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Title: Dose dependent effects of alcohol on insulin signaling: Partial explanation for biphasic alcohol impact on human health

item HE, LING

Submitted to: Molecular Endocrinology
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 7/3/2007
Publication Date: 10/1/2007
Citation: He, L., Serrero, G., Simmen, F.A., Ronis, M.J., Badger, T.M. 2007. Dose dependent effects of alcohol on insulin signaling: Partial explanation for biphasic alcohol impact on human health. Molecular Endocrinology. 21(10):2541-2550.

Interpretive Summary: Alcohol is consumed by millions of Americans, and alcohol accounts for both a significant percentage of total caloric intake and also has important health effects that have not been well explored. It is well known that moderate alcohol consumption of between one drink per week and 14 drinks per week is associated with generally better health outcomes, including lower risk of diseases such as hypertension and insulin sensitivity. On the other hand, high levels of alcohol intake have adverse health effects. In this study, we fed rats diets containing high or low levels of alcohol and found what we think is an important mechanism by which alcohol improves insulin sensitivity. Low-dose alcohol will essentially increase the way insulin can signal the cell to react; whereas, high-dose alcohol impairs this communication.

Technical Abstract: Routine consumption of alcohol at low doses is associated with decreased risk of acquiring type 2 diabetes; whereas, chronic and excessive alcohol consumption increases the risk. Although there is good epidemiologic evidence for these biphasic effects, careful validation of these effects on insulin signaling has not been reported, nor have biological mechanisms underlying these biphasic effects been proposed. In this study, we provide evidence in rats that low-dose alcohol intake (4 g/kg/d) enhances hepatic insulin signaling by suppressing p55' (a PI3K regulatory subunit isofrom) at the post-transcriptional level, leading to the increased association of the PI3K catalytic subunit (p110) with IRS1 (P<0.05) and subsequent activation of downstream effectors, such as Akt, GSK3' and nSREBP-1. These results, combined with our previous data (which are confirmed in the present study) demonstrating that ethanol intake at high doses (13 g/kg/d) disrupts hepatic insulin signaling by inducing TRB3 which prevented activation of downstream effectors (such as Akt, GSK3' and nSREBP-1) provide clear mechanistic validation of the biphasic effects of ethanol on insulin signaling. We also report that ethanol induction of TRB3 can be partially blocked (P<0.01) by compounds (4-phenyl butyric acid and taurine-ursodeoxycholic acid) known to reduce endoplasmic reticulum (ER) stress. Thus, alcohol exerts biphasic actions on hepatic insulin signaling, such that low doses activate insulin signaling pathways associated with reduced p55' to increase nSREBP-1, while high doses of ethanol elevate TRB3 and suppress insulin signaling to decrease SREBP-1.