Diabetes was the sixth leading cause of death in the United States in 2002 based on death certificate data which specifically linked type 2 diabetes mellitus (T2DM) to more than 213,000 deaths. Over 18.2 million Americans 20 years of age and older (~6.3% of the population) are estimated to have diabetes, 1.3 million new cases of T2DM are diagnosed yearly and the total (direct and indirect) annual cost in 2002 of all cases of Diabetes in the United States was estimated at over $132 billion. Skeletal muscle insulin resistance and T2DM have been shown to result from genetic origins as well as environmental factors such as alterations in dietary composition and/or lack of physical activity. However, it has not been extensively addressed whether defects in skeletal muscle insulin signaling are differentially manifested based on how the disease develops and if these defects are correctable. In this project we will direct our attention to the high fat-fed rat (an """"""""environmental"""""""" model) and the obese Zucker rat (a genetic model) and specifically focus on the classical (phosphoinositide 3-kinase [PI3-K] dependent) and novel (purportedly PI3-K independent) insulin signaling cascades in the skeletal muscles of these rodent models. Our hypothesis is that although skeletal muscle insulin resistance is due to impaired insulin signaling, impairments in the insulin signaling cascades are not identical across all models of insulin resistance but the impairments can be improved with any mode of exercise.
The specific aims of this application are: 1) To identify if impairments in insulin signaling cascades are manifested similarly in skeletal muscle of two distinct models of insulin resistance, the high fat- fed rat and obese Zucker rat, and 2) To determine if exercise, regardless of mode (i.e., aerobic exercise vs. resistance exercise), will similarly enhance insulin signaling in the skeletal muscle of the high fat fed rat and obese Zucker rat. Yaspelkis III, B.B. Project Narrative We expect to establish whether the mechanisms that contribute to defects in skeletal muscle metabolism in genetic and environmental models of insulin resistance share a commonality or are unique to each particular model and if the defects in skeletal muscle metabolism are reversible. The significance of this approach is that efforts in this area will lead to the discovery of the cellular/molecular pathways underlying how insulin works and in turn will allow for the identification of key targets for which alternative therapies can be designed to reverse insulin resistance and prevent diabetes in humans. ? ? ?
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