The insulin receptor substrates (IRSs) function in insulin signaling. Four
members of the family, IRS-1 through IRS-4, are known. Previously, mice wit
h targeted disruption of the genes for IRS-1, -2, and -3 have been characte
rized. To examine the physiological role of IRS-4, we have generated and ch
aracterized mice lacking IRS-4. Male IRS-4-null mice were similar to 10% sm
aller in size than wild-type male mice at 9 wk of age and beyond, whereas t
he female null mice were of normal size. Breeding pairs of IRS-4-null mice
reproduced less well than wild-type mice. IRS-4-null mice exhibited slightl
y lower blood glucose concentration than the wild-type mice in both the fas
ted and fed states, but the plasma insulin concentrations of the IRS-4-null
mice in the fasted and fed states were normal. IRS-4-null mice also showed
a slightly impaired response in the oral glucose tolerance test. Thus the
absence of IRS-4 caused mild defects in growth, reproduction, and glucose h
omeostasis.