Intracellular Mediators of Insulin Action

Abstract

Controversy about the intracellular mechanism of insulin action has focused for a decade on identifying an intracellular mediator of the actions of the hormone. During this time, extensive efforts have been made to specify a cellular component that is altered in response to insulin and, in turn, directly affects enzyme activities and other cellular functions. A wide range of possibilities has been considered for this role, including cAMP, Ca²⁺, H₂0₂, membrane potential, and cellular pH. Interest in each possibility has been generated by data correlating changes in these parameters with changes in one or more insulin-sensitive enzyme or process. But in each case, opposing evidence has subsequently dissociated changes in the levels of the regulatory components from other insulin-sensitive functions, making it impossible to consider any of these a primary, central element of the insulin effector system. The failure of all candidates thus far proposed to satisfy all the criteria of a hormone’s second messenger has led to the development of an experimental approach designed to isolate from cells components that possess the characteristics of an insulin mediator. This approach embodies two criteria of an insulin mediator, the ability to directly regulate insulin-sensitive enzymes in vitro, and a change in activity in response to insulin treatment of the cell source of the mediator.