Author
RONIS, MARTIN - ACNC/UAMS | |
HE, LING - ACNC/UAMS | |
BADGER, THOMAS - ACNC/UAMS |
Submitted to: Research Society on Alcoholism
Publication Type: Abstract Only Publication Acceptance Date: 2/14/2007 Publication Date: 6/15/2007 Citation: Ronis, M.J., He, L., Badger, T.M. 2007. Chronic alcohol consumption has biphasic effects on hepatic insulin signaling dependent on dose [abstract]. Alcoholism, Clinical & Experimental Research. 31(6):293A. Program No. 179. Interpretive Summary: Daily consumption of 1-2 average alcohol beverages is associated with decreased death rates from most diseases, including diabetes. However, the mechanism by which this occurs is unknown. We have found that high dose alcohol impairs insulin actions and eventually leads to type 2 diabetes. We therefore hypothesized that low dose alcohol might be acting on the same or similar insulin pathways. In this study we found that low levels of alcohol in the diet of rats increased the insulin sensitivity in the liver, and this may in part explain the biphasic effects of alcohol-consumption on diabetes risk and identify a new potential molecular target for the health beneficial effects of low level alcohol consumption. Technical Abstract: Epidemiological studies have shown paradoxical biphasic effects of alcohol on health. Moderate drinkers have lower overall mortality than teetotalers or than heavy drinkers. There are protective effects of low levels of alcohol consumption (less than one drink day) on diabetes risk and other chronic diseases such as cardiovascular disease. In contrast, chronic heavy alcohol use is an important risk factor for development of type 2 diabetes in alcoholics. Alcohol consumption appears to alter insulin signaling in several tissues including liver and fat, but the molecular mechanisms underlying these effects are not well understood. Here we provide evidence that low dose alcohol intake in the rat (4 g/kg/d, resulting in little or no detectible blood alcohol concentration) enhances insulin signaling in the liver by suppressing p55' (an inhibitory regulatory subunit of phosphatidylinositol triphosphate kinase (PI3 kinase) a downstream signaling molecule linked to the insulin receptor through insulin receptor substrate-1 (IRS-1) 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 signaling proteins, such as Akt (protein kinase B), GSK3' and the transcription factor nSREBP-1. We previously reported that chronic and excessive alcohol intake (13 g/kg/d which produces an average blood alcohol level of 200-300 mg/dl, 2-3-times the legal limit) disrupts liver insulin signaling by alcohol-induced TRB3 (a negative protein regulator of Akt) in rats. We now provide evidence that the TRB3 effects are associated with increased endoplasmic reticulum stress which is often linked to impaired protein folding and to increased expression of the ER stress-stimulated protein CHOP-10 (p< 0.01). Blockade of ER stress and CHOP expression by 4-phenyl butyric acid and taurine-ursodeoxycholic acid in the FGC-4 rat liver cell line (p<0.05) was associated with a lower alcohol-induced increase in TRB3 (p<0.05). Thus, alcohol exerts biphasic actions on insulin signaling in the liver, such that low doses activate insulin signaling pathways to increase nSREBP-1 while ER stress evoked by high doses of ethanol suppress insulin signaling to decrease SREBP-1. These data may in part explain the biphasic effects of alcohol-consumption on diabetes risk and identify a new potential molecular target for the health beneficial effects of low level alcohol consumption. |