Grant: Operating Grant

Along with the rise in obese Canadians, there is an alarming increase in the number of Canadians with glucose intolerance and diabetes. In healthy individuals, a rise in blood sugar (glucose) stimulates insulin release from beta-cells in the pancreas. This insulin then helps bring the glucose levels back down again. In some obese individuals and the pre-diabetic state, high levels of fats and glucose damage and kill the beta-cells. A group of proteins, known as the Bcl-2 family, control the survival and death of cells under such stress. Recently it has been proposed that such 'survival/death' proteins may also regulate normal cell function. Bcl-2 and a similar protein Bcl-xL, are well known pro-survival members of this group, but we have not yet determined if these proteins have important roles in the pancreatic beta-cell other than protecting the stressed cell from committing 'cellular suicide'. Our goal is to identify new connections between beta-cell function and survival. We wish to understand better the mechanisms by which beta-cells normally sense glucose and release insulin and we aim to clarify how these important cells fail under obesity-associated stress. We will examine if Bcl-2 and Bcl-xL control beta-cell glucose sensing and how these proteins affect the impact of a high fat diet on the risk of developing diabetes. To do so we have generated novel types of genetically-modified mice in which we can use a drug to remove the Bcl-2 or Bcl-xL proteins. We will examine these mice, their beta-cells and their proteins using microscopy and detailed studies of how the genetic defects combined with a high fat diet affects blood glucose levels and diabetes. Our studies will help reveal important new ways to promote beta-cell survival and function. Such discoveries will help prevent the progression of diabetes in at-risk individuals and ultimately control the growing global diabetes epidemic in Canada and the world.