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Role of Central Nervous System Glucagon-Like Peptide-1 Receptors in Enteric Glucose Sensing

  1. Claude Knauf1,
  2. Patrice D. Cani12,
  3. Dong-Hoon Kim3,
  4. Miguel A. Iglesias1,
  5. Chantal Chabo1,
  6. Aurélie Waget1,
  7. André Colom1,
  8. Sophie Rastrelli1,
  9. Nathalie M. Delzenne2,
  10. Daniel J. Drucker4,
  11. Randy J. Seeley3 and
  12. Remy Burcelin1
  1. 1Institut de Medecine Moleculaire de Rangueil, Institut National de la Santé et de la Recherche Médicale U858, IFR31, Centre Hospitalier Universitaire Rangueil, Toulouse, France
  2. 2Unit of Pharmacokinetics, Metabolism, Nutrition, and Toxicology, Université Catholique de Louvain, Brussels, Belgium
  3. 3Department of Psychiatry, Genome Research Institute, University of Cincinnati, Cincinnati, Ohio
  4. 4Banting and Best Diabetes Centre, Samuel Lunenfeld Research Institute, Mt. Sinai Hospital, University of Toronto, Canada
  1. Corresponding author: Remy Burcelin, remy.burcelin{at}inserm.fr

Abstract

OBJECTIVE—Ingested glucose is detected by specialized sensors in the enteric/hepatoportal vein, which send neural signals to the brain, which in turn regulates key peripheral tissues. Hence, impairment in the control of enteric-neural glucose sensing could contribute to disordered glucose homeostasis. The aim of this study was to determine the cells in the brain targeted by the activation of the enteric glucose-sensing system.

RESEARCH DESIGN AND METHODS—We selectively activated the axis in mice using a low-rate intragastric glucose infusion in wild-type and glucagon-like peptide-1 (GLP-1) receptor knockout mice, neuropeptide Y–and proopiomelanocortin–green fluorescent protein–expressing mice, and high-fat diet diabetic mice. We quantified the whole-body glucose utilization rate and the pattern of c-Fos positive in the brain.

RESULTS—Enteric glucose increased muscle glycogen synthesis by 30% and regulates c-Fos expression in the brainstem and the hypothalamus. Moreover, the synthesis of muscle glycogen was diminished after central infusion of the GLP-1 receptor (GLP-1Rc) antagonist Exendin 9-39 and abolished in GLP-1Rc knockout mice. Gut-glucose–sensitive c-Fos–positive cells of the arcuate nucleus colocalized with neuropeptide Y–positive neurons but not with proopiomelanocortin-positive neurons. Furthermore, high-fat feeding prevented the enteric activation of c-Fos expression.

CONCLUSIONS—We conclude that the gut-glucose sensor modulates peripheral glucose metabolism through a nutrient-sensitive mechanism, which requires brain GLP-1Rc signaling and is impaired during diabetes.

Footnotes

  • Published ahead of print at http://diabetes.diabetesjournals.org on 2 June 2008.

    Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

    The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

    • Accepted May 28, 2008.
    • Received December 19, 2007.
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This Article

  1. Diabetes vol. 57 no. 10 2603-2612
  1. All Versions of this Article:
    1. db07-1788v1
    2. 57/10/2603 most recent