Hepatic insulin resistance

Hepatic insulin resistance describes the selective failure of the liver to suppress gluconeogenesis and glycogenolysis in response to postprandial insulin, while lipogenesis may paradoxically remain insulin-responsive — a dissociation termed selective hepatic insulin resistance. The result is excessive fasting and postprandial hepatic glucose output, driving compensatory hyperinsulinemia that further promotes de novo lipogenesis and hypertriglyceridemia. Primary drivers include intrahepatic lipid accumulation from excess free fatty acid influx, fructose metabolism, and impaired mitochondrial fat oxidation, converging on serine phosphorylation of the insulin receptor substrate (IRS-1/IRS-2). Hepatic insulin resistance is an early and mechanistically central feature of metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes, and epidemiologically associates with elevated cardiometabolic and all-cause mortality risk.