Location: Arkansas Children's Nutrition CenterTitle: Low dose ethanol consumption improves insulin sensitivity in rats) Author
Submitted to: Society of Toxicology
Publication Type: Abstract Only
Publication Acceptance Date: 12/5/2008
Publication Date: 3/1/2009
Publication URL: https://www.toxicology.org/ai/pub/Toxicologist_archive.asp
Citation: He, L., Ferguson, M.E., Blackburn, M., Badeaux, J., Shankar, K., Ronis, M.J., Badger, T.M. 2009. Low dose ethanol consumption improves insulin sensitivity in rats [abstract]. The Toxicologist. 108(1):281. Abstract No. 1363. Interpretive Summary: Data from clinical epidemiological studies of alcohol intake and risks of type 2 diabetes/cardiovascular disease suggest that there is a u-shaped relationship, with decreased risk at low levels of intake associated with social drinking (1-2 drinks/d) compared to increased risk at intakes associated with alcoholism. This is part of the so-called French Paradox (lower mortality and heart disease in the French despite high saturated fat intake). The current study was designed to determine if low-dose alcohol exposure results in increased whole body insulin sensitivity in a rat model in which we have previously demonstrated increased insulin signaling in the liver through the Akt-SREBP-ADH pathway to increase ethanol breakdown to acetaldehyde. Rats were exposed to alcohol diets (4 g/kg/d) at the same energy intake as controls using tube feeding into the stomach (enteral feeding). A glucose challenge (tolerance test) was performed and demonstrated a reduced insulin response in the low-dose ethanol group, indicating greater whole body insulin sensitivity. One potential explanation might be suppression of glucose production by the liver after low-dose alcohol. The rate limiting step in this process is an enzyme called PEPCK which is down-regulated by insulin via the Akt pathway. We demonstrated that in these same low-dose-alcohol-fed rats, liver PEPCK expression was significantly reduced and Akt-SREBP/FOXO signaling which is known to down-regulate PEPCK was increased. These data suggest that levels of alcohol resulting from social drinking may increase whole body insulin sensitivity consistent with epidemiological data as a result of enhanced insulin signaling in the liver to reduce hepatic glucose output.
Technical Abstract: While chronic consumption of high doses of ethanol is well known to have adverse health consequences, intake of low doses have been reported to improve several markers of health outcomes. Published results from our laboratory using total enteral nutrition (TEN) in rats, in which ethanol-containing diets are infused directly into the stomach, have clearly demonstrated that chronic ethanol intake results in disruption of hepatic insulin signaling. Based upon previous literature reports we posited that using the same TEN model, but with chronic low EtOH doses, insulin sensitivity would increase. Young adult male Spraque-Dawley rats (age 60 days) were surgically fitted with an intragastric cannula and fed a high-fat diet plus low-dose EtOH (4 g/kg/d). After 4 weeks of this diet, rats had gained weight equal to control rats that were fed the same isocaloric diet (except EtOH calories were replaced with carbohydrate calories). Rats were fasted over night and a standard oral glucose tolerance test was administered. Rats fed low-dose EtOH had a greater (P<0.05) whole body insulin response than control rats fed a diet with no ethanol. Moreover, hepatic Akt-GSK3'-SREBP-1 signaling was enhanced (P< 0.05) and expression of the gluconeogenic enzyme PEPCK was suppressed in low-dose EtOH vs. control animals (P<0.05). We conclude that chronic intake of a diet containing low-dose EtOH can improve insulin sensitivity.