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Insulin resistance in experimental alcohol‐induced liver disease
Author(s) -
De La Monte Suzanne M,
Yeon JongEun,
Tong Ming,
Longato Lisa,
Chaudhry Rajeev,
Pang MaoYin,
Duan Kevin,
Wands Jack R.
Publication year - 2008
Publication title -
journal of gastroenterology and hepatology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.214
H-Index - 130
eISSN - 1440-1746
pISSN - 0815-9319
DOI - 10.1111/j.1440-1746.2008.05339.x
Subject(s) - endocrinology , medicine , insulin receptor , insulin resistance , insulin , steatosis , insulin like growth factor , oxidative stress , foxo1 , receptor , growth factor , signal transduction , biology , protein kinase b , biochemistry
Background and Aim: 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‐β‐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.