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.

Data from the UKPDS (U.K. Prospective Diabetes Study) indicate a continuous decline in ␤-cell function in patients with type 2 diabetes. We studied longitudinal changes in ␤-cell function (follow-up of 5.2 years) in subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and type 2 diabetes, using acute insulin response (AIR) and insulin sensitivity index (S i ) from a frequently sampled intravenous glucose tolerance test among African-American, Hispanic, and non-Hispanic white subjects aged 40 -69 years. At baseline, decreasing levels of both S i and AIR (either unadjusted or adjusted for S i ) mirrored deteriorating glucose tolerance status at baseline and at follow-up. A different pattern was found with respect to longitudinal changes; S i declined in each glucose tolerance category, ranging from ؊0.81 ؋10 ؊4 min ؊1 ⅐ U ؊1⅐ ml ؊1 in NGT at baseline and NGT at follow-up (NGT/NGT) to ؊1.06 ؋10 ؊4 in NGT/diabetes, whereas the directional change in AIR principally determined the glucose tolerance status at follow-up. In NGT/NGT S i decreased by 35% and AIR increased by 34%. Results were similar in each of the three ethnic groups. These data shed light on the natural course of ␤-cell function; over 5.2 years, mean insulin sensitivity declined in each glucose tolerance category. The change in AIR, however, principally determined glucose tolerance status at follow-up; NGT was maintained by a compensatory increase in insulin secretion. Failure to increase insulin secretion led to IGT, and a decrease in insulin secretion led to overt diabetes. This data may have important implications for the prevention and treatment of type 2 diabetes. Diabetes 55:1114 -1120, 2006 I mpaired insulin secretion and impaired insulin action (increased insulin resistance) are the two major components contributing to the pathophysiology of type 2 diabetes (1-3); their complex relationship has been mathematically described as a curvilinear relationship (4 -6). Longitudinal studies indicate that compromised ␤-cell function is detectable in pre-diabetic individuals long before the onset of actual type 2 diabetes (1,7). The natural course of ␤-cell function over time, however, is poorly understood, and published data are scarce. A longitudinal study in Pima Indians highlighted the importance of declining ␤-cell function in individuals transitioning from normal glucose tolerance (NGT) to impaired glucose tolerance (IGT) and IGT to diabetes, respectively (3). In the U.K. Prospective Diabetes Study (UKPDS), a continuous decline in ␤-cell function in patients with type 2 diabetes, irrespective of glucose-lowering treatment, was demonstrated (8). No data on the natural course of ␤-cell function is currently available in a large population, across different ethnic groups, and using a direct measure of insulin secretion. Therefore, we studied longitudinal changes in ␤-cell function over 5.2 years by acute insulin response (AIR) relative to insulin sensitivity index (S i ), as assessed from a frequently sampled intravenous gluco...

HAN, THANG S., KEN WILLIAMS, NAVEED SATTAR, KELLY J. HUNT, MICHAEL E.J. LEAN, AND STEVEN M. HAFFNER. Analysis of obesity and hyperinsulinemia in the development of metabolic syndrome: San Antonio Heart Study. Obes Res. 2002;10:923-931. Objective: To use standardized cut-offs of body mass index (BMI), waist circumference, waist-to-hip ratio, and fasting insulin levels to predict the development of metabolic disorders and metabolic syndrome. Research Methods and Procedures:We performed an 8-year follow-up study of 628 non-Hispanic whites and 1340 Mexican Americans, ages 25 to 64 years, from the second cohort of the San Antonio Heart Study. We defined metabolic disorders as dyslipidemia (triglycerides Ն2.26 mM or high-density lipoprotein Ͻ0.91 mM in men and Ͻ1.17 mM in women), hypertension (blood pressure Ն140/Ն90 mm Hg, or receiving antihypertensive medications), and type 2 diabetes (fasting glucose Ն7.0 mM, 2-hour test glucose Ն11.1 mM, or receiving anti-diabetic medications). People with at least two metabolic disorders were defined as having metabolic syndrome. Results: High waist-to-hip ratio and fasting insulin levels were significant predictors of developing metabolic syndrome. High anthropometric indices remained significant predictors of metabolic syndrome after adjusting for fasting insulin. Waist circumference, BMI, and insulin had similar areas under the receiver operating characteristic curves (0.74 to 0.76). Further multivariate analyses combining these indices showed minimal increase in prediction. Of subjects who had a combination of high BMI (Ն30 kg/m 2 ) and high waist circumference (above "Action Level 2"), 32% developed metabolic syndrome, compared with 10% of subjects with both low BMI and low waist circumference. Discussion: These findings support the National Institutes of Health recommendations for reducing the risk of metabolic syndrome. Adjustment for baseline fasting insulin levels had only a small effect on the ability of anthropometric indices to predict the metabolic syndrome.

Background-Several studies have shown that fibrinolytic and coagulation abnormalities as well as low-grade inflammation predict cardiovascular disease and type 2 diabetes. We studied in the Insulin Resistance Atherosclerosis Study the relation of incident diabetes to dynamic changes of plasminogen activator inhibitor-1 (PAI-1) and fibrinogen.