To determine the molecular mechanism(s) linking fetal adaptations in intra-uterine growth restriction (IUGR) to adult maladaptations of type 2 diabetes mellitus, we investigated the effect of prenatal semi-nutrient restriction, modified by early postnatal ad lib access to nutrients (CM/SP) or semi-nutrient restriction (SM/SP), versus early postnatal semi-nutrient restriction alone (SM/CP) or control nutrition (CM/CP), on skeletal muscle post-receptor insulin signaling pathway in the adult offspring. The altered in-utero hormonal/metabolic milieu was associated with no change in basal total IRS1, p85 and p110 subunits of P-I-3-kinase, PKC and PKC concentrations, but an increase in basal IRS2 (p<0.05) only in the CM/SP group, and an increase in basal p-PDK-1 (p<0.05), p-Akt (p<0.05) and p-PKC (p<0.05) concentrations in the CM/SP and SM/SP groups. Insulin stimulated increase in p-PDK-1 (p<0.05) and p-Akt (p<0.0007) with no increase in p-PKC, was seen both in CM/SP and SM/SP groups. SHP2 (p<0.03) and PTP1B (p<0.03) increased only in SM/SP with no change in PTEN in CM/SP and SM/SP groups. Aberrations in kinase and phosphatase moieties in the adult IUGR offspring were initiated in-utero but further sculpted by the early postnatal nutritional state. While the CM/SP group demonstrated enhanced kinase activation, the SM/SP group revealed an added increase in phosphatase concentrations, with the net result of heightened basal insulin sensitivity in both groups. The inability to further respond to exogenous insulin was due to the key molecular distal road block consisting of a resistance to phosphorylate and activate PKC necessary for GLUT4 translocation. This protective adaptation may become maladaptive and serve as a forerunner for gestational and type 2 diabetes mellitus.