IRS2 and diabetes mellitus: Regarding its possible role in the pathogenesis of T2 DM, a study [10] suggested that increased MG53 expression in muscle may cause insulin resistance through E3-ligase-mediated degradation of insulin receptor substrate 1 (IRS-1); however, two separate studies [21, 22] argued that IRS-2, IRS-3, and IRS-4 also contribute to insulin signaling and that disruption of IRS-1 alone is insufficient to trigger the development of T2 DM.