Endocrinology, Vol 137, 4108-4114, Copyright © 1996 by Endocrine Society

ARTICLES

Glucagon acts through its own receptors in the presence of functional glucagon-like peptide-1 receptors on hamster insulinoma

JC Marie, C Boissard, G Skoglund, G Rosselin and B Breant
Unite de Recherches sur les Peptides Neurodigestifs et le Diabete, Institut National de la Sante et de la Recherche Medicale, Paris, France.

The observations that glucagon binds to glucagon-like peptide-1 (tGLP- 1) receptors have raised the question of whether glucagon receptors mediate the insulinotropic effect of glucagon. We have investigated the presence and selective activation of glucagon and tGLP-1 receptors on tumor-derived cells. Northern blot analysis detected either glucagon or tGLP-1 receptor messenger RNA in hamster (HIT) and mouse (beta TC3) beta-cell lines, respectively, whereas both receptor messenger RNA were revealed in Syrian hamster insulinoma. Their expression in insulinoma plasma membranes was confirmed by specific covalent labeling with either [125I]glucagon or [125I]tGLP-1. Both glucagon and tGLP-1 receptors showed a single class of high affinity binding sites with respective Kd values of 1.11 +/- 0.11 and 0.82 +/- 0.11 nM. [125I]tGLP binding was dose dependently inhibited with a hierarchy of exendin-4 > tGLP-1 > exendin-(9-39) > oxyntomodulin > glucagon. [125I]Glucagon binding was only inhibited by glucagon and oxyntomodulin. Both glucagon and tGLP-1 increased cAMP formation in insulinoma plasma membranes in a dose-dependent manner, with ED50 values of 170.0 +/- 25.0 and 3.1 +/- 0.4 pM, respectively. Exendin-(9-39), a tGLP-1 receptor antagonist, inhibited tGLP-1-induced, but not glucagon-induced, cAMP formation. Our data demonstrate on hamster insulinoma the presence of high affinity glucagon and tGLP-1 receptors selectively coupled to adenylyl cyclase. The observed low affinity of tGLP-1 receptors for glucagon sustains the idea that each hormone has a direct insulinotropic effect.

This article has been cited by other articles:

				K. Masur, E. C. Tibaduiza, C. Chen, B. Ligon, and M. Beinborn Basal Receptor Activation by Locally Produced Glucagon-Like Peptide-1 Contributes to Maintaining {beta}-Cell Function Mol. Endocrinol., May 1, 2005; 19(5): 1373 - 1382. [Abstract] [Full Text] [PDF]

				L. Portois, B. Maget, M. Tastenoy, J. Perret, and M. Svoboda Identification of a Glucose Response Element in the Promoter of the Rat Glucagon Receptor Gene J. Biol. Chem., March 19, 1999; 274(12): 8181 - 8190. [Abstract] [Full Text] [PDF]

				J.-C. Marie, A. Wakkach, A.-M. Coudray, E. Chastre, S. Berrih-Aknin, and C. Gespach Functional Expression of Receptors for Calcitonin Gene-Related Peptide, Calcitonin, and Vasoactive Intestinal Peptide in the Human Thymus and Thymomas from Myasthenia Gravis Patients J. Immunol., February 15, 1999; 162(4): 2103 - 2112. [Abstract] [Full Text] [PDF]

				V. Serre, W. Dolci, E. Schaerer, L. Scrocchi, D. Drucker, S. Efrat, and B. Thorens Exendin-(9-39) Is an Inverse Agonist of the Murine Glucagon-Like Peptide-1 Receptor: Implications for Basal Intracellular Cyclic Adenosine 3',5'-Monophosphate Levels and {beta}-Cell Glucose Competence Endocrinology, November 1, 1998; 139(11): 4448 - 4454. [Abstract] [Full Text] [PDF]