|Badger, Thomas - ACNC/UAMS|
|He, Ling - ACNC/UAMS|
|Simmen, Frank - ACNC/UAMS|
|Ronis, Martin - ACNC/UAMS|
Submitted to: Alcoholism: Clinical and Experimental
Publication Type: Abstract Only
Publication Acceptance Date: May 26, 2006
Publication Date: September 10, 2006
Citation: Badger, T.M., He, L., Simmen, F.A., Ronis, M.J. 2006. Alcohol-induced insulin resistance in liver: Potential roles in regulation of ADH expression; ethanol clearnace and alcohol liver disease [abstract]. Alcoholism: Clinical and Experimental Research. 30(s2):49A. 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 consume 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 effects 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: Using total enteral nutrition (TEN), we demonstrated that low carbohydrate, high alcohol-containing diets (10-12 g/kg/dO produced alcoholic liver disease (ALD) in adult male Sprague-Dawley rats (300 g). Intragastric infusion of this diet generates regular pulses of blood ethanol concentrations (BECs) that fluctuate between 0 and 500 mg/dl. High BECs (>300 mg/dL) are required for hepatic damage in rodents, and the ethanol (EtOH) metabolism that produces pulsatile BECs may be a key factor in development of ALD. Traditionally, EtOH was not considered to induce hepatic Class 1 Alcohol Dehydrogenase (ADH) expression. But, in the TEN model and in a highly differentiated rat hapatoma cell line (FGC-4), we demonstrated that EtOH transcriptionally induces ADH correspondent with reduced levels of C/BEP beta (LIP), increased C/BEP beta (LAP), and reduced mature, nuclear SREBP-1, an insulin-induced transcriptional repressor of the ADH gene. Since chronic EtOH intake in humans can result in EtOH-induced type 2 diabetes, we monitored changes in hepatic insulin signaling. Insulin inhibited ADH gene expression. This was abolished by the P13K inhibitor LY294002 and by siRNA knockdown of SREPB-1. Chronic EtOH intake led to phosphorylation of Akt (PKB) at Thr308, greater physophorylation of Akt at Ser473, and decreased phosphorylation of GSK beta (a downstream effector of Akt). Hepatic membrane-associated Akt content was decreased and cysosolic Akt content increased in rats fed EtOH; TRB3, a negative regulator of Akt, was induced in liver of EtOH-fed rats. In EtOH-treated FGC-4 cells, siRNA knockdown of TRB3 increased membrane-associated Akt and the physphorylation of Akt at Thr308. Thus, disruptive effects of EtOH on insulin signaling occurred via impaired physphorylation of Akt at Thr308. These results suggest that chronic EtOH feeding to rats via TEN impairs insulin signaling and results in insulin resistance by inducing TRB3 (which through binding to the PH domain of Akt prevents plasma membrane association), Akt-Thr308 phosphoylation, and subsequent Akt-mediated signaling EtOH inhibition of insulin signaling reduces nSREBP accumulation and results in disinhibition of Class 1 ADH transcription.