Grant: Operating Grant

Type 2 diabetes is a major cause of disease and death, currently affecting 2.5 million Canadians. ABCA1 is crucial for removing cholesterol from cells thereby preventing its accumulation within cells. Lack of ABCA1 in beta cells leads to cholesterol accumulation in these cells, reduces insulin secretion and leads to impaired glucose tolerance in mice. In addition, ABCA1 may affect glucose tolerance via its essential role in HDL production by the liver. Low plasma HDL in humans is a risk factor for development of diabetes. The objectives of our proposed studies are to: 1) Assess novel approaches to up-regulate ABCA1 in beta cells and its impact on insulin secretion. 2) Determine how alterations in plasma HDL induced by changes in liver ABCA1 levels affect beta cell function in mice. 3) Evaluate how genetic variations in ABCA1 change glucose metabolism in humans We will examine whether small molecules called microRNA can be used to increase ABCA1 levels in beta cells and thereby reduce beta cell cholesterol accumulation, improve insulin secretion and glucose tolerance in disease mouse models. Secondly, we will use these microRNAs to change ABCA1 levels in the liver and assess its impact on glucose tolerance and beta cell function in mice. Lastly, we will evaluate beta cell function and glucose metabolism in family members with genetic alterations in ABCA1 activity. These studies will provide crucial information about liver effects on beta cell function and the role of ABCA1 in cholesterol regulation and insulin secretion in beta cells, and may contribute to the development of therapeutic strategies to modulate cholesterol in beta cells and reverse or prevent diabetes.