Skeletal muscle plays a central role in systemic carbohydrate metabolism by oxidizing or storing glucose.The mechanisms of reduced glucose clearance by skeletal muscle, the hallmark of type 2 diabetes, arepoorly understood and for this reason a proposed role of mitochondrial dysfunction has attractedconsiderable interest. According to this picture, reduced fatty acid oxidation by mitochondria leads tobuildup of intracellular triglyceride stores, followed by accumulation of byproducts of intracellular fatty acidmetabolism that interfere with insulin signaling. However, in spite of intense scientific and public interest inobesity and type 2 diabetes, this hypothesis is difficult to test because of the limitations of standardmetabolic studies of muscle. New NMR methods have been developed using instruments operating in therange of 1.5 - 3.0 T to noninvasively probe mitochondrial function and intramyocellular triglycerides, butthese methods are difficult to apply because of low signal and relatively poor chemical shift resolution. Ourrecent observations on healthy volunteers indicate that both limitations will be substantially improved at 7 T.The project will focus on the hypothesis that abnormal function of skeletal muscle mitochondria causesinsulin resistance through accumulation of triglycerides. Mitochondrial function will be assessed by twomethods, the rate of TCA cycle flux measured by oxidation of [2-13C]acetate and by the rate of ATPsynthesis at rest. Intramyocellular lipids will be measured directly by single-voxel 1H NMR spectroscopy. Inthis project we will examine four populations: patients with type 2 diabetes, lean offspring of patients withtype 2 diabetes, patients with type 2 diabetes before and after weight loss, and patients before and afteracute weight gain. If the hypothesis is correct, all patients with type 2 diabetes and lean offspring of diabeticparents should have both abnormal mitochondrial function and excess intramyocellular lipids, whereasweight gain should not cause changes in mitochondrial function. This project requires close interaction withDrs. Cohen and Hobbs (Project 7), Drs. Elmquist and Tamminga (Project 2), and Drs. Parks, Browning andBurgess (Project 6).
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