Insulin resistance in experimental alcohol-induced liver disease.
OBJECTIVE
Chronic ethanol consumption impairs liver regeneration due, in part, to inhibition of insulin signaling. This study characterizes the mechanisms and consequences of ethanol-impaired insulin signaling in relation to oxidative injury and altered gene expression.


METHODS
Long-Evans rats were fed for 8 weeks with isocaloric liquid diets containing 0% (control) or 37% ethanol (caloric content). Livers were used to examine histopathology, indices of oxidative stress, gene expression required for insulin and insulin-like growth factor (IGF) signaling, insulin-responsive gene expression, i.e. glyceraldehydes-3-phosphate dehydrogenase (GAPDH) and aspartyl-asparaginyl-beta-hydroxylase (AAH), and competitive equilibrium binding to the insulin, IGF-I, and IGF-II receptors.


RESULTS
Chronic ethanol exposure caused liver injury with increased hepatocellular steatosis, inflammation, apoptosis, and increased immunoreactivity for activated caspase-3, 8-hydroxy-2'-deoxyguanosine, and 4-hydroxy-2,3-nonenol. These effects were associated with increased expression of IGF-I receptor, IGF-II, and IGF-II receptor, and expression of IGF-I, AAH, and GAPDH, which mediate energy metabolism and cell motility/remodeling, and reduced binding to the insulin receptor.


CONCLUSIONS
Chronic ethanol-induced liver injury causes insulin resistance with inhibition of insulin-responsive genes needed for metabolism, remodeling, and regeneration. In contrast, the IGF-I and IGF-II signaling mechanisms remain relatively preserved, suggesting that insulin-regulated hepatic functions may be selectively vulnerable to the toxic effects of ethanol.
de la Monte
Suzanne M
SM
Departments of Medicine, Liver Research Center, Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA. suzanne_delamonte_md@brown.edu
Yeon
Jong-Eun
JE
Tong
Ming
M
Longato
Lisa
L
Chaudhry
Rajeev
R
Pang
Mao-Yin
MY
Duan
Kevin
K
Wands
Jack R
JR
D000428:Alcohol Drinking / Q000009:adverse effects; D000434:Alcoholic Beverages / Q000009:adverse effects; D000818:Animals; D004195:Disease Models, Animal; D000431:Ethanol / Q000009:adverse effects; D015870:Gene Expression; D007333:Insulin Resistance / Q000235:genetics*; D008108:Liver Diseases, Alcoholic / Q000235:genetics / Q000503:physiopathology*; D008115:Liver Regeneration / Q000235:genetics / Q000502:physiology; D008297:Male; D018384:Oxidative Stress; D051381:Rats; D020318:Rats, Long-Evans; D015398:Signal Transduction
D000431:Ethanol