Excessive gluconeogenesis causes the hepatic insulin resistance paradox and its sequelae

Hepatic insulin signaling suppresses gluconeogenesis but promotes de novo lipid synthesis. Paradoxically, hepatic insulin resistance (HIR) enhances both gluconeogenesis and de novo lipid synthesis. Elucidation of the etiology of this paradox, which participates in the pathogenesis of non-alcoholic fatty liver disease (NAFLD), cardiovascular disease, the metabolic syndrome and hepatocellular carcinoma, has not been fully achieved. This article briefly outlines the previously proposed hypotheses on the etiology of the HIR paradox. It then discusses literature consistent with an alternative hypothesis that excessive gluconeogenesis, the direct effect of HIR, is responsible for the aberrant lipogenesis. The mechanisms involved therein are explained, involving de novo synthesis of fructose and uric acid, promotion of glutamine anaplerosis, and induction of glucagon resistance. Thus, gluconeogenesis via lipogenesis promotes hepatic steatosis, a component of NAFLD, and dyslipidemia. Gluconeogenesis-centred mechanisms for the progression of NAFLD from simple steatosis to non-alcoholic steatohepatitis (NASH) and fibrosis are suggested. That NAFLD often precedes and predicts type 2 diabetes is explained by the ability of lipogenesis to cushion against blood glucose dysregulation in the earlier stages of NAFLD. HIR-induced excessive gluconeogenesis is a major cause of the HIR paradox and its sequelae. Such involvement of gluconeogenesis in lipid synthesis rationalizes the fact that several types of antidiabetic drugs ameliorate NAFLD. Thus, dietary, lifestyle and pharmacological targeting of HIR and hepatic gluconeogenesis may be a most viable approach for the prevention and management of the HIR-associated network of diseases. [Display omitted] Polyol pathway; Hexosamine biosynthetic pathway; Reactive oxygen species; Endoplasmic reticulum stress; Reductive stress; Reductive carboxylation.