Insulin signalling in heart involves insulin receptor substrates-1 and -2, activation of phosphatidylinositol 3-kinase and the JAK 2-growth related pathway.
OBJECTIVE
Hyperinsulinemia is a common feature of obesity and hypertension and may be associated with abnormal metabolism and growth of heart muscle and vascular wall. Most of the known actions of insulin were characterised in muscle, adipose tissue and liver. In this study we investigate the initial steps of insulin signalling in rat heart.


METHODS
After insulin infusion in the cava vein of male Wistar rats, the insulin receptor, insulin receptor substrates-1 and -2, phosphatidylinositol 3-kinase activity and Janus kinase (JAK) 2 engagement were studied by immunoprecipitation and immunoblot of heart extracts.


RESULTS
An insulin load induces rapid autophosphorylation of the insulin receptor which is followed by the phosphorylation of insulin receptor substrates-1 and -2. The phosphorylation of these early intracellular substrates leads to the association of the p85 subunit of phosphatidylinositol 3-kinase and subsequent activation of its catalytic p110 subunit. Besides activation of the lipid metabolising enzyme phosphatidylinositol 3-kinase, the phosphorylation of insulin receptor substrates-1 and -2 engages the intracellular kinase JAK 2 and induces JAK 2-STAT 1 complex formation.


CONCLUSIONS
We demonstrate that the early steps of insulin signalling in heart include the phosphorylation-activation of the insulin receptor, engagement of insulin receptor substrates-1 and -2 with the consequent activation of phosphatidylinositol 3-kinase and the involvement of the recently discovered growth related pathway--JAK 2-STAT 1.
Velloso
L A
LA
Department of Internal Medicine, University of Campinas-UNICAMP, Brazil.
Carvalho
C R
CR
Rojas
F A
FA
Folli
F
F
Saad
M J
MJ
D000818:Animals; D004268:DNA-Binding Proteins / Q000032:analysis / Q000378:metabolism; D004789:Enzyme Activation; D015151:Immunoblotting; D007328:Insulin / Q000378:metabolism* / Q000494:pharmacology; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; D053614:Janus Kinase 2; D008297:Male; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000032:analysis / Q000378:metabolism*; D010750:Phosphoproteins / Q000032:analysis / Q000378:metabolism; D010766:Phosphorylation; D011233:Precipitin Tests; D011505:Protein-Tyrosine Kinases / Q000032:analysis / Q000378:metabolism*; D011518:Proto-Oncogene Proteins; D051381:Rats; D017208:Rats, Wistar; D011972:Receptor, Insulin / Q000032:analysis / Q000378:metabolism*; D050794:STAT1 Transcription Factor; D015398:Signal Transduction; D015534:Trans-Activators / Q000032:analysis / Q000378:metabolism
D004268:DNA-Binding Proteins; D007328:Insulin; D055504:Insulin Receptor Substrate Proteins; D047908:Intracellular Signaling Peptides and Proteins; C526296:Irs1 protein, rat; C526299:Irs2 protein, rat; D010750:Phosphoproteins; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; D015534:Trans-Activators; D019869:Phosphatidylinositol 3-Kinases; D011505:Protein-Tyrosine Kinases; D011972:Receptor, Insulin; C507927:Jak2 protein, rat; D053614:Janus Kinase 2