Ethanol inhibits insulin expression and actions in the developing brain

• DOI: 10.1007/s00018-005-4571-z
• Publication Date: 2005-05-03T05:51:29Z
• Authors: S. M. de la Monte; X. J. Xu; J. R. Wands
• Keywords: Neurons; 0301 basic medicine; Ethanol; Monosaccharide Transport Proteins; Brain; Gene Expression Regulation, Developmental; Receptor Protein-Tyrosine Kinases; Protein-Tyrosine Kinases; Receptor, Insulin; Rats; 03 medical and health sciences; Adenosine Triphosphate; Glucose; Animals, Newborn; Fetal Alcohol Spectrum Disorders; Pregnancy; Cerebellum; Models, Animal; Animals; Insulin; Female; Rats, Long-Evans

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.