Submitted to: Society of Toxicology
Publication Type: Abstract Only
Publication Acceptance Date: 11/15/2005
Publication Date: 3/15/2006
Citation: Badger, T.M., He, L., Simmen, F.A., Ronis, M.J. 2006. Chronic feeding alcohol-containing diets via total enteral nutrition induces alcohol dehydrogenase (ADH) and insulin resistance [abstract]. The Toxicologist. 90(1):491.
Interpretive Summary: Alcohol represents a significant part of the total caloric intake of many Americans. Higher levels of alcohol intake can result in insulin resistance and type 2 diabetes. We have studied the effects of alcohol-containing diets on insulin-regulated metabolism in rats and found that alcohol prevents insulin from acting normally, and this could be the reason for development of insulin resistance in humans. Furthermore, we identified the exact location in the metabolic pathways that alcohol works. Future studies will determine the effects of various dietary factors on protecting against these effects.
Technical Abstract: Induction of Class 1 ADH occurs in rats fed alcohol chronically, and we have reported that C/EBPs and SREBP-1 are important signaling factors in this process. Chronic alcohol intake in humans can result in alcohol-induced diabetes. We have studied insulin signaling pathways in adult male Sprague-Dawley rats (300 g) fed alcohol-containing diets for more than 25 days (n = 6/group). A single intragastric cannula was surgically inserted into each rat, and they were allowed to recover for 10 days. Rats were fed by total enteral nutrition (TEN) using published diets formulated to provide the nutrients necessary for normal growth and development of the male Sprague-Dawley rat. Ethanol was substituted for carbohydrate to keep the control and ethanol diets isocaloric and ethanol was infused at 10-12 g/kg/d, which resulted in pulsatile blood ethanol concentrations (BECs) typical of intragastrically infused rats (between 0 and 500 mg/dl). All rats gained weight and appeared healthy and active. We found chronic alcohol-induced hepatic ADH (mRNA, protein and activity, P<0.05) and decreased (P<0.05) expression of hepatic SREBP-1, but serum insulin did not differ between groups. Furthermore, phosphorylated Akt-Thr308 was decreased (P<0.05) in hepatic whole cell lysates of ethanol-fed rats. Studies also demonstrated that ethanol-treated rats had reduced (P<0.05) membrane associated Akt and increased (P<0.05) cytosolic Akt. These results suggest that chronic ethanol feeding to rats impairs insulin signaling and results in insulin resistance, perhaps by preventing translocation of Akt to the membrane and subsequent phosphorylation.