POITOUT LABORATORY
Canada Research Chair in Diabetes and Pancreatic ß-cell Function

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Novel G protein-coupled receptors and regulatery proteins in beta-cell

Summary

The deorphanization of the G-protein coupled receptor FFA1/GPR40 in 2003 and the demonstration that it was activated by medium-to-long-chain fatty acids and selectively expressed in pancreatic beta cells sparked tremendous interest in this and other fatty acid receptors as potential therapeutic targets to enhance insulin secretion in a glucose-dependent manner in type 2 diabetes. Over the last decade we have conducted a series of studies aimed to better understand the role of fatty acid receptors in pancreatic islet function and glucose homeostasis and to identify their mechanisms of action. Using GPR40 knock-out mice, we have shown that GPR40 mediates approximately 50% of the stimulatory effect of fatty acids on insulin secretion in vitro and in vivo, but is not implicated in their long-term, deleterious effects on beta-cell function. We have shown that GPR40 plays a role in the maintenance of glucose homeostasis in vivo via a mechanism of action that does not involve changes in intracellular fuel metabolism in islets. We have identified the mechanisms by which glucose regulates the expression of GPR40 and have shown, in collaboration with the group of Patrick MacDonald at the University of Alberta, that activation of GPR40 triggers a signaling cascade that involves protein kinase D and PAK4, and leads to depolymerization of cortical actin and stimulation of second-phase insulin secretion. In collaboration with the group of Michel Bouvier at the University of Montreal, we have demonstrated that GPR40 is subject to biased agonism.(More)

The pancreatic beta-cell response to metabolic stress

Summary

The beta-cell has a strong capacity to adjust to a changing metabolic environment. For example, the vast majority of people who gain weight and become resistant to the action of insulin do not develop diabetes because their beta-cells are able to compensate for insulin resistance by two mechanisms: 1- a large increase in insulin secretion; 2- cell proliferation which leads to enhanced functional beta-cell mass. In about 20% of individuals, however, these compensatory mechanisms are deficient or absent and type 2 diabetes develops. Our laboratory tries to understand the cellular and molecular basis of these compensatory mechanisms and their failure under conditions of metabolic stress.(More)









 
 
       
 
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