Project 466798

When deprived of sugar due to starvation, our tissues need an alternative source of energy, so they turn to ketone bodies. Our skeletal muscles are the main location for sugar uptake following a meal, but they are also able to oxidize ketone bodies. The research outlined in this proposal contributes to a greater picture examination into the potential mechanism of action by which ketone bodies in the muscle can affect blood sugar levels. Although the role of ketone bodies during starvation is well-understood, their implication with diseases such as type 2 diabetes, where individuals affected have an impaired ability to take in sugar for use as a source of energy, and therefore high blood sugar levels, remains to be elucidated. The experiments performed will involve the use of muscle obtained through a biopsy from healthy subjects, and subjects with type 2 diabetes. The specific objectives of the proposed research include determining whether activity of an important enzyme involved in ketone body oxidation (succinyl-CoA:3-ketoacid-CoA transferase (SCOT)) is elevated in the skeletal muscle of humans affected by type 2 diabetes, relative to unaffected individuals. Additional experiments will be performed to determine if inhibiting SCOT, thereby preventing the skeletal muscles from using ketone bodies for energy, results in an increase in the use of sugar in subjects with type 2 diabetes. Specifically, the uptake and storage of sugar within the cells, as well as the activation of enzymes involved in sugar metabolism will be investigated. By studying the implication of ketone body oxidation in individuals affected by type 2 diabetes, the results will hopefully serve to improve our understanding of how we can regulate blood sugar levels in patients with the disease.