Antidiabetic mechanisms of angiotensin-converting enzyme inhibitors and angiotensin II receptor antagonists: beyond the renin-angiotensin system.

Several lines of evidence suggest that angiotensin-converting enzyme (ACE) inhibitors and some angiotensin II receptor blockers (ARBs) may improve insulin sensitivity and decrease the risk for type 2 diabetes. It is widely assumed that the potential antidiabetic properties of these agents are largely mediated by their ability to interfere with the adverse metabolic effects of angiotensin II. However, recent studies suggest that ACE inhibitors might improve glucose metabolism primarily through effects on kinin-nitric oxide pathways. In addition, one ARB in particular, telmisartan, has been found to effectively activate the peroxisome proliferator activated receptor gamma (PPARgamma), a well-known target for insulin-sensitizing, antidiabetic drugs. Thus, the beneficial metabolic effects of some ACE inhibitors and ARBs may go well beyond their effects on the renin-angiotensin system. Moreover, the identification of telmisartan as a unique angiotensin II receptor antagonist with selective PPARgamma modulating ability suggests new opportunities for developing third-generation ARBs and PPARgamma activators, with enhanced potential for treating hypertension, diabetes and the metabolic syndrome.