Crosstalk between insulin and angiotensin II signalling systems

F. Folli, M. J.A. Saad, L. Velloso, H. Hansen, O. Carandente, E. P. Feener, C. R. Kahn

Research output: Contribution to journalArticlepeer-review

129 Scopus citations


Insulin resistance and hypertension commonly occur together. Pharmacological inhibition of the renin-angiotensin system has been found to reduce not only hypertension, but also insulin resistance. This raises the possibility that the renin-angiotensin system may interact with insulin signalling. We have investigated the relationship between insulin and angiotensin II (AII) intracellular signalling in vivo using an intact rat heart model, and in vitro using rat aorta smooth muscle cells (RASMC). Results generated in the in vitro studies indicate that, like insulin, AII stimulates tyrosine phosphorylation of the insulin receptor substrates IRS-1 and IRS-2. This leads to binding of IRS-1 and IRS-2 to PI3-kinase. However in contrast to the effect of insulin, IRS-1- and IRS-2-associated PI3-kinase activity is inhibited by AII in a dose-dependent manner. Moreover, AII inhibits insulin-stimulated IRS-1/IRS-2-associated PI3-kinase activity. The in vivo effects of AII are mediated via the AT1 receptor. The results of the in vitro studies indicate that AII inhibits insulin-stimulated, IRS-1-associated PI3-kinase activity by interfering with the docking of IRS-1 with the p85 regulatory subunit of PI3-kinase. It appears that AII achieves this effect by stimulating serine phosphorylation of the insulin receptor β-subunit IRS-1, and the p85 regulatory subunit of PI3-kinase. These actions result in the inhibition of normal interactions between the insulin signalling pathway components. Thus, we believe that AII negatively modulates insulin signalling by stimulating multiple serine phosphorylation events in the early components of the insulin signalling cascade. Overactivity of the renin-angiotensin system is likely to impair insulin signalling and contribute to insulin resistance observed in essential hypertension.

Original languageEnglish (US)
Pages (from-to)133-139
Number of pages7
JournalExperimental and Clinical Endocrinology and Diabetes
Issue number2
StatePublished - 1999


  • Angiontensin II
  • IRS-1
  • IRS-2
  • Insulin
  • PI3-kinase
  • Serine phosphorylation

ASJC Scopus subject areas

  • Internal Medicine
  • Endocrinology, Diabetes and Metabolism
  • Endocrinology


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