Grant: Project Grant

Type 2 diabetes (T2D) is increasing at an alarming rate in Canada. Disproportionally affected are Canada's Indigenous Peoples. The Oji-Cree linguistic group that lives in Central Canada experiences up to 5X higher rates and much earlier onset of T2D compared to the general Canadian population. Almost 20 years ago, it was discovered that a considerable number of Oji-Cree people carry a genetic variant in the hepatocyte nuclear factor-1 alpha (HNF-1a) gene. The gene variation is called HNF-1aG319S or just G319S. This gene variant not only strongly associates with T2D in the Oji-Cree sub-population, but also strongly associates with a younger age-of-onset of T2D. Despite being discovered almost 2 decades ago, we currently do not understand how this gene variant affects the insulin-secreting beta cells leading to increased risk for T2D development. In this study, we will use newly developed, state-of-the-art mouse models (cells and whole animal) to examine how the G319S variant affects insulin secretion from the beta cell as well as how the G319S variant influences the susceptibility of the beta cell to relevant environmental stresses associated with T2D in the Oji-Cree. Finally, we will study the impact of the G319S variant on human beta-like cells derived directly from people who carry the G319S variant. This study will be the first to examine the mechanistic impact of the G319S variant on both mouse and human beta cells and will provide much needed understanding of the basic pathophysiology of a gene variant that strongly influences the health of a considerable number of Indigenous Canadians. The new knowledge gained from this study will not only inform potential modifications to current treatment regimens for G319S carriers living with T2D, but also identify novel drugable targets for the development of new, more effective treatment approaches for carriers of HNF-1a mutations.