Effect of Rosiglitazone Treatment on Nontraditional Markers of Cardiovascular Disease in Patients With Type 2 Diabetes Mellitus

Abstract

Background-Markers of systemic inflammation (eg, C-reactive protein [CRP] and interleukin-6 [IL-6]) have been proposed to be "nontraditional" risk factors for cardiovascular disease in patients with type 2 diabetes mellitus. Matrix metalloproteinase-9 (MMP-9) has been implicated in the pathogenesis of atherosclerotic plaque rupture, which raises the possibility of the use of MMP-9 levels as a marker for future myocardial infarction or unstable angina. In vitro and animal studies suggest that thiazolidinediones can reduce the expression of these markers. The purpose of this analysis was to determine whether rosiglitazone alters serum concentrations of CRP, IL-6, MMP-9, and white blood cell count (WBC) and to examine the relationship of these effects with demographic and disease variables. Methods and Results-CRP, IL-6, MMP-9, and WBC were analyzed from stored frozen serum samples obtained from patients with type 2 diabetes who completed a 26-week randomized, double-blind, placebo-controlled study. After 26 weeks of rosiglitazone treatment, the percentage reductions in mean CRP, MMP-9, and WBC levels were statistically significant compared with baseline and placebo (PϽ0.01). The percentage reduction in mean IL-6 was small and similar in the rosiglitazone and placebo groups. The change in each inflammatory marker from baseline to week 26 was significantly correlated (PϽ0.05) with each of the other markers, as well as with the homeostasis model assessment estimate of insulin resistance. Conclusions-Rosiglitazone reduces serum levels of MMP-9 and the proinflammatory marker CRP in patients with type 2 diabetes, which indicates potentially beneficial effects on overall cardiovascular risk.

PPARα agonists inhibit nitric oxide production by enhancing iNOS degradation in LPS‐treated macrophages

“…Rosiglitazone has also been reported to decrease plasma concentrations of C-reactive protein and matrix metalloproteinase-9 (Haffner et al, 2002), and inhibit the development of atherosclerosis in low-density lipoprotein receptor-deficient mice (Li et al, 2000). However, although there are a large number of studies reporting anti-inflammatory actions of PPAR ligands, some observations suggest that PPAR agonists may also have pro- Figure 5 Dose-dependent effects of PPARa agonists on iNOS protein expression in J774 macrophages.…”

Rosiglitazone reduces urinary albumin excretion in type II diabetes

“…The activation of PPARg by thiazolidinediones has been shown to have a range of beneficial vascular effects, including vasorelaxation via blockade of K + channels 7 and reduction of voltage-gated Ca 2+ current, 8 inhibition of the proliferation and migration of vascular smooth muscle cells, 9,10 inhibition of angiogenesis, 11 and improvement in markers of inflammation and fibrinolysis. [12][13][14] These observations indicate a potential for thiazolidinediones to modify risk of vascular complications in diabetes.…”

Regulation of adipocytokines and insulin resistance

“…Thus, 26 weeks of rosiglitazone treatment does not affect IL-6 serum concentrations in one study (Table 1) [45]. β-adrenergic activation stimulates IL-6 mRNA expression in 3T3-L1 adipocytes and this effect is mediated via a classic G S -protein-coupled pathway (Table 1) [46].…”