Grant: Operating Grant

Nutrient fuels, including carbohydrates, proteins and fats, are essential for body and function of the cells. However, continuous supply of any of these nutrients in excess can be toxic due to interference with normal functions of the cells in the body, resulting in obesity and diabetes. Thus, beta cells of pancreas, which produce insulin in response to glucose in blood, fail to do so if they are continuously exposed to high fat and glucose. Under such conditions of excess fuel supply, other body tissues also do not respond normally to insulin and cannot use blood glucose effectively. These toxic effects of excessive fuels result from the accumulation of fat in tissues, decreased useable energy production, abnormal protein synthesis and increased production of harmful oxygen free radicals. The mechanisms by which, cells handle and dispose-off toxic chemicals coming from environment, are relatively well understood. Surprisingly, we know much less about the way the cells escape from the toxicity of excess fuels. This is particularly important in conditions like obesity and diabetes, which are often associated with fuel oversupply. In the present proposal, we are planning to investigate how the beta cells of pancreas get rid-of excess fuels. Many cells harbor a central cyclic process, which handles fatty acids coming from fat and glycerol coming from glucose. This procedure is important in storing excess fatty acids as fat droplets in the cells, and in transporting some of the breakdown products produced during this process out of the cell. We will study different steps of this process and their relative contribution to dispose of excessive fuels. This information will help in understanding how cells and tissues cope-up with the toxicity due to too much fuel supply, how they fail in this process, and what therapeutic measures can be implemented to prevent this failure.