Crosstalk between insulin and angiotensin II signalling systems

Insulin resistance and hypertension commonly occur together. Pharmacologica l inhibition of the renin-angiotensin system has been found to reduce not o nly 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 (A II) intracellular signalling ill vivo using an intact rat heart model, and hz vitro using rat aorta smooth muscle cells (RASMC). Results generated in the in vivo studies indicate that, like insulin, AII stimulates tyrosine ph osphorylation of the insulin receptor substrates IRS-1 and IRS-3. This lead s to binding of IRS-I and IRS-2 to PI3-kinase. However, in contrast to the effect of insulin, IRS-1- and IRS-2-associated PI3-kinase activity is inhib ited by AII in a dose-dependent manner. Moreover, AII inhibits insulin-stim ulated IRS-1/IRS-2-associated PI3-kinase activity. The in vivo effects of A II are mediated via the AT(1) receptor. The results of the in vitro studies indicate that AII inhibits insulin-stim ulated, IRS-l-associated PI3-kinase activity by interfering with the dockin g of IRS-I with the p85 regulatory subunit of PI3-kinase. It appears that A II achieves this effect by stimulating serine phosphorylation of the insuli n receptor beta-subunit IRS-I, 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 stimul ating multiple serine phosphorylation events in the early components of the insulin signalling cascade. Overactivity of the renin-angiotensin system i s likely to impair insulin signalling and contribute to insulin resistance observed in essential hypertension.