Insulin signaling through insulin receptor substrate 1 and 2 in normal liver development

Background & Aims: The insulin growth factor signal transduction pathway is an important regulator of adult hepatocyte proliferation. The purpose of this study was to determine the roles of the insulin receptor substrate (IRS-1 and IRS-2)-mediated growth cascades in rapidly growing fetal rat liver. Methods: We determined the expression and tyrosyl phosphorylation of the insulin receptor beta subunit (IRbeta), IRS-1 and IRS-2, the binding of phosphatidylinositol 3-kinase (PIU), and activation of the mitogen-activated protein kinase (MAPK) pathway in the presence or absence of insulin stimulation in vivo during development and in the adult liver. In addition, activation of other downstream components including PI3K, Akt, GSK3beta, Bad, and p70S6 kinase was studied. Results: We observed reduced expression and tyrosyl phosphorylation of IRS-1 in the fetal liver compared with the adult liver. These developmental changes resulted in a lack of sensitivity to insulin stimulation and subsequent downstream activation of the PI3K and MAPK cascades until the postneonatal period. In contrast, there was a high level of IRS-2 expression and insulin-stimulated tyrosyl phosphorylation as early as embryonic day 15 with robust PI3K binding and activation, which may enhance hepatocyte survival during the rapid growth phase of the liver. Conclusions: The IRS-1 signal transduction pathway does not play a major role in fetal liver growth because IRS-2 functions as the major insulin responsive molecule in early development. However, insulin-mediated IRS-1/MAPK cascade activation contributes to growth in the adult.