Project 171044

Pancreatic beta cells make insulin, which is secreted into the blood to control the levels of blood sugar/glucose. In type 2 diabetes, insulin secretion is impaired, leading to high blood glucose, a condition termed hyperglycemia. Prolonged hyperglycemia leads to many associated medical complications including heart disease, kidney disease and neurological problems that decrease the quality of life and can lead to premature death. In the present grant we strive to understand what causes beta cells to fail to function properly. Three possibilities are that the cells lose the ability to respond to glucose, they die, or a combination of both. In beta cells, the mitochondria, a type of cellular organelle, produce cellular energy and have been linked to both glucose sensing and cell death activation. In the present grant we propose to study what happens to mitochondria that causes them to malfunction and cause diabetes. Three specific aims are proposed in this grant: The first investigates the role of a mitochondrial protein elevated in diabetes called UCP2, which we hypothesize can cause beta cells to lose glucose sensing and the ability to secrete insulin effectively. The second aim attempts to identify and investigate a drug to suppress UCP2 activity, which we anticipate should restore beta cell function and insulin secretion. The third aim will identify other mitochondrial proteins in beta cells that cause them to die. By understanding what proteins cause beta cell dysfunction (glucose sensing and cell death), we anticipate new sensitive techniques will be identified to detect type 2 diabetes in individuals and new drugs developed that could be used to treat or prevent insulin deficiency in this disease.

investigating the role of mitochondrial uncoupling proteins in beta cell dysfunction and developing novel drugs to target these pathways