The prevalence of type II diabetes mellitus is rapidly increasing in the world at large and the management of this disease and its chronic complications has a major impact on health care expenses. The preliminary data indicates potential interactions between glucose and protein metabolism, which may play a key role in the pathogenesis of type II diabetes and its chronic complications. Little attention has been focused on this issue, however. Recent advances in biomedical mass spectrometry and protein purification will be applied to measure synthesis rates of individual proteins from needle biopsy samples and to measure tissue bed protein dynamics in both diabetic and control subjects. Although insulin anti-catabolic effect on muscle protein has been known for seven decades, the mechanism of this of this key insulin effect continues to be controversial. The current proposal addresses this issue by measuring the absolute muscle protein breakdown and synthesis from the isotope labels in amino acyl tRNA and intracellular compartment (combining muscle biopsy and microdialysis). Applying this approach, the P.I. will test a novel hypothesis that muscle protein breakdown adapts to the chronic insulin exposure by developing a resistance to insulin. Resistance to insulin-induced glucose disposal in muscle is reported to be inversely associated with the proportion of oxidative muscle fibers and mitochondrial oxidative capacity. The composition of muscle Myosin Heavy Chain (MHC) is a key determinant of muscle fiber type, which is reported to be genetically determined. The P.I. will determine whether people with type II diabetes have reduced synthesis rates and relative composition of MHC1 and 2A isoforms and a higher proportion of MHC2B. In addition, the investigator will determine whether the people with type II diabetes have reduced muscle mitochondrial protein synthesis, mitochondrial enzymes and capacity for ATP production, which could explain their increased muscle fatigability and reduced endurance capacity. The Principal Investigator (P.I) also seeks to determine whether the changes in synthesis and composition of MHC isoforms and mitochondrial functions response to exercise are less pronounced in people with type II diabetes. Groups of twenty people with type II diabetes and obese and lean controls will be studied in the baseline (sedentary) state and then after either three months of aerobic exercise training or placebo period. These studies will define more clearly the interaction between synthesis and expression of MHC isoforms, mitochondrial functions and insulin resistance to glucose metabolism. The P.I. expects that further advances in our understanding of mitochondrial protein synthesis and other protein turnover abnormalities in diabetes will be forthcoming from these experiments. These results will allow us to better understand the pathophysiology of this disorder and its chronic complications.
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