The role of glucagonlike peptide1 in the improvement of food intake fat development and diabetic state by nondigestible oligosaccharides

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7.6.1 Non-digestible oligosaccharides and glucose/insulin homeostasis: lessons from animal models

GLP-1, besides its effect on food intake, is considered a key peptide in the control of glucose tolerance, and glucose-dependent insulin release by pancreatic P-cells (Meier & Nauck 2005). Moreover, it is also responsible for increased P-cell neogenesis in streptozotocin-treated newborn rats - a model of diabetes - thus allowing a partial recuperation of pancreatic function with age (Tourrel et al. 2001). We reported that OFS improves glycae-mia and plasma insulin, both in the post-prandial state and after an oral glucose load in streptozotocin-treated diabetic rats (STZ). Moreover, the treatment with OFS allows an improvement of pancreatic insulin and P-cell mass. Endogenous GLP-1 production was increased in STZ-OFS rats as compared with other groups (Cani et al. 2005a). This GLP-1 overproduction might be part of the protective effect of dietary fructans. Such a mechanism has been proposed to explain the effectiveness of guar gum in improving hyperglycaemia in hyperphagic diabetic rats (Cameron-Smith et al. 1997). We may not exclude the fact that the satietogenic effect of OFS could be involved in the improvement of glucose and pancreatic function. By investigating the putative effect of food restriction alone, we have drawn two conclusions: (a) the higher GLP-1 synthesis in STZ-control rats is clearly linked to hyperphagia, since it is avoided by a drastic caloric restriction; (b) the beneficial effect of OFS is not due to food restriction only, since the improvement in glucose tolerance and pancreatic P-cell mass is observed in STZ-OFS rats and not in food-restricted rats.

In another model (mice fed a high-fat diet), we have also shown that OFS improves hepatic insulin sensitivity and increases plasma insulin; these effects of OFS could also be due to a permanent intestinally released GLP-1, promoting perhaps in part progressive insulin sensitivity associated with reduced weight gain.

7.6.2 Is glucagon-like peptide-1 a key hormone involved in the oligofructose effects?

The physiological importance of GLP-1 action can be studied using GLP-1R antagonists or GLP-1 R-/- mice. The infusion of the peptide exendin (9-39) (Ex-9) in rats, mice, baboons and humans, increases fasting glycaemia and glycaemic excursions after a glucose load, in association with reduced levels of circulating insulin (D'Alessio et al. 1996; Schirra et al. 1998; Meeran et al. 1999; Burcelin et al. 2001). Other studies have shown that injection of Ex-9 increases food intake and weight gain in healthy animals (Meeran et al. 1999), consistent with a role for endogenous GLP-1 in the control of body weight. The importance of GLP-1 for the regulation of energy metab olism has also been illustrated by the analysis of mice with genetic disruption of the GLP-1R gene, GLP-1R-/- mice (Scrocchi et al. 1998). By using both models of: (a) transient disruption of GLP-1R action by infusing Ex-9 in wild-type mice or (b) genetic elimination of GLP-1R action in GLP-1R-/- mice, we have shown that 4 weeks of OFS treatment during high-fat feeding reduces the development of hyperglycaemia, glucose intolerance and body weight gain in mice, whereas Ex-9 abolishes all the OFS effects (Cani et al. 2005c). The importance of intact GLP-1R signalling mechanisms for the anti-diabetic actions of OFS were further illustrated in experiments wherein OFS treatment of GLP-1R-/- mice was not able to reduce the high-fat-induced body weight gain and control food intake.

The issue of peripheral versus intraportal GLP-1 delivery is likely to be important since previous studies have demonstrated that GLP-1R-/- mice or wild-type mice with Ex-9 infused into the portal vein have impaired hepato-portal glucose sensor function and reduced insulin secretory capacity (Burcelin et al. 2001). We propose that the production of GLP-1 in the proximal colon of OFS-fed mice is a key event explaining the metabolic effect of this NDO, since the decrease in food intake, in fat mass and in glycemia classically observed after OFS treatment is abolished in GLP-1R-/- mice or in EX-9-infused mice (Cani et al. 2006a). In addition to the therapeutic effect of GLP-1 through its direct pancreatic effect on insulin or glucagon secretion, the anti-hyperglycaemic effect of OFS could also be attributed to the extra-pancreatic indirect actions of GLP-1 on hepatoportal neural mechanisms. Other authors have recently debated the GLP-1 levels that need to be reached to achieve metabolic effects (Holst & Deacon 2005). The extensive degradation of GLP-1 that occurs before it enters the systemic circulation has led to the suggestion that GLP-1 exerts numerous actions either locally in the gut or in the hepatic portal bed. Once released, but before it comes into contact with endothelial DPPIV, GLP-1 may interact with afferent sensory nerve fibres arising from the nodose ganglion, which send afferent impulses to the nucleus of the solitary tract and onwards to the hypothalamus which may be efferent transmitted to the pancreas (Nishizawa et al. 2000; Nakagawa et al. 2004). Thus, under physiological conditions, the neural pathway may be more important than the endocrine route for GLP-1-stimulated insulin secretion. This supports the relevance of our observations, showing a higher GLP-1 content in the proximal colon segment of NDO-treated mice or rats.

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