INSULIN SIGNALING AND INSULIN ACTIONS IN THE MUSCLES AND LIVERS OF INSULIN-RESISTANT, INSULIN-RECEPTOR SUBSTRATE 1-DEFICIENT MICE

We and others recently generated mice with a targeted disruption of th e insulin receptor substrate 1 (IRS-1) gene and demonstrated that they exhibited growth retardation and had resistance to the glucose loweri ng effect of insulin. Insulin initiates its biological effects by acti vating at least two major signalling pathways, one involving phosphati dylinositol 3-kinase (PI3-kinase) and the other involving a ras/mitoge n-activated protein kinase (MAP kinase) cascade. In this study, we inv estigated the roles of IRS-1 and IRS-2 in the biological actions in th e physiological target organs of insulin by comparing the effects of i nsulin in wild-type and IRS-l-deficient mice. In muscles from IRS-l-de ficient mice, the responses to insulin-induced PI3-kinase activation, glucose transport, p70 S6 kinase and MAP kinase activation, mRNA trans lation, and protein synthesis were significantly impaired compared wit h those in wild-type mice. Insulin-induced protein synthesis was both wortmannin sensitive and insensitive in wild-type and IRS-l-deficient mice. However, in another target organ, the liver, the responses to in sulin-induced PI3-kinase and MAP kinase activation were not significan tly reduced. The amount of tyrosine-phosphorylated IRS-2 (in IRS-l-def icient mice) was roughly equal to that of IRS-1 (in wild-type mice) in the liver, whereas it was only 20 to 30% of that of IRS-I in the musc les. In conclusion, (i) IRS-1 plays central roles in two major biologi cal actions of insulin in muscles, glucose transport and protein synth esis; (ii) the insulin resistance of IRS-l-deficient mice is mainly du e to resistance in the muscles; and (iii) the degree of compensation f or IRS-1 deficiency appears to be correlated with the amount of tyrosi ne-phosphorylated IRS-2 (in IRS-l deficient mice) relative to that of IRS-I (in wild-type mice).