Ethanol inhibits insulin expression and actions in the developing brain.
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.
de la Monte
S M
SM
Department of Pathology and Medicine, Pierre Galletti Research Building, Rhode Island Hospital, Providence, USA. Suzanne_DeLaMonte_MD@Brown.edu
Xu
X J
XJ
Wands
J R
JR
D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D000831:Animals, Newborn; D001921:Brain / Q000187:drug effects* / Q000196:embryology / Q000378:metabolism; D002531:Cerebellum / Q000187:drug effects / Q000378:metabolism; D000431:Ethanol / Q000494:pharmacology*; D005260:Female; D063647:Fetal Alcohol Spectrum Disorders / Q000235:genetics* / Q000378:metabolism; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects* / Q000235:genetics; D005947:Glucose / Q000378:metabolism; D007328:Insulin / Q000235:genetics*; D023421:Models, Animal; D009004:Monosaccharide Transport Proteins / Q000235:genetics; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D011247:Pregnancy; D011505:Protein-Tyrosine Kinases / Q000378:metabolism; D051381:Rats; D020318:Rats, Long-Evans; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D011972:Receptor, Insulin / Q000235:genetics; D017451:Receptors, Somatomedin / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction / Q000379:methods; D013002:Somatomedins / Q000235:genetics
D007328:Insulin; D009004:Monosaccharide Transport Proteins; D017451:Receptors, Somatomedin; D013002:Somatomedins; D000431:Ethanol; D000255:Adenosine Triphosphate; D011505:Protein-Tyrosine Kinases; D020794:Receptor Protein-Tyrosine Kinases; D011972:Receptor, Insulin; D005947:Glucose