Exendin(9-39)amide Is an Antagonist of Glucagon-Like peptide-1(7-36)amide in Humans

J Clin Invest. 1998 Apr 1;101(7):1421-30. doi: 10.1172/JCI1349.

Abstract

The gastrointestinal hormone, glucagon-like peptide-1(7-36)amide (GLP-1) is released after a meal. The potency of synthetic GLP-1 in stimulating insulin secretion and in inhibiting glucagon secretion indicates the putative physiological function of GLP-1. In vitro, the nonmammalian peptide, exendin(9-39)amide [ex(9-39)NH2], is a specific and competitive antagonist of GLP-1. This in vivo study examined the efficacy of ex(9-39)NH2 as an antagonist of exogenous GLP-1 and the physiological role of endogenous GLP-1. Six healthy volunteers underwent 10 experiments in random order. In each experiment, a 30-min period of euglycemia was followed by an intravenous infusion of glucose for 150 min that established a stable hyperglycemia of 8 mmol/liter. There was a concomitant intravenous infusion of one of the following: (1) saline, (2) GLP-1 (for 60 min at 0.3 pmol . kg-1 . min-1 that established physiological postprandial plasma levels, and for another 60 min at 0.9 pmol . kg-1 . min-1 to induce supraphysiological plasma levels), (3-5) ex(9-39)NH2 at 30, 60, or 300 pmol . kg-1 . min-1 + GLP-1, (6-8) ex(9-39)NH2 at 30, 60, or 300 pmol . kg-1 . min-1 + saline, (9 and 10) GIP (glucose-dependent insulinotropic peptide; for 60 min at 0.8 pmol . kg-1 . min-1, with saline or ex(9-39)NH2 at 300 pmol . kg-1 . min-1). Each volunteer received each of these concomitant infusions on separate days. ex(9-39)NH2 dose-dependently reduced the insulinotropic action of GLP-1 with the inhibitory effect declining with increasing doses of GLP-1. ex(9-39)NH2 at 300 pmol . kg-1 . min-1 blocked the insulinotropic effect of physiological doses of GLP-1 and completely antagonized the glucagonostatic effect at both doses of GLP-1. Given alone, this load of ex(9-39)NH2 increased plasma glucagon levels during euglycemia and hyperglycemia. It had no effect on plasma levels of insulin during euglycemia but decreased plasma insulin during hyperglycemia. ex(9-39)NH2 did not alter GIP-stimulated insulin secretion. These data indicate that in humans, ex(9-39)NH2 is a potent GLP-1 antagonist without any agonistic properties. The pancreatic A cell is under a tonic inhibitory control of GLP-1. At hyperglycemia, the B cell is under a tonic stimulatory control of GLP-1.

Publication types

  • Clinical Trial
  • Randomized Controlled Trial
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • C-Peptide / blood
  • Glucagon / antagonists & inhibitors*
  • Glucagon / blood
  • Glucagon-Like Peptide 1
  • Glucagon-Like Peptide-1 Receptor
  • Glucose / metabolism
  • Humans
  • Insulin / blood
  • Male
  • Peptide Fragments / antagonists & inhibitors*
  • Peptide Fragments / blood
  • Peptide Fragments / pharmacology*
  • Protein Precursors / antagonists & inhibitors*
  • Protein Precursors / blood
  • Receptors, Glucagon / antagonists & inhibitors*
  • Time Factors

Substances

  • C-Peptide
  • GLP1R protein, human
  • Glucagon-Like Peptide-1 Receptor
  • Insulin
  • Peptide Fragments
  • Protein Precursors
  • Receptors, Glucagon
  • exendin (9-39)
  • Glucagon-Like Peptide 1
  • Glucagon
  • Glucose