Improvement of glucose tolerance and hepatic insulin sensitivity by oligofructose requires a functional glucagon-like peptide 1 receptor.
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-kappaB and inhibitor of kappaB kinase beta 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.
Cani
Patrice D
PD
CNRS-UMR 5018, University Paul Sabatier, Hôpital Rangueil, 1 BP 84225, 31432 Toulouse cedex 4, France.
Knauf
Claude
C
Iglesias
Miguel A
MA
Drucker
Daniel J
DJ
Delzenne
Nathalie M
NM
Burcelin
Rémy
R
D000273:Adipose Tissue / Q000033:anatomy & histology; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000097:blood / Q000235:genetics / Q000503:physiopathology*; D004822:Epididymis; D005215:Fasting; D000067757:Glucagon-Like Peptide-1 Receptor; D005951:Glucose Tolerance Test; D007328:Insulin / Q000032:analysis / Q000097:blood; D007515:Islets of Langerhans / Q000737:chemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009844:Oligosaccharides / Q000627:therapeutic use*; D052336:Proglucagon / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics; D018027:Receptors, Glucagon / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D001786:Blood Glucose; C000593834:Glp1r protein, mouse; D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D009844:Oligosaccharides; D012333:RNA, Messenger; D018027:Receptors, Glucagon; C120489:oligofructose; D052336:Proglucagon