Mechanisms of Ramipril Reduction in the Onset of Type 2 Diabetes

Several studies have demonstrated that therapeutic agents used to reduce glucose levels and/or weight can delay the onset of type 2 diabetes. Intriguingly, angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARB) also result in reduction in the onset of type 2 DM. The most striking effect was found with Ramipril in the HOPE study. The onset of new type 2 DM was reduced by 34% (p\<0.001) as compared to placebo. Furthermore, the results of the DREAM trial demonstrate that Ramipril at a dose of 15 mg can significantly reverse impaired glucose tolerance. However, the mechanisms underlying Ramipril effects to delay type 2 diabetes are not known. The proposal will be focused on determining the integrated in-vivo mechanisms responsible for Ramipril's effects on delaying type 2 DM and restoring normal glycemia in patients with impaired glucose tolerance. The specific aims of the project are: * to determine the effect of Ramipril on insulin resistance at the level of the liver and peripheral tissues, * to determine the effect of Ramipril on endothelial function, * to determine the effects of Ramipril on insulin secretion, and * to determine the effects of Ramipril on substrate flux, lipolysis and inflammatory cytokines.