IRS1 and Obesity: Finally, note that liver plays an important role in DIO/MetS/T2DM, even when systemic insulin resistance is initiated or abetted by (a) adipocyte aberrations in obesity that lead to excesses in circulating ceramide levels22 and (b) muscle aberrations, for example, in Het‐MλKO mice, where an initial defect in muscle glucose transport34 leads to hyperinsulinemia and secondary increases in activity of hepatic aPKC,44 which is controlled by IRS‐2/PI3K and, unlike IRS‐1/PI3Kdependent Akt, is conserved in T2DM.17, 18