Diabetes, Vol 48, Issue 1 86-93, Copyright © 1999 by American Diabetes Association

ARTICLES

Glucagon-like peptide 1 has a physiological role in the control of postprandial glucose in humans: studies with the antagonist exendin 9-39

CM Edwards, JF Todd, M Mahmoudi, Z Wang, RM Wang, MA Ghatei and SR Bloom
Imperial College School of Medicine Endocrine Unit, Hammersmith Hospital, London, UK.

Glucagon-like peptide 1(7-36) amide (GLP-1) is postulated to be the major physiological incretin in humans, but evidence is indirect. We report the first studies examining the physiological role of GLP-1 in the postprandial state in humans using the GLP-1 antagonist exendin 9-39. Exendin 9-39 completely blocked GLP-1-induced glucose-stimulated insulin release from perifused human islets of Langerhans. In healthy fasted volunteers, intravenous infusion of exendin 9-39 at 500 pmol x kg(-1) x min(-1) in the hyperglycemic state abolished the insulinotropic effect of a physiological dose of GLP-1 and fully reversed the glucose-lowering effect of GLP-1. Nine healthy subjects consumed a 150-g oral glucose tolerance test and were infused with 500 pmol x kg(-1) x min(-1) exendin 9-39 or saline. Exendin 9-39 increased the peak postprandial glucose level (exendin 9-39, 8.67 +/- 0.35 vs. saline, 7.67 +/- 0.35 mmol/l, P < or = 0.005) and increased postprandial plasma glucose incremental area under the curve by 35% (exendin 9-39, 152 +/- 19 vs. saline, 113 +/- 16 mmol x min x l(-1), P < or = 0.05). This could be explained as partly secondary to the blockade of glucose-induced suppression of glucagon and maybe also to an increased rate of gastric emptying. Thus, in humans exendin 9-39 acts as an antagonist of GLP-1 both in vitro and in vivo. When infused alone, exendin 9-39 causes a deterioration in postprandial glycemic control, suggesting that GLP-1 may be important for maintenance of normal postprandial glucose homeostasis in humans.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. E. Ayala, D. P. Bracy, T. Hansotia, G. Flock, Y. Seino, D. H. Wasserman, and D. J. Drucker Insulin Action in the Double Incretin Receptor Knockout Mouse Diabetes, February 1, 2008; 57(2): 288 - 297. [Abstract] [Full Text] [PDF]

				T. P. Vahl, M. Tauchi, T. S. Durler, E. E. Elfers, T. M. Fernandes, R. D. Bitner, K. S. Ellis, S. C. Woods, R. J. Seeley, J. P. Herman, et al. Glucagon-Like Peptide-1 (GLP-1) Receptors Expressed on Nerve Terminals in the Portal Vein Mediate the Effects of Endogenous GLP-1 on Glucose Tolerance in Rats Endocrinology, October 1, 2007; 148(10): 4965 - 4973. [Abstract] [Full Text] [PDF]

				P. A. M. Smeets, S. Vidarsdottir, C. de Graaf, A. Stafleu, M. J. P. van Osch, M. A. Viergever, H. Pijl, and J. van der Grond Oral glucose intake inhibits hypothalamic neuronal activity more effectively than glucose infusion Am J Physiol Endocrinol Metab, September 1, 2007; 293(3): E754 - E758. [Abstract] [Full Text] [PDF]

				K. G. Murphy, W. S. Dhillo, and S. R. Bloom Gut Peptides in the Regulation of Food Intake and Energy Homeostasis Endocr. Rev., December 1, 2006; 27(7): 719 - 727. [Abstract] [Full Text] [PDF]

				G. E. Lim and P. L. Brubaker Glucagon-Like Peptide 1 Secretion by the L-Cell: The View From Within Diabetes, December 1, 2006; 55(Supplement_2): S70 - S77. [Abstract] [Full Text] [PDF]

				J. C. Parker, K S Lavery, N Irwin, B D Green, B Greer, P Harriott, F P M O'Harte, V A Gault, and P R Flatt Effects of sub-chronic exposure to naturally occurring N-terminally truncated metabolites of glucose-dependent insulinotrophic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), GIP(3-42) and GLP-1(9-36)amide, on insulin secretion and glucose homeostasis in ob/ob mice. J. Endocrinol., October 1, 2006; 191(1): 93 - 100. [Abstract] [Full Text] [PDF]

				V. Ionut, I. F. Liberty, K. Hucking, M. Lottati, D. Stefanovski, D. Zheng, and R. N. Bergman Exogenously imposed postprandial-like rises in systemic glucose and GLP-1 do not produce an incretin effect, suggesting an indirect mechanism of GLP-1 action Am J Physiol Endocrinol Metab, October 1, 2006; 291(4): E779 - E785. [Abstract] [Full Text] [PDF]

				T. J. Little, A. N. Pilichiewicz, A. Russo, L. Phillips, K. L. Jones, M. A. Nauck, J. Wishart, M. Horowitz, and C. Feinle-Bisset Effects of Intravenous Glucagon-Like Peptide-1 on Gastric Emptying and Intragastric Distribution in Healthy Subjects: Relationships with Postprandial Glycemic and Insulinemic Responses J. Clin. Endocrinol. Metab., May 1, 2006; 91(5): 1916 - 1923. [Abstract] [Full Text] [PDF]

				M Horowitz and M A Nauck To be or not to be--an incretin or enterogastrone? Gut, February 1, 2006; 55(2): 148 - 150. [Full Text] [PDF]

				M. C. Riddle and D. J. Drucker Emerging Therapies Mimicking the Effects of Amylin and Glucagon-Like Peptide 1 Diabetes Care, February 1, 2006; 29(2): 435 - 449. [Full Text] [PDF]

				S. M. Gardiner, J. E. March, P. A. Kemp, and T. Bennett Mesenteric Vasoconstriction and Hindquarters Vasodilatation Accompany the Pressor Actions of Exendin-4 in Conscious Rats J. Pharmacol. Exp. Ther., February 1, 2006; 316(2): 852 - 859. [Abstract] [Full Text] [PDF]

				J Schirra, M Nicolaus, R Roggel, M Katschinski, M Storr, H J Woerle, and B Goke Endogenous glucagon-like peptide 1 controls endocrine pancreatic secretion and antro-pyloro-duodenal motility in humans Gut, February 1, 2006; 55(2): 243 - 251. [Abstract] [Full Text] [PDF]

				W. S. Dhillo, O. B. Chaudhri, M. Patterson, E. L. Thompson, K. G. Murphy, M. K. Badman, B. M. McGowan, V. Amber, S. Patel, M. A. Ghatei, et al. Kisspeptin-54 Stimulates the Hypothalamic-Pituitary Gonadal Axis in Human Males J. Clin. Endocrinol. Metab., December 1, 2005; 90(12): 6609 - 6615. [Abstract] [Full Text] [PDF]

				E. M Sinclair and D. J. Drucker Proglucagon-Derived Peptides: Mechanisms of Action and Therapeutic Potential Physiology, October 1, 2005; 20(5): 357 - 365. [Abstract] [Full Text] [PDF]

				J. J. Meier, G. Kemmeries, J. J. Holst, and M. A. Nauck Erythromycin Antagonizes the Deceleration of Gastric Emptying by Glucagon-Like Peptide 1 and Unmasks Its Insulinotropic Effect in Healthy Subjects Diabetes, July 1, 2005; 54(7): 2212 - 2218. [Abstract] [Full Text] [PDF]

				B D Green, N Irwin, V A Gault, C J Bailey, F P M O'Harte, and P R Flatt Chronic treatment with exendin(9-39)amide indicates a minor role for endogenous glucagon-like peptide-1 in metabolic abnormalities of obesity-related diabetes in ob/ob mice J. Endocrinol., May 1, 2005; 185(2): 307 - 317. [Abstract] [Full Text] [PDF]

				S. B Haugaard, O. Andersen, F. Dela, J. J. Holst, H. Storgaard, M. Fenger, J. Iversen, and S. Madsbad Defective glucose and lipid metabolism in human immunodeficiency virus-infected patients with lipodystrophy involve liver, muscle tissue and pancreatic {beta}-cells Eur. J. Endocrinol., January 1, 2005; 152(1): 103 - 112. [Abstract] [Full Text] [PDF]

				M. A. Nauck, B. Baller, and J. J. Meier Gastric Inhibitory Polypeptide and Glucagon-Like Peptide-1 in the Pathogenesis of Type 2 Diabetes Diabetes, December 1, 2004; 53(suppl_3): S190 - S196. [Abstract] [Full Text] [PDF]

				J. J. Holst and J. Gromada Role of incretin hormones in the regulation of insulin secretion in diabetic and nondiabetic humans Am J Physiol Endocrinol Metab, August 1, 2004; 287(2): E199 - E206. [Abstract] [Full Text] [PDF]

				C M. B Edwards GLP-1: target for a new class of antidiabetic agents? J R Soc Med, June 1, 2004; 97(6): 270 - 274. [Full Text] [PDF]

				D. A. D'Alessio and T. P. Vahl Glucagon-like peptide 1: evolution of an incretin into a treatment for diabetes Am J Physiol Endocrinol Metab, June 1, 2004; 286(6): E882 - E890. [Abstract] [Full Text] [PDF]

				M. R. Druce, C. J. Small, and S. R. Bloom Minireview: Gut Peptides Regulating Satiety Endocrinology, June 1, 2004; 145(6): 2660 - 2665. [Abstract] [Full Text] [PDF]

				G. A Bray, S. J. Nielsen, and B. M Popkin Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity Am. J. Clinical Nutrition, April 1, 2004; 79(4): 537 - 543. [Abstract] [Full Text] [PDF]

				D. J. Drucker Enhancing Incretin Action for the Treatment of Type 2 Diabetes Diabetes Care, October 1, 2003; 26(10): 2929 - 2940. [Abstract] [Full Text] [PDF]

				D. D. De Leon, S. Deng, R. Madani, R. S. Ahima, D. J. Drucker, and D. A. Stoffers Role of Endogenous Glucagon-Like Peptide-1 in Islet Regeneration After Partial Pancreatectomy Diabetes, February 1, 2003; 52(2): 365 - 371. [Abstract] [Full Text] [PDF]

				Y. Li, T. Hansotia, B. Yusta, F. Ris, P. A. Halban, and D. J. Drucker Glucagon-like Peptide-1 Receptor Signaling Modulates beta Cell Apoptosis J. Biol. Chem., January 3, 2003; 278(1): 471 - 478. [Abstract] [Full Text] [PDF]

				E. E. Daniel, M. Anvari, J. E. T. Fox-Threlkeld, and T. J. McDonald Local, exendin-(939)-insensitive, site of action of GLP-1 in canine ileum Am J Physiol Gastrointest Liver Physiol, September 1, 2002; 283(3): G595 - G602. [Abstract] [Full Text] [PDF]

				C. L. Dakin, I. Gunn, C. J. Small, C. M. B. Edwards, D. L. Hay, D. M. Smith, M. A. Ghatei, and S. R. Bloom Oxyntomodulin Inhibits Food Intake in the Rat Endocrinology, October 1, 2001; 142(10): 4244 - 4250. [Abstract] [Full Text] [PDF]

				M.-B. Toft-Nielsen, M. B. Damholt, S. Madsbad, L. M. Hilsted, T. E. Hughes, B. K. Michelsen, and J. J. Holst Determinants of the Impaired Secretion of Glucagon-Like Peptide-1 in Type 2 Diabetic Patients J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3717 - 3723. [Abstract] [Full Text] [PDF]

				A. Brandt, M. Katschinski, R. Arnold, K. S. Polonsky, B. Goke, and M. M. Byrne GLP-1-induced alterations in the glucose-stimulated insulin secretory dose-response curve Am J Physiol Endocrinol Metab, August 1, 2001; 281(2): E242 - E247. [Abstract] [Full Text] [PDF]

				C. T. Peters, Y.-H. Choi, P. L. Brubaker, and G. H. Anderson A Glucagon-Like Peptide-1 Receptor Agonist and an Antagonist Modify Macronutrient Selection by Rats J. Nutr., August 1, 2001; 131(8): 2164 - 2170. [Abstract] [Full Text] [PDF]

				C. M. B. Edwards, S. A. Stanley, R. Davis, A. E. Brynes, G. S. Frost, L. J. Seal, M. A. Ghatei, and S. R. Bloom Exendin-4 reduces fasting and postprandial glucose and decreases energy intake in healthy volunteers Am J Physiol Endocrinol Metab, July 1, 2001; 281(1): E155 - E161. [Abstract] [Full Text] [PDF]

				D. J. Drucker Minireview: The Glucagon-Like Peptides Endocrinology, February 1, 2001; 142(2): 521 - 527. [Abstract] [Full Text] [PDF]

				S. Dhanvantari, A. Izzo, E. Jansen, and P. L. Brubaker Coregulation of Glucagon-Like Peptide-1 Synthesis with Proglucagon and Prohormone Convertase 1 Gene Expression in Enteroendocrine GLUTag Cells Endocrinology, January 1, 2001; 142(1): 37 - 42. [Abstract] [Full Text] [PDF]

				A. E Brynes, C M. Edwards, A. Jadhav, M. A Ghatei, S. R Bloom, and G. S Frost Diet-induced change in fatty acid composition of plasma triacylglycerols is not associated with change in glucagon-like peptide 1 or insulin sensitivity in people with type 2 diabetes Am. J. Clinical Nutrition, November 1, 2000; 72(5): 1111 - 1118. [Abstract] [Full Text] [PDF]

				K. Persson, R. L. Gingerich, S. Nayak, K. Wada, E. Wada, and B. Ahren Reduced GLP-1 and insulin responses and glucose intolerance after gastric glucose in GRP receptor-deleted mice Am J Physiol Endocrinol Metab, November 1, 2000; 279(5): E956 - E962. [Abstract] [Full Text] [PDF]

				L. Baggio, T. J. Kieffer, and D. J. Drucker Glucagon-Like Peptide-1, But Not Glucose-Dependent Insulinotropic Peptide, Regulates Fasting Glycemia and Nonenteral Glucose Clearance in Mice Endocrinology, October 1, 2000; 141(10): 3703 - 3709. [Abstract] [Full Text] [PDF]

				K. Filipsson, J. J. Holst, and B. Ahren PACAP contributes to insulin secretion after gastric glucose gavage in mice Am J Physiol Regulatory Integrative Comp Physiol, August 1, 2000; 279(2): R424 - R432. [Abstract] [Full Text] [PDF]

				M. Ebinger, D. R. Jehle, R. D. Fussgaenger, H. C. Fehmann, and P. M. Jehle Glucagon-like peptide-1 improves insulin and proinsulin binding on RINm5F cells and human monocytes Am J Physiol Endocrinol Metab, July 1, 2000; 279(1): E88 - E94. [Abstract] [Full Text] [PDF]

				S. Mojsov Glucagon-like Peptide-1 (GLP-1) and the Control of Glucose Metabolism in Mammals and Teleost Fish Integr. Comp. Biol., April 1, 2000; 40(2): 246 - 258. [Abstract] [Full Text] [PDF]

				R. P. Boushey, B. Yusta, and D. J. Drucker Glucagon-like peptide 2 decreases mortality and reduces the severity of indomethacin-induced murine enteritis Am J Physiol Endocrinol Metab, November 1, 1999; 277(5): E937 - E947. [Abstract] [Full Text] [PDF]

				C. F. Deacon, A. Plamboeck, S. Moller, and J. J. Holst GLP-1-(9-36) amide reduces blood glucose in anesthetized pigs by a mechanism that does not involve insulin secretion Am J Physiol Endocrinol Metab, April 1, 2002; 282(4): E873 - E879. [Abstract] [Full Text] [PDF]