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Improvement of Glucose Tolerance and Hepatic Insulin Sensitivity by Oligofructose Requires a Functional Glucagon-Like Peptide 1 Receptor

  1. Patrice D. Cani12,
  2. Claude Knauf1,
  3. Miguel A. Iglesias1,
  4. Daniel J. Drucker3,
  5. Nathalie M. Delzenne2 and
  6. Rémy Burcelin1
  1. 1Unité Mixte de Recherche (UMR), Centre National De La Recherche Scientifique, University Paul Sabatier, Toulouse, France
  2. 2Unit of Pharmacokinetics, Metabolism, Nutrition and Toxicology, Université catholique de Louvain, Brussels, Belgium
  3. 3Banting and Best Diabetes Centre, Toronto General Hospital, University of Toronto, Canada
  1. Address correspondence and reprint requests to Prof. Rémy Burcelin, PhD, CNRS-UMR 5018, Hôpital Rangueil, 1 BP 84225, Toulouse 31432 cedex 4, France. E-mail: burcelin{at}toulouse.inserm.fr. Or Prof. Nathalie M. Delzenne, Phn, PhD, Université catholique de Louvain, PMNT 73/69, Av. E. Mounier, 73/69, 1200 Brussels, Belgium. E-mail: delzenne{at}pmnt.ucl.ac.be

Abstract

Nondigestible fermentable dietary fibers such as oligofructose (OFS) exert an antidiabetic effect and increase the secretion of glucagon-like peptide 1 (GLP-1). To determine the importance of GLP-1 receptor-dependent mechanisms for the actions of OFS, we studied high-fat-fed diabetic mice treated with OFS for 4 weeks in the presence or absence of the GLP-1 receptor antagonist exendin 9-39 (Ex-9). OFS improved glucose tolerance, fasting blood glucose, glucose-stimulated insulin secretion, and insulin-sensitive hepatic glucose production and reduced body weight gain. Ex-9 totally prevented the beneficial effects of OFS. Furthermore, GLP-1 receptor knockout mice (GLP-1R−/−) were completely insensitive to the antidiabetic actions of OFS. At the molecular level, the effects of OFS on endogenous glucose production correlated with changes of hepatic IRS (insulin receptor substrate)-2 and Akt phosphorylation in an Ex-9-dependent manner. As inflammation is associated with diabetes and obesity, we quantified nuclear factor-κB and inhibitor of κB kinase β in the liver. The activity of both intracellular inflammatory effectors was reduced by OFS but, importantly, this effect could not be reverted by Ex-9. In summary, our data show that the antidiabetic actions of OFS require a functional GLP-1 receptor. These findings highlight the therapeutic potential of enhancing endogenous GLP-1 secretion for the treatment of type 2 diabetes.

Footnotes

  • 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 January 23, 2006.
    • Received October 18, 2005.
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