Grant: Project Grant

Diabetes results from either the loss of insulin-producing beta-cells (type 1 diabetes: T1D) or their impairment relative to the body's insulin needs (type 2 diabetes; T2D). At the same time another important group of endocrine cells in the pancreas, the alpha-cells that make the sugar-raising hormone glucagon, are also impaired in both T1D and T2D - helping to both drive increased blood sugar and impair the ability to sense dangerous lows. The mechanisms driving dysfunction in these cells, particularly in human diabetes, is not well known. Complicating the issue are recent findings suggesting that there are different 'sub-populations' of these cells. That is, not all beta-cells or alpha-cells are the same. In fact, some sub-types of these cells may be key drivers of impaired hormone secretion in diabetes, while other cell sub-types may be resistant to such dysfunction. Even in the absence of diabetes, islet cell sub-populations may shift and change over time - adjusting hormone secretion accordingly. Underlying all of this is the control of gene expression to determine the function and proportions of islet cell sub-groupings, which may partly underlie the genetic risk to both T1D and T2D. Understanding the relationships and function of islet cell sub-populations will provide important insight into the mechanism(s) that drive altered insulin and glucagon secretion, and therefore blood sugar regulation, in diabetes. In this project, we will use our unique biobank of pancreas and islet cell tissues from human organ donors with or without T2D or T1D, combined with cutting edge approaches to study the function of the cells in combination with their molecular makeup, and computational approaches to examine cells and genetic links to diabetes from large datasets, to delineate mechanisms that define whether an islet cell - whether producing insulin or glucagon - becomes dysfunctional and potentially drives the development or progression of the major forms of diabetes.