Grant: Operating Grant

The maturity onset form of diabetes, Type 2 diabetes (T2D), afflicts more than 2 million Canadians and costs the healthcare system billions of dollars annually. As the disease progresses T2D can cause many severe health problems including; blindness, kidney failure and heart attacks. T2D is in part caused by genetics and by environmental influences like obesity. We have recently shown that a large population of humans are at risk to develop T2D because they possess a genetic variant of a protein called ZnT8. At present, the function of this protein is not well understood, but it is expressed in insulin producing B cells and can regulate the transport of zinc ions into cells from the blood. It has been known for many years that zinc is an extremely important element to B cells because it is required for both the production of insulin. Additionally, zinc is co-released with insulin from B cells to inhibit the secretion of glucagon, a hormone known to counter insulin's actions and raise blood sugar. Thus, zinc can greatly influence blood sugar by stimulating insulin production and by suppressing glucagon secretion. In the present application, we propose 3 distinct experiments. First will determine how ZnT8 functions in B cells to control insulin secretion by studying mice that are designed not to possess this protein. In a second set of studies we will determine how one specific human genetic variant of the ZnT8 protein called ZnT8325R that is found in the majority of people, increases your risk of developing T2D. To do this, we will study mice that are genetically modified to express human ZnT8325R in their insulin-producing B cells. In a third set of experiments we will determine if new drugs that increase ZnT8 protein activity, can enhance insulin secretion and thereby be used to treat T2D. Overall these studies will allow us to better understand how ZnT8 increases T2D risk and may lead to new methods to treat this disease.