions in humans might be due, at least in part, to the metabolic effects of the pentapeptide that is cleaved from the pro-peptide, GLP-1(9–36)amide in the circulation.