INSULIN SIGNALING IN CHICK-EMBRYOS EXPOSED TO ALCOHOL

Although insulin is known to be an important generator of regulatory s ignals during fetal growth and development, neither the immediate nor long-term effects of alcohol (ethanol) on insulin action are well unde rstood. in the rat, fetal exposure to alcohol has been shown to be cor related with a subsequent abnormal response to a glucose load in the n eonate and adult. Further, fetal hypoplasia secondary to maternal alco hol consumption is correlated with decreased placental glucose transpo rt and with a lowering of the glucose levels in fetal tissues. However , the fetal effects of alcohol cannot be completely overcome by glucos e/caloric supplementation, suggesting that factors other than glucose transport are involved. Using an embryonic chick model that negates th e factors of maternal/placental metabolism and transport, the current study found that fetal alcohol exposure markedly increased insulin bin ding in developing tissue, but had little effect on the binding of the insulin-like growth factors. Competitive binding experiments revealed a marked increase in insulin receptor numbers, but no change in bindi ng affinity as a result of the alcohol exposure. Basal uptake of 2-deo xyglucose by fetal tissue was lowered by alcohol exposure, but incubat ion with exogenous porcine insulin (1 x 10(-7) M) resulted in a signif icant increase in glucose uptake by the alcohol-exposed embryos. The i ncreases in insulin binding and in insulin-dependent glucose uptake no twithstanding, exogenous insulin could not induce normal levels of orn ithine decarboxylase activity in embryonic cells previously exposed to alcohol. Furthermore, insulin treatment seemed to inhibit growth in a lcohol-exposed whole embryos. Molecular changes in the insulin signali ng cascade occurring as the result of alcohol exposure included an inc rease in specific phosphotyrosine content that was markedly decreased following insulin stimulation. The decrease in phosphotyrosine content did not seem to involve the insulin receptor substrate-1:phosphoinosi tol-3 (PI-3) kinase complex, because alcohol-treated embryos had signi ficantly elevated basal PI-3 kinase activity that was not altered by i nsulin exposure. In summary, alcohol-induced growth suppression in the chick embryo is associated with several changes in insulin signaling and thus data suggest that this important mitogenic pathway is impaire d as the result of fetal alcohol exposure.