|
|
||||||||
Department of Physiology and Biophysics, Keck School of Medicine, University of Southern California, Los Angeles, California
Submitted 11 February 2008 ; accepted in final form 14 May 2008
Exenatide is a long-acting glucagon-like peptide-1 (GLP-1) mimetic used in the treatment of type 2 diabetes. There is increasing evidence that GLP-1 can influence glycemia not only via pancreatic (insulinotropic and glucagon suppression) and gastric-emptying effects, but also via an independent mechanism mediated by portal vein receptors. The aim of our study was to investigate whether exenatide has an islet- and gastric-independent glycemia-reducing effect, similar to GLP-1. First, we administered mixed meals, with or without exenatide (20 µg sc) to dogs. Second, to determine whether exenatide-induced reduction in glycemia is independent of slower gastric emptying, in the same animals we infused glucose intraportally (to simulate meal test glucose appearance) with exenatide, exenatide + the intraportal GLP-1 receptor antagonist exendin-(9-39), or saline. Exenatide markedly decreased postprandial glucose: net 0- to 135-min area under the curve = +526 ± 315 and –536 ± 197 mg·dl–1·min–1 with saline and exenatide, respectively (P < 0.05). Importantly, the decrease in plasma glucose occurred without a corresponding increase in postprandial insulin but was accompanied by delayed gastric emptying and lower glucagon. Significantly lower glycemia was induced by intraportal glucose infusion with exenatide than with saline (92 ± 1 vs. 97 ± 1 mg/dl, P < 0.001) in the absence of hyperinsulinemia or glucagon suppression. The exenatide-induced lower glycemia was partly reversed by intraportal exendin-(9-39): 95 ± 3 and 92 ± 3 mg/dl with exenatide + antagonist and exenatide, respectively (P < 0.01). Our results suggest that, similar to GLP-1, exenatide lowers glycemia via a novel mechanism independent of islet hormones and slowing of gastric emptying. We hypothesize that receptors in the portal vein, via a neural mechanism, increase glucose clearance independent of islet hormones.
glucagon-like peptide-1; insulin-independent; glucose regulation
This article has been cited by other articles:
![]() |
R. A. DeFronzo From the Triumvirate to the Ominous Octet: A New Paradigm for the Treatment of Type 2 Diabetes Mellitus Diabetes, April 1, 2009; 58(4): 773 - 795. [Full Text] [PDF] |
||||
![]() |
Highlights From The Literature Physiology, February 1, 2009; 24(1): 4 - 7. [Full Text] [PDF] |
||||
![]() |
D. Zheng, V. Ionut, V. Mooradian, D. Stefanovski, and R. N. Bergman Exenatide Sensitizes Insulin-Mediated Whole-Body Glucose Disposal and Promotes Uptake of Exogenous Glucose by the Liver Diabetes, February 1, 2009; 58(2): 352 - 359. [Abstract] [Full Text] [PDF] |
||||
![]() |
D. S. Edgerton, K. M.S. Johnson, D. W. Neal, M. Scott, C. H. Hobbs, X. Zhang, A. Duttaroy, and A. D. Cherrington Inhibition of Dipeptidyl Peptidase-4 by Vildagliptin During Glucagon-Like Peptide 1 Infusion Increases Liver Glucose Uptake in the Conscious Dog Diabetes, January 1, 2009; 58(1): 243 - 249. [Abstract] [Full Text] [PDF] |
||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Visit Other APS Journals Online |