Hepatocytes: critical for glucose homeostasis

Abstract

Maintaining blood glucose levels within a narrow range is a critical physiological function requiring multiple metabolic pathways and involving several cell types, including a prominent role for hepatocytes. Under hormonal control, hepatocytes can respond to either feeding or fasting conditions by storing or producing glucose as necessary. In the fasting state, the effects of glucagon avoid hypoglycemia by stimulating gluconeogenesis and glycogenolysis and initiating hepatic glucose release. Postprandially, insulin prevents hyperglycemia, in part, by suppressing hepatic gluconeogenesis and glycogenolysis and facilitating hepatic glycogen synthesis. Both transcriptional regulation of rate limiting enzymes and modulation of enzyme activity through phosphorylation and allosteric regulation are involved. Type 2 diabetes mellitus is the most common serious metabolic condition in the world, and results from a subnormal response of tissues to insulin (insulin resistance) and a failure of the insulin-secreting β cells to compensate. In type 2 diabetes, glucose is overproduced by the hepatocyte and is ineffectively metabolized by other organs. Impairments in the insulin signal transduction pathway appear to be critical lesions contributing to insulin resistance and type 2 diabetes. Cell facts • The hepatocyte plays a critical role in glucose metabolism and can store or produce glucose depending on the requirement. • Insulin-dependent activation of the insulin receptor tyrosine kinase initiates a signal transduction pathway resulting in increased glycogen synthesis while suppressing gluconeogenesis and glycogenolysis in hepatocytes. The effects of insulin are both acute (post-translational modification of key enzymes) and chronic (gene expression). • There is evidence for both direct and indirect effects of insulin on the liver to suppress gluconeogenesis. • The counterregulatory hormone glucagon activates protein kinase A (PKA), raising cyclic AMP concentrations, inducing gluconeogenesis enzymes, activating glycogenolysis, and resulting in net glucose release into the circulation. • Peroxisome proliferative activated receptor-γ coactivator 1 (PGC-1α) is induced by glucagon and promotes increased transcription of the gluconeogenic enzymes phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase (G6Pase) as a key mechanism for controlling glucose production in hepatocytes. • The insulin resistance of type 2 diabetes leads to inappropriate hepatic glucose production and decreased hepatic glucose utilization. Obesity is a major correlate of insulin resistance. Several molecular mechanisms that link obesity and hepatic insulin resistance have been proposed.