INSULIN SIGNALING IN HEART INVOLVES INSULIN-RECEPTOR SUBSTRATE-1 AND SUBSTRATE-2, ACTIVATION OF PHOSPHATIDYLINOSITOL 3-KINASE AND THE JAK 2-GROWTH RELATED PATHWAY

Objective: Hyperinsulinemia is a common feature of obesity and hyperte nsion and may be associated with abnormal metabolism and growth of hea rt muscle and vascular wall. Most of the known actions of insulin were characterised in muscle, adipose tissue and liver. In this study we i nvestigate the initial steps of insulin signalling in rat heart. Metho ds: After insulin infusion in the cava vein of male Wistar rats, the i nsulin receptor, insulin receptor substrates-l and -2, phosphatidylino sitol 3-kinase activity and Janus kinase (JAK) 2 engagement were studi ed by immunoprecipitation and immunoblot of heart extracts. Results: A n insulin load induces rapid autophosphorylation of the insulin recept or which is followed by the phosphorylation of insulin receptor substr ates-l and -2. The phosphorylation of these early intracellular substr ates leads to the association of the p85 subunit of phosphatidylinosit ol 3-kinase and subsequent activation of its catalytic p110 subunit. B esides activation of the lipid metabolising enzyme phosphatidylinosito l 3-kinase, the phosphorylation of insulin receptor substrates-l and - 2 engages the intracellular kinase JAK 2 and induces JAK 2-STAT 1 comp lex formation. Conclusion: We demonstrate that the early steps of insu lin signalling in heart include the phosphorylation-activation of the insulin receptor, engagement of insulin receptor substrates-l and -2 w ith the consequent activation of phosphatidylinositol 3-kinase and the involvement of the recently discovered growth related pathway-JAK 2-S TAT 1. (C) 1998 Elsevier Science B.V. All rights reserved.