Type 2 diabetes is caused by a strong resistance of the body's tissues to the hormone insulin and a reduced production of insulin by the pancreas. Both hereditary and lifestyle factors can cause insulin resistance but these factors are not yet understood. We will identify genes and proteins that contribute to the development of insulin resistance in human skeletal muscle, the largest tissue in the body, as well as mechanisms for how the genes may be affected by lifestyle factors. By unbiasedly investigating two different processes for how the environment can affect the genes, we can find genes that contribute to insulin resistance in the cells through the influence of lifestyle factors. The two processes we will focus on are so-called epigenetic changes of DNA (DNA methylation) and microRNA. By looking at all the DNA methylations that occur in insulin resistance, we can find the genes that are affected. In addition, we will scan all microRNA (miRNA) changes in insulin resistance to understand the role of these genes in the development of type 2 diabetes. Finally, we will validate the new genes identified above by investigating their function on insulin sensitivity in mouse models of Type 2 diabetes. Information on which genes are affected will enable future development of new drugs as well as new dietary and exercise programs to treat and prevent the onset of Type 2 diabetes.