Grant: Joint Canada-Israel Health Research Program

Type 2 Diabetes (T2D) is a metabolic disease characterized by elevated circulating sugar levels that results from reduced insulin secretion from pancreatic beta-cells and reduced sensitivity to insulin. Over 3 million individuals are living with diabetes in Canada. While current treatments are effective in reversing many of the symptoms, they do not stop the progression of the metabolic dysfunction. As a result, over 80% of Canadians with diabetes will die from a heart attack or stroke, and diabetes remains the main cause of blindness, kidney failure and non-traumatic amputations. There is an urgent need to develop new treatments. Both genetic and functional studies have identified G protein-coupled receptors (GPCR) and regulators of G protein signalling expressed in beta-cells as potential targets for the development of new treatments. The value of GPCR-targeted therapy for T2D has been demonstrated by drugs targeting the glucagon-like peptide-1 (GLP1) receptor. However, their use is accompanied by various side effects, including nausea, hypoglycemic episodes and no long-term restoration of beta-cell function. An underlying cause of these undesirable effects relates to the fact that each GPCR can engage several signalling pathways that are responsible for their different actions. Recent progress in GPCR studies revealed that it should be possible to design drugs that selectively regulate the therapeutically relevant pathways while sparing those responsible for the adverse effects. For this purpose, a better understanding of the molecular determinants controlling the different pathways engaged by a given GPCR and its cognate G proteins is needed. Combining, structure-based in-silico modelling with biochemical/biophysical assays, we propose to identify protein partners and function/specificity determinants to probe the role of the individual signalling pathways engaged by the GLP1 receptor that will allow the development of more efficacious and safer drugs.