Control of the intestinal barrier function by the local action of insulin


A common feature of metabolic disorders, such as obesity and insulin resistance, is their association with chronic inflammatory processes, as well as a general increased risk of infections. In this context, intestinal hyperpermeability has emerged as one of the mechanistic bases contributing to this metaflammation. Among the elements triggering or supporting this loss of epithelial integrity during the "diabesity" cascade, intestinal dysbiosis, food composition and hyperglycemia have been proposed as prime candidates.

However, our results reveal that intestinal insulin sensitivity is reduced during nutritional obesity and that it controls (independently of hyperglycemia or adiposity) two essential components of the intestinal barrier: bactericide abilities and the renewal of the epithelium. Our project therefore aims to study the role of the insulin receptor as a guarantor of intestinal integrity, by determining in the case of a specific alteration of insulin signaling in the intestinal epithelium: (i) the molecular and cellular mechanisms underlying the defect of anti-microbial defenses, (ii) whether insulin signaling represents an intrinsic mechanism of intestinal stem cells for the maintenance of the intestinal barrier.

The success of this project is based on (i) the development of original murine models with a specific deficiency of insulin action, without parallel hyperglycemia or obesity, and (ii) the alternative use of murine and human intestinal organoids for the pharmacological and selective screening of insulin receptor effectors. These tools will allow the exploration of the mechanisms underlying the deterioration of intestinal integrity following the local loss of insulin signaling, essential data for the design of preventive and therapeutic strategies.




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Networks & Collaborations


Sandra Guilmeau

Inserm U1016 - CNRS UMR8104 - University Paris Cité.

22 rue Méchain, 75014 Paris.

Team "Insulin & glucose signaling, Glucotoxicity".
Faculty building, 3rd floor, room #3515.

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