Insulin Mediators and Their Control of Covalent Phosphorylation

We have detailed two separate mechanisms for insulin to activate glycogen synthase. In mechanism I, insulin acts without glucose present via a mediator to convert the cyclic AMP-dependent protein kinase to a desensitized holoenzyme, effectively lowering the response of the cell machinery to existing concentrations of cyclic AMP. Mechanism II, originally discovered in rat adipocytes, is seen in the presence of glucose, or of a hexose whose transport is accelerated by insulin. Enhanced phosphorylation of the 6 position is also required, since the hexose-6-phosphate acts informationally to activate the phospho-protein phosphatase to convert glycogen synthase to its dephospho state. Today I should like to discuss recent findings of our laboratory which demonstrate the presence of mechanism II in muscle, namely, mouse diaphragm, pointing out the generality of this mechanism and discuss our recent studies on the identification of insulin mediators which control protein phosphorylation state.