Crosstalk between insulin and angiotensin II signalling systems

Summary

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 (All) 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 vivo studies indicate that, like insulin, All 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 All in a dose-dependent manner. Moreover, All inhibits insulin-stimulated IRS-l/IRS-2-associated PI3-kinase activity. The in vivo effects of AH are mediated via the AT₁ receptor.

The results of the in vitro studies indicate that All 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 All 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 All 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.

Key words

Insulin - angiontensin II - IRS-1 - IRS-2 - PI3-kinase - serine phosphorylation