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item HE, LING

Submitted to: Society of Toxicology
Publication Type: Abstract Only
Publication Acceptance Date: 12/15/2006
Publication Date: 3/15/2007
Citation: He, L., Simmen, F.A., Ronis, M.J., Badger, T.M. 2007. Chronic alcohol consumption induces TRB3 and disrupts insulin signaling through increased ER stress [abstract]. The Toxicologist. 96(1):328. Program No. 1585.

Interpretive Summary: Alcohol is a significant component of the total caloric intake of a significant percentage of Americans. The vast majority of alcohol drinkers consume alcohol in moderate amounts, while a minority of people consumes alcohol to excess. Alcohol has biphasic health effects, with low daily intake having several documented health benefits and higher intake having adverse effects. Since alcohol accounts for a significant percentage of total calories and has significant biological affects that alter health outcomes, we are interested in defining the effects of low and high does alcohol on health. One important aspect of alcohol actions related to diabetes, since alcohol-induced diabetes is common among alcoholics. High levels of alcohol impair insulin actions. However, alcohol at lower doses also has effects on insulin actions, and this study is one of several that we have conducted to learn how alcohol affects insulin action and how it might be important in type 2 diabetes and obesity. Our results suggest that alcohol is working on insulin regulation of cell function by altering the production of a protein, TRB3, that appears to be regulated by other factors that stress the cell. Future studies will explore these effects to learn the mechanisms and determine how this information can be used to prevent insulin resistance, type 2 diabetes, and other conditions related to obesity and overweight.

Technical Abstract: Prospective cohort studies have shown that chronic and excessive alcohol consumption is an important and modifiable risk factor for type 2 diabetes. Alcohol consumption alters insulin signaling, but the molecular mechanisms underlying this effect are not well understood. We previously reported that chronic and excessive alcohol intake disrupts insulin signaling via alcohol-induced TRB3 (a negative effector of Akt) in rats. In this report, we provide evidence that alcohol-induced TRB3 effects are associated with increased ER stress. ER stress in FGC4 cells was blocked by 4-phenyl butyric acid and taurine-ursodeoxycholic acid (p<0.05), and this was associated with a lower alcohol-induced increase in TRB3 (p<0.05). In vivo treatment with diallyl sulfide abolished hepatic ER stress (p<0.05), blocked alcohol's effect on TRB3 (p<0.05), and restored insulin signaling. Alcohol induced CYP2E1, and this was blocked by diallyl sulfide. Our results suggest that enhancement of ER stress is a potential mechanism by which alcohol induces TRB3 and inhibits insulin signaling. CYP2E1 may mediate this alcohol effect. Furthermore, our results may have therapeutic implications for treatment of alcohol-associated diabetes.