Kinase-dependent pathways and the development of insulin resistance in hepatocytes.

Hepatic insulin resistance is considered to be a dominant component in the pathogenesis of fasting hyperglycemia in Type 2 diabetes. The role of nutrients, free fatty acids and secretory inflammatory factors released by visceral fat in the pathogenesis of liver insulin resistance requires clarification, but a number of signaling pathways and serine kinases have been implicated. These include the discovery of c-Jun N-terminal kinase, I κβ kinase, protein kinase C θ, δ and ε, and ribosomal protein S6 kinase 1 as critical regulators of insulin action and steatosis in liver. In this article, the causes and mechanisms involved in the development of hepatic insulin resistance, and the signaling pathways and kinases involved, will be discussed. Elucidation of the molecular mechanisms underlying regulation and specificity may prompt novel approaches to the pharmacological modulation of protein kinase activities involved in hepatic insulin resistance. This review will detail recent discoveries and highlight emerging kinase targets that hold potential to reduce hepatic insulin resistance and normalize blood glucose.