JAP-01098-2004.R1 FINAL ACCEPTED VERSION In Vivo Insulin Signaling through PI 3-kinase is Impaired in Skeletal Muscle of Adult Rat Offspring Exposed to Ethanol in Utero

It is now known that prenatal ethanol (EtOH) exposure is associated with impaired glucose tolerance and insulin resistance in the rat offspring, but the underlying mechanism(s) is not known. To test the hypothesis that in vivo insulin signaling through PI 3-kinase is reduced in skeletal muscle of adult rat offspring exposed to EtOH in utero, we gave insulin intravenously to these rats and probed steps in the PI 3-kinase insulin signaling pathway. Following insulin treatment, EtOH-exposed rats had decreased tyrosine phosphorylation of the insulin receptor β-subunit and of insulin receptor substrate-1 (IRS-1), as well as reduced IRS-1-associated PI 3-kinase in the gastrocnemius muscle, compared with control rats. There was no significant difference in basal or insulin-stimulated Akt activity between EtOH-exposed rats and controls. Insulinstimulated PKCζ phosphorylation and membrane association were reduced in EtOHexposed rats compared with controls. Muscle insulin binding and peptide contents of insulin receptor, IRS-1, p85 subunit of PI 3-kinase, Akt/protein kinase B and atypical protein kinase C isoform ζ (PKCζ) were not different between EtOH-exposed rats and controls. Thus, insulin resistance in rat offspring exposed to EtOH in utero may be explained, at least in part, by impaired insulin signaling through the PI-3 kinase pathway in skeletal muscle.