Insulin receptor substrate 3 is not essential for growth or glucose homeostasis

The insulin receptor substrates (IRS) 1 and 2 are required for normal growt h and glucose homeostaisis in mice. To determine whether IRS-3, a recently cloned member of the IRS family, is also involved in the regulation of thes e, we have generated mice with a targeted disruption of the IRS-3 gene and characterized them. Compared with wild-type mice, the IRS-3-null mice showe d normal body weight throughout development, normal blood glucose levels in the fed and fasted state and following an oral glucose bolus, and normal f ed and fasted plasma insulin levels. IRS-3 is most abundant in adipocytes a nd is tyrosine-phosphorylated in response to insulin in these cells. Theref ore, isolated adipocytes were analyzed for changes in insulin effects, Insu lin-stimulated glucose transport in the adipocytes from the IRS-3-null mice was the same as in wild-type cells. The extent of tyrosine phosphorylation of IRS-1/2 following insulin stimulation was similar in adipocytes from IR S-3-null and wild-type mice, and the insulin-induced association of tyrosin e-phosphorylated IRS-1/2 with phosphatidylinositol 3-kinase and SHP-2 was n ot detectably increased by IRS-3 deficiency. Thus, IRS-3 was not essential for normal growth, glucose homeostasis, and glucose transport in adipocytes , and in its absence no significant compensatory augmentation of insulin si gnaling through IRS-1/2 was evident.