Perturbed skeletal muscle insulin signaling in the adult female intrauterine growth-restricted rat

To determine the molecular mechanism(s) linking fetal adaptations in intrauterine growth restriction ( IUGR) to adult maladaptations of type 2 diabetes mellitus, we investigated the effect of prenatal seminutrient restriction, modified by early postnatal ad libitum access to nutrients ( CM/SP) or seminutrient restriction ( SM/SP), vs. early postnatal seminutrient restriction alone ( SM/CP) or control nutrition ( CM/CP) on the skeletal muscle postreceptor insulin-signaling pathway in the adult offspring. The altered in utero hormonal/ metabolic milieu was associated with no change in basal total IRS-1, p85, and p110 beta subunits of PI 3- kinase, PKC theta, and PKC zeta concentrations but an increase in basal IRS-2 ( P < 0.05) only in the CM/SP group and an increase in basal phospho ( p)- PDK-1 ( P < 0.05), p-Akt ( P < 0.05), and p- PKC zeta ( P < 0.05) concentrations in the CM/SP and SM/SP groups. Insulin-stimulated increases in p-PDK-1 ( P < 0.05) and p-Akt ( P < 0.0007), with no increase in p- PKC zeta, were seen in both 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. Although 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 roadblock consisting of resistance to phosphorylate and activate PKC zeta necessary for GLUT4 translocation. This protective adaptation may become maladaptive and serve as a forerunner for gestational and type 2 diabetes mellitus.