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DOI: 10.2337/db05-1360
© 2006 by the American Diabetes Association
Improvement of Glucose Tolerance and Hepatic Insulin Sensitivity by Oligofructose Requires a Functional Glucagon-Like Peptide 1 Receptor
1 Unité Mixte de Recherche (UMR), Centre National De La Recherche Scientifique, University Paul Sabatier, Toulouse, France
2 Unit of Pharmacokinetics, Metabolism, Nutrition and Toxicology, Université catholique de Louvain, Brussels, Belgium
3 Banting and Best Diabetes Centre, Toronto General Hospital, University of Toronto, Canada
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
Abbreviations:
ELISA, enzyme-linked immunosorbent assay; GLP-1, glucagon-like peptide 1; IKK, inhibitor of 
B kinase; IRS, insulin receptor substrate; OFS, oligofructose; NF-B, nuclear factor-B
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-B and inhibitor of B kinase ß 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.
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