Coordinated targeting of ER-mitochondria contact sites in cells from the gut, pancreas and liver, triumvirate for optimal control of glucose homeostasis – TriMAMvirate

Actual strategies to treat type 2 diabetes (T2D) are based on improving either insulin action OR secretion. In the needed quest to find new therapeutics, it is interesting to note that there is no strategy that simultaneously improve insulin action AND secretion, partly due to our limited understanding of common mechanisms of peripheral tissues and beta cells dysfunction. During the last years, we evidenced a new role of endoplasmic reticulum (ER)-mitochondria contact sites, called mitochondria-associated membranes (MAMs), in the control of insulin action and secretion. Importantly, we recently further made 2 original discoveries involving the gut and showing that MAMs are also involved in nutrient-induced GLP1 secretion in enteroendocrine cells, and in GLP1-mediated improvement of insulin action and secretion. Altogether, these highly original observations suggest that targeting MAMs in the splanchnic triumvirate formed by the gut, the endocrine pancreas and the liver could be a new and more efficient strategy to improve glucose homeostasis in T2D.
Therefore, the objective of the "TriMAMvirate" project is to understand the dynamic regulation of MAMs in the cells of the splanchnic triumvirate formed from the intestine, the pancreas and the liver in the postprandial period, following nutritional challenge and GLP1 action. The co-regulation of MAMs in these 3 organs should allow to control the intestinal secretion of GLP1 and its action on both pancreatic insulin secretion and hepatic insulin action, and ultimately to better regulate postprandial glucose homeostasis. Alterations in this regulation of MAMs by nutrients and GLP1 could participate in hyperglycemia during obesity and T2DM. Thus, the screening (carried out in parallel with this project) of new nutritional and/or pharmacological strategies to stimulate MAMs simultaneously in these 3 organs will allow to propose at the end of the project a new therapeutic strategy to improve glycemia in preclinical models of obesity and T2D. By combining in vitro approaches, different preclinical models, validation in human tissues, and innovative imaging, as well as the expertise of 3 fundamentalists and a clinician, we hope:
1) To characterize the role of MAMs in nutrient-induced GLP1 secretion. Analyse in STC1 cells, intestinal organoids and in L cells from both GLU-Venus and int-FXR_KO mice the effects of nutrients on ER-mitochondria interactions and Ca2+ exchange, cAMP-PKA pathways activation, IP3R phosphorylation and nutrient-induced GLP1 secretion. Validation of the involvement of MAMs by overexpressing available molecular organelle spacer or linker.
2) To characterize the role of MAMs in the action of GLP1 in the liver and beta cells of pancreas. Analyse the effects of GLP1 (and of oxyntomodulin for the liver) on MAM integrity and function, cAMP-PKA signalling pathways, IP3R phosphorylation and insulin action or secretion, in both mouse hepatocytes and pancreatic beta cells. Validate the involvement of MAMs in these effects by blocking the upregulation of MAMs using an organelle spacer in several in vitro and in vivo models.
3) To validate both in mice and humans the co-regulation of MAMs in the gut, pancreas and the liver and the alterations in this co-regulation during obesity and T2D. Analysis of MAMs in the three organs of Glu-Venus mice under both an SD and HFHSD in response to a nutritional challenge or an intestinal TGR5 agonist. Analysis of the dialogue between intestinal incretins and MAMs in the liver and beta cells in human tissues.
This project should validate that targeting MAMs simultaneously in gut, endocrine pancreas and the liver could be an original strategy to stimulate both insulin action and secretion, and thus to improve more efficiently glucose homeostasis in T2D preclinical models.