Grant: Operating Grant - PA: Inst of Nutrition, Metabolism and Diabetes -Bridge Funding

Nutrient fuels, like carbohydrates, proteins and fats, are essential for body and cellular functions. However, chronic excess of any of these nutrients can be toxic and interferes with normal cellular functions resulting in disease conditions like obesity and diabetes. Thus, pancreatic beta cells, which produce insulin in response to glucose in blood, fail to do so if they are chronically exposed to elevated fatty acids and glucose. Under such conditions of excess fuel supply, other body tissues also do not respond normally to circulating insulin and cannot use blood glucose effectively. These toxic effects of excessive fuels result from the increased production of oxygen free radicals, which cause cellular damage, accumulation of fats in the cells, decreased useable energy production from the fuels and abnormal protein synthesis. The mechanisms by which, cells handle and dispose-off toxic exogenous chemicals are relatively well understood. Surprisingly, we know much less about the way the cells escape from the toxic effects of fuel surfeit. This is particularly important in conditions like obesity and diabetes, which are often associated with fuel surfeit. In the present proposal, we are planning to investigate the molecular mechanisms of fuel detoxification in pancreatic beta cells. Many cells harbor a central metabolic pathway, named glycerolipid/fatty acid cycling, which handles fatty acids and glycerol coming from glucose. This pathway is important in alleviating the toxicity of fuels either by storing excess fatty acids as fat droplets in the cells or by transporting some of the breakdown products from this pathway, out of the cell. We will study different segments of this pathway, their relative contribution to fuel detoxification. This information will help in deciphering how cells cope-up with toxicity due to excess fuel supply, when they fail in this process and what therapeutic measures can be implemented to counter this failure of cellular function