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Effects of GLP-1-(7–36)NH₂, GLP-1-(7–37), and GLP-1- (9–36)NH₂ on Intravenous Glucose Tolerance and Glucose-Induced Insulin Secretion in Healthy Humans

Division of Metabolism, Endocrinology, and Nutrition, University of Washington (B.W.P., B.D.F., R.L.P., D.A.D.) and Veterans Affairs Puget Sound Health Care System (R.L.P.), Seattle, Washington 98195; and Division of Endocrinology, University of Cincinnati (T.P.V., D.A.D.), Cincinnati, Ohio 45267

Address all correspondence and requests for reprints to: David D’Alessio, M.D., Division of Endocrinology, University of Cincinnati, ML-0547, Cincinnati, Ohio 45267-0547. E-mail: david.d'alessio{at}uc.edu.

Glucagon-like peptide 1 (GLP-1) is an insulin secretagogue synthesized in the intestine and released in response to meal ingestion. It is secreted primarily in two forms, GLP-1-(7–37) and GLP-1-(7–36)NH₂, both of which bind to a specific GLP-1 receptor (GLP-1r) on the pancreatic ß-cell and augment glucose-stimulated insulin secretion. Once secreted, GLP-1-(7–36)NH₂ is rapidly metabolized to GLP-1-(9–36)NH₂, which is the predominant form of GLP-1 in postprandial plasma because of its relatively slower clearance. Although no clear biological role for GLP-1-(9–36)NH₂ in humans has been identified, recent studies in animals suggest two potential effects: to antagonize the effects of intact GLP-1 and to promote glucose disappearance in peripheral tissues. In the studies reported here we compared the independent effects of GLP-1-(7–36)NH₂, GLP-1-(7–37), and GLP-1-(9–36)NH₂ on parameters of iv glucose tolerance and determined whether GLP-1-(9–36)NH₂ inhibits the insulinotropic actions of GLP-1. Ten healthy subjects underwent 4 separate frequently sampled iv glucose tolerance tests during infusions of GLP-1-(7–37), GLP-1-(7–36)NH₂, GLP-1-(9–36)NH₂, or saline. Results from the iv glucose tolerance test were used to obtain indexes of ß-cell function (acute insulin response to glucose) and iv glucose tolerance (glucose disappearance constant), and the minimal model of glucose kinetics was used to obtain indexes of glucose effectiveness and insulin sensitivity. Compared with control studies, both GLP-1-(7–36)NH₂ and GLP-1-(7–37) significantly increased acute insulin response to glucose, glucose disappearance constant, glucose effectiveness, and glucose effectiveness at zero insulin, but did not change the insulin sensitivity index. In contrast, none of the parameters of glucose tolerance was measurably affected by GLP-1-(9–36) amide. In a second set of experiments, 10 healthy subjects had glucose-stimulated insulin secretion measured during an infusion of GLP-1-(7–36)NH₂ alone or with a simultaneous infusion of GLP-1-(9–36)NH₂ that increased plasma levels approximately 10-fold over those produced by unmetabolized GLP-1. Augmentation of glucose-stimulated insulin secretion by GLP-1-(7–36)NH₂ was not altered by the coadministration of GLP-1-(9–36)NH₂. Based on these results we conclude that GLP-1-(9–36)NH₂ does not regulate insulin release or glucose metabolism in healthy humans.

T.P.V. and B.W.P. contributed equally to this work.

This work was supported by a Clinical Research Award from the American Diabetes Association and Grants R01-DK-54263 and M01-RR-08084.

Abbreviations: AIR_glu, Acute insulin response to glucose; DPP-IV, Dipeptidyl peptidase IV; GEZI, glucose effectiveness at zero insulin; GLP-1, glucagon-like peptide 1; GLP-1r, GLP-1 receptor; -ir, immunoreactivity; IVGTT, iv glucose tolerance test; k_g, glucose disappearance constant; S_G, glucose effectiveness; S_I, insulin sensitivity index.

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