Insulin Resistance, Inflammation and Vascular Remodeling

Beth Israel Deaconess Medical Center, Boston MA

Investigators

Linked publications & trials

Abstract

Obesity and the metabolic syndrome are occuring at epidemic rates in the United States and worldwide, and[unreadable] contribute to the development of coronary heart disease (CHD), the leading cause of death and disabilty in[unreadable] our society. Recent studies demonstrate chronic subacute inflammation is associated with obesity- and dietinduced[unreadable] insulin resistance and may well be involved in the pathogenesis of CHD. Diets rich in calories,[unreadable] animal fats, and sugars have been shown to induce fatty livers, insulin resistance, dyslipidemia, increase[unreadable] activity of the inflammatory NF-KB pathway, and increase levels of inflammatory markers such as C reactive[unreadable] protein (CRP), serum amyloid A (SAA), and fibrinogen in both animals and humans. This pattern has also[unreadable] been associated with increased CHD risk. Our lab has identified anti-inflammatory salicylates as a potential[unreadable] new class of drugs for the treatment of these disorders and the IKKp/NF-KB pathway as the molecular target[unreadable] of this therapy. We hypothesize activation of IKKP/NF-KB signaling pathways contributes to the development[unreadable] of atherosclerosis. Moreover this process can be inhibited or prevented by administration of high dose[unreadable] salicylates which inhibit NF-KB activity. The effect of NF-KB on the vasculature may occur directly, through[unreadable] regulation of adipokines and cytokines that lead to vascular injury, or indirectly through metabolic changes in[unreadable] insulin sensitivity as intervention studies which have improved insulin resistance using metformin or[unreadable] thiazolidendiones have been shown to decrease CHD risk or effect on vascular remodeling in humans.[unreadable] Remodeling of CHD, especially of soft, vulnerable, non-calcified plague, can now be assessed with a[unreadable] minimally invasive technique by multi-detector computed tornographic angiography (MD-CTA) after injection[unreadable] of intravenous contrast material. This modality can also be used to assess visceral and liver fat content. This[unreadable] project will specifically assess inhibition of NF-KB using the salicylate, salsalate (DisalsidTM), to[unreadable] reduce inflammation and insulin resistance and promote vascuar remodeling in 400 patients with CHD and[unreadable] the metabolic syndrome in a double masked placebo controlled trial design. This project will test the[unreadable] hypothesis that aggressive treatment of inflammation and insulin resistance with salsalate can have[unreadable] significant favorable effects on coronary vascular remodeling as assessed by change in non-calcified plaque[unreadable] volume, cardiac endpoints, visceral and liver fat, lipid and circulating markers and mediatiors of inflammation.[unreadable]