This project is aimed at identifying important phosphatases that dephosphorylate the activated form of the insulin receptor, thereby terminating the early steps in insulin action. By intervening at the level of these phosphatases one could approach the problem of insulin resistance in maturity onset diabetic states. These studies have required the preparation of several new reagents and optimization of cellular systems. Modern techniques in peptide/protein chemistry, receptor biochemistry and mammalian cell culture were used successfully to study the dynamics of insulin receptor phosphorylation/dephosphorylation. Several novel peptides were synthesized and tested for their ability to modulate insulin receptor activity. Among them two sets of tyrosine-modified peptides appeared to specifically regulate insulin receptor kinase and tyrosine phosphatase activities. These studies provide new directions for the research in both the identification and inhibition of insulin receptor phosphatase, as well as the study of other aspects of the insulin signal transduction pathway. Our long term goal is the development of safe and effective therapeutic interventions for the treatment of older patients with diabetes.
