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

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 insulinsensitive 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 ␤ 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. Diabetes 55: 1484 -1490, 2006 T he recent growing occurrence of the metabolic diseases diabetes and obesity in Westernized countries is associated with changes in feeding habits, where fat constitutes an increasing percentage of total caloric intake (1). The central and early pathological consequences of high-fat feeding includes the development of insulin resistance (2,3) and ␤-cell dysfunction. The mechanisms through which these functions are impaired are not completely identified but could be related to inflammation (4,5), lipotoxicity (2,6), and chronic hyperinsulinemia (7,8) primarily affecting the liver (9) and the muscles (10). Therapeutic strategies for reversing these defects involve pharmacological or nutritional approaches. Whereas the former aims at targeting tissues and molecules directly involved in insulin action or secretion, nutritional approaches aim at stimulating endogenous physiological functions that secondarily regulate energy homeostasis.Glucagon-like peptide 1 (GLP-1) amide (7-36) is an enteroendocrine-derived peptide secreted in response to nutrient ingestion. GLP-1 stimulates insulin secretion in a glucose-dependent manner (11). Clinical trials showed that continuous GLP-1 treatment for 6 weeks improved glycemic control and body weight and reduced food intake (12). Consequently, therapeutic strategies aimed at stimulating GLP-1 secretion represent alternative approaches to pharmacological approaches delivering exogenous GLP-1.Human studies have demonstrated that oligofructose (OFS), a nondigestible fermentable carbohydrate, lowers plasma lipid concentrations (13), incr...

Selective increases of bifidobacteria in gut microflora improve high-fat-diet-induced diabetes in mice through a mechanism associated with endotoxaemia

“…According to these results, we have previously shown that HF-diet-induced hepatic insulin resistance was normalised in OFS fed mice, without significant improvement in whole-body insulin sensitivity [18]. Moreover, the improved hepatic insulin sensitivity observed in HF-OFS fed mice was strongly associated with a significantly lower hepatic inflammatory tone [18]. Since we observed higher endotoxaemia in HF-diet-fed mice, we measured plasma and adipose tissue inflammatory markers.…”

“…Diet and experimental groups Mice (n=8 per group) were fed four different experimental diets for 14 weeks as follows: (1) standard diet (control) (A04; UAR, Villemoisson-sur-Orge, France) [17]; (2) HF diet containing 49.5% fat (g/100 g of total dry diet) corresponding to 72% of the total energy content (UAR, Epinay-sur-Orge, France); (3) a mix of HF diet and a fermentable dietary fibre (OFS) (HF-OFS) (kind gift from Orafti, Tienen, Belgium) [18]; and (4) a mix of HF diet and a non-fermentable dietary fibre (microcrystalline cellulose [HF-Cell]) (Vivapur microcrystalline cellulose; J. Rettenmaier & Söhne, Weissenborn, Germany). Dietary fibre was added in a proportion of 90:10 (weight of HF diet:weight of fibre).…”

“…We have previously described how OFS feeding promotes endogenous glucagon-like peptide-1 (GLP-1) production (i.e. colonic proglucagon mRNA) [17,18,[27][28][29]. We therefore measured colonic proglucagon mRNA in the present study.…”

Coenzyme Q10 supplementation lowers hepatic oxidative stress and inflammation associated with diet-induced obesity in mice

“…An oral glucose tolerance test was performed 7 weeks after the beginning of the feeding period [7,28,29]. Six-hour-fasted mice received an oral load of glucose (Fluka, Buchs, Switzerland) of 3 g/kg body wt with a 660 g/l glucose solution.…”

Implication de la flore intestinale dans le métabolisme énergétique

“…Des arguments expérimen-taux d'une autre nature suggèrent que la fermentation de glucides non digestibles n'augmente pas la masse grasse, mais, au contraire, contribue à réduire les altérations métaboliques associées à l'obésité. Ainsi, notre équipe et d'autres auteurs ont montré qu'une alimentation riche en fibres « fermentescibles » non digestibles (fructanes) diminuait le poids corporel, le développement de la masse adipeuse et la sévérité du diabète dans plusieurs modèles animaux [15][16][17][18][19]. Ces fibres alimentaires sont totalement fermentées dans le côlon, permettant aux bactéries utilisant préférentiellement ces composés comme source énergétique -en l'occurrence les bifidobactéries -de se développer.…”