Insulin receptor substrates (IRSs) couple insulin/IGF receptors to the PI3-kinase and extra cellular signal-regulated (ERK), MAPK cascades, in the insulin signaling pathways. Insulin resistance is a serious medical problem that leads to type 2 diabetes when pancreatic B-cells fails to compensate by increasing the amount of secreted insulin(De Fronzo.,1997). At the physiological level, obesity, inactivity, and aging are common causes of insulin resistance. Although moderate compensatory hyperinsulinemia might be well tolerated in the short term,chronic hyperinsulinemia exacerbates insulin resistance and contributes to B-cell failure and diabetes (Pessin and Saltiel.,2000). Although the molecular mechanisms that cause insulin resistance in humans are largely unknown, some common themes involving a role for the IRSs proteins are emerging. Various cytokines or metabolites promote serine phosphorylation of the IRSs proteins that inhibit signal transduction. For example, circulating free fatty acids, diacylglycerol, or ceramides promote serine phosphorylation of IRS-1/IRS-2 (Shulman.,2000). Adipose-derived cytokines, especially tumor necrosis factor (TNF)-alpha, stimulate serine/threonine phosphorylation of IRS-1/IRS-2, which inhibit signaling(Hotamisligil et al.,1996).