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.