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

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 180 min hyperglycemic clamp(basal glucose +98 mg/dl) in a cross-over design. Saline or pentapeptide (30 pmol kg(-1) min(-1)) was infused during the last 120 min after commencement of the hyperglycemic clamp in a primed continuous manner. During the last 30 min of the pentapeptide infusion, glucose utilization (M) significantly increased to 21.4 +/- 2.9 mg kg(-1) min(-1)c ompared to M of 14.3 +/- 1.1 mg kg(-1) min(-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 +/- 2.5 mu U/ml, P = NS) or glucagon secretion (34.0 +/- 2.1 vs. 31.7 +/- 1.8 pg/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. (C) 2014 Elsevier Inc. All rights reserved.