G protein functional selectivity in metabolic disorders

Type 2 diabetes is a metabolic disease characterized by elevated circulating sugar levels that result from reduced insulin secretion from pancreatic beta cells and reduced sensitivity to insulin. Current treatments are effective in reversing many of the symptoms, but they do not stop the progression of the metabolic dysfunction. As a result, the vast majority of patients with diabetes will die from a heart attack or stroke, and the disease 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 signaling expressed in beta cells as potential targets for the development of new treatments. The value of GPCR-targeted therapy for type 2 diabetes has been demonstrated by drugs targeting the glucagon-like peptide-1 (GLP1) receptor, but various side effects accompany their use, 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 signaling 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, this project aims to identify protein partners and function/specificity determinants to probe the role of the individual signaling pathways engaged by the GLP1 receptor that will allow the development of more efficacious and safer drugs against type 2 diabetes.

This project was selected for funding through the fifth research competition of the Joint Canada-Israel Health Research Program. This initiative is a partnership between IDRC, the Canadian Institutes of Health Research, the Israel Science Foundation, and the Azrieli Foundation.