Ethanol inhibits insulin expression and actions in the developing brain

• Published in: Cellular and molecular life sciences : CMLS Vol. 62; no. 10; pp. 1131 - 1145
• Main Authors: de la Monte, S M, Xu, X J, Wands, J R
• Format: Journal Article
• Language: English
• Published: Switzerland Springer Nature B.V 01.05.2005
• Subjects: Adenosine Triphosphate - metabolism; Animals; Animals, Newborn; ATP; Brain; Brain - drug effects; Brain - embryology; Brain - metabolism; Cerebellum - drug effects; Cerebellum - metabolism; Ethanol; Ethanol - pharmacology; Female; Fetal Alcohol Spectrum Disorders - genetics; Fetal Alcohol Spectrum Disorders - metabolism; Fetal alcohol syndrome; Gene Expression Regulation, Developmental - drug effects; Gene Expression Regulation, Developmental - genetics; Glucose - metabolism; Insulin; Insulin - genetics; Kinases; Models, Animal; Monosaccharide Transport Proteins - genetics; Neurons - drug effects; Neurons - metabolism; Pregnancy; Protein-Tyrosine Kinases - metabolism; Proteins; Rats; Rats, Long-Evans; Receptor Protein-Tyrosine Kinases - metabolism; Receptor, Insulin - genetics; Receptors, Somatomedin - genetics; Reverse Transcriptase Polymerase Chain Reaction - methods; Somatomedins - genetics
• ISSN: 1420-682X; 1420-9071
• DOI: 10.1007/s00018-005-4571-z

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.