Ubiquitin-mediated degradation of IRS1 and IRS2 promotes insulin resistance. IRS2 dysfunction is critical in the development of type 2 diabetes. Insulin was not able to suppress gluconeogenic gene expression in primary hepatocytes lacking IRS-2, but when IRS-2 signaling was reconstituted, these cells recovered this response to insulin. This evidence concerns the gene IRS1 and type 2 diabetes mellitus.