title: GLP-1(32-36)amide, a novel pentapeptide cleavage product of GLP-1, modulates whole body glucose metabolism in dogs.
abstract: 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)compared 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 μU/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.
authors.affiliation: Cardiovascular Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States. Electronic address: dariush.elahi@iconplc.com.
authors.forename: Dariush
authors.initials: D
authors.lastname: Elahi
authors.affiliation: Cardiovascular Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
authors.forename: Franca S
authors.initials: FS
authors.lastname: Angeli
authors.affiliation: Cardiovascular Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
authors.forename: Amin
authors.initials: A
authors.lastname: Vakilipour
authors.affiliation: Diabetes Section, Clinical Laboratory of Investigation, National Institute on Aging, National Institute of Health, Baltimore, MD, United States.
authors.forename: Olga D
authors.initials: OD
authors.lastname: Carlson
authors.affiliation: Laboratory of Molecular Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
authors.forename: Eva
authors.initials: E
authors.lastname: Tomas
authors.affiliation: Diabetes Section, Clinical Laboratory of Investigation, National Institute on Aging, National Institute of Health, Baltimore, MD, United States.
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Egan
authors.affiliation: Laboratory of Molecular Endocrinology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, United States.
authors.forename: Joel F
authors.initials: JF
authors.lastname: Habener
authors.affiliation: Cardiovascular Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States.
authors.forename: Richard P
authors.initials: RP
authors.lastname: Shannon
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D004285:Dogs; D052216:Glucagon-Like Peptide 1 / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; C000598373:GLP-1(32-36)amide; D052216:Glucagon-Like Peptide 1
keywords: Diabetes; Glucagon-like peptide-1; Glucose utilization; Insulin resistance; Obesity