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Ethanol inhibits insulin expression and actions in the developing brain

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Abstract.

Ethanol-induced cerebellar hypoplasia is associated with inhibition of insulin-stimulated survival signaling. The present work explores the mechanisms of impaired insulin signaling in a rat model of fetal alcohol syndrome. Real-time quantitative RT-PCR demonstrated reduced expression of the insulin gene in cerebella of ethanol-exposed pups. Although receptor expression was unaffected, insulin and insulin-like growth factor (IGF-I) receptor tyrosine kinase (RTK) activities were reduced by ethanol exposure, and these abnormalities were associated with increased PTP1b activity. In addition, glucose transporter molecule expression and steady-state levels of ATP were reduced in ethanol-exposed cerebellar tissue. Cultured cerebellar granule neurons from ethanol-exposed pups had reduced expression of genes encoding insulin, IGF-II, and the IGF-I and IGF-II receptors, and impaired insulin- and IGF-I-stimulated glucose uptake and ATP production. The results demonstrate that ethanol inhibits insulin-mediated actions in the developing brain by reducing local insulin production and insulin RTK activation, leading to inhibition of glucose transport and ATP production.

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Correspondence to S. M. de la Monte.

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Received 30 December 2004; received after revision 1 March 2005; accepted 10 March 2005

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Monte, S.M.d.l., Xu, X.J. & Wands, J.R. Ethanol inhibits insulin expression and actions in the developing brain. CMLS, Cell. Mol. Life Sci. 62, 1131–1145 (2005). https://doi.org/10.1007/s00018-005-4571-z

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  • DOI: https://doi.org/10.1007/s00018-005-4571-z

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