Scheme illustrating the interaction between fructose and ethanol ingested simultaneously to elicit metabolic imbalance.

<p>The portal vein delivers the secreted insulin in addition to approximately 80% of the ingested ethanol and most of the fructose and other nutrients to the liver. Fructose and ethanol provide the metabolites that serve as the substrates for <i>de novo</i> lipogenesis. Fructose catabolism requires ATP to form F-1-P, glyceraldehyde, and pyruvate. The subsequent process of reducing these metabolites yields NAD⁺, a necessary coenzyme required in alcohol oxidation by ADH. An uncontrolled NADH/NAD⁺ ratio could affect mitochondrial functions. Both nutrients also induce JNK-1 activation, phosphorylating hepatic IRS-1/2 and rendering it inactive while contributing to hepatic insulin resistance. The last effect promotes hyperinsulinemia and influences the substrate’s deposition into fat, promoting hepatic steatosis, gluconeogenesis, and hyperglycemia. The liver is the major site of insulin clearance and has a first-pass clearance above 75%. <i>Tna-α</i> (a pro-apoptotic mediator) is expressed in such steatosic livers. ADH: alcohol dehydrogenase, IRS-1/2: insulin receptor substrate-1/2, JNK-1: c-jun N-terminal kinase, F-1-P: fructose-1-phosphate.