Identification of a proteomic signature in blood and gut that correlates with islet-beta cell function recovery. – BariMice

Type 2 diabetes is a chronic disease characterized by a central obesity, an insulin resistance and a reduction of insulin secretion. Bariatric surgery is an important tool for the discovery of novel therapeutic targets for restoring beta-cell function. We have validated and published a bariatric surgery procedure (enterogastro-anastomosis with pyloric ligature, EGA) in high fat diet mice that recapitulate the effects of the gastric bypass procedure in humans. We have demonstrated in the high fat diet mice model that, as in humans, diabetes resolution is observed 10 days after the EGA surgery. This effect was independent of the body weight loss and was explained by a reduction of insulin resistance and an increase of insulin secretion. We next have performed the EGA procedure in ob mice, a model of type 2 diabetes. In contrast to the high fat diet model, resolution of diabetes after bariatric surgery was observed in ob mice despite persistent hyperphagia, obesity, altered GLP-1 secretion, massive insulin resistance and inflammation. In this model, resolution of diabetes was explained by a dramatic improvement of insulin secretion linked to specific changes in mIRs expression in pancreatic islets. We next performed a transcriptomic analysis and a Go enrichment analysis of functional pathways. We showed that recovery of beta cell functionality during surgery was associated with enrichment of pathways involved in insulin secretion, calcium homeostasis, hexose metabolism, cellular response to insulin or peptide hormone, lipids or cholesterol metabolism and second-messenger-mediated signaling. In order to test the hypothesis that secreted peptides/proteins from the gut after the surgery may contribute to the improvement of beta cell function, we performed a proteomic analysis of alimentary intestine from EGA and sham ob-mice. We showed that 319 secreted proteins were differentially regulated by the surgery and may be involved in the gut-beta cell axis. Thus, this model will help us to found novel pathways for beta cells recovery by limiting confounding factors (such as body weight loss or reduced food intake) that may generate unspecific targets or may regulate various pathways unrelated with beta cells function. Thus, our study is expected to identify new important factors for restoring beta cells function in diabetes, an important challenge in the field of diabetology.