Background-Inflammation has been suggested as a risk factor for the development of atherosclerosis. Recently, some components of the insulin resistance syndrome (IRS) have been related to inflammatory markers. We hypothesized that insulin insensitivity, as directly measured, may be associated with inflammation in nondiabetic subjects. Methods and Results-We studied the relation of C-reactive protein (CRP), fibrinogen, and white cell count to components of IRS in the nondiabetic population of the Insulin Resistance Atherosclerosis Study (IRAS) (nϭ1008; age, 40 to 69 years; 33% with impaired glucose tolerance), a multicenter, population-based study. None of the subjects had clinical coronary artery disease. Insulin sensitivity (S I ) was measured by a frequently sampled intravenous glucose tolerance test, and CRP was measured by a highly sensitive competitive immunoassay. All 3 inflammatory markers were correlated with several components of the IRS. Strong associations were found between CRP and measures of body fat (body mass index, waist circumference), S I , and fasting insulin and proinsulin (all correlation coefficients Ͼ0.3, PϽ0.0001). The associations were consistent among the 3 ethnic groups of the IRAS. There was a linear increase in CRP levels with an increase in the number of metabolic disorders. Body mass index, systolic blood pressure, and S I were related to CRP levels in a multivariate linear regression model. Conclusions-We suggest that chronic subclinical inflammation is part of IRS. CRP, a predictor of cardiovascular events in previous reports, was independently related to S I . These findings suggest potential benefits of anti-inflammatory or insulin-sensitizing treatment strategies in healthy individuals with features of IRS. (Circulation. 2000;102:42-47.)

The peroxisome proliferator-activated receptor-gamma (PPARgamma) is a transcription factor that has a pivotal role in adipocyte differentiation and expression of adipocyte-specific genes. The PPARgamma1 and gamma2 isoforms result from alternative splicing and have ligand-dependent and -independent activation domains. PPARgamma2 has an additional 28 amino acids at its amino terminus that renders its ligand-independent activation domain 5-10-fold more effective than that of PPARgamma1. Insulin stimulates the ligand-independent activation of PPARgamma1 and gamma2 (ref. 5), however, obesity and nutritional factors only influence the expression of PPARgamma2 in human adipocytes. Here, we report that a relatively common Pro12Ala substitution in PPARgamma2 is associated with lower body mass index (BMI; P=0.027; 0.015) and improved insulin sensitivity among middle-aged and elderly Finns. A significant odds ratio (4.35, P=0.028) for the association of the Pro/Pro genotype with type 2 diabetes was observed among Japanese Americans. The PPARgamma2 Ala allele showed decreased binding affinity to the cognate promoter element and reduced ability to transactivate responsive promoters. These findings suggest that the PPARgamma2 Pro12Ala variant may contribute to the observed variability in BMI and insulin sensitivity in the general population.

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Objective: To determine the association between features of the insulin resistance syndrome and Alzheimer's disease. Design: Cross sectional population based study.

Microalbuminuria is associated with excess cardiovascular mortality in both diabetic and nondiabetic subjects. Patients with NIDDM and microalbuminuria are more insulin resistant than those without microalbuminuria. However, the relationship between insulin resistance and microalbuminuria in patients with NIDDM could be due to hyperglycemia, which can cause both insulin resistance and an increase in albumin excretion rate. Little is known about microalbuminuria and insulin resistance in nondiabetic subjects. Therefore, we examined, cross-sectionally, the relationship of insulin sensitivity (S(I) x 10(-4) min x microU(-1) x ml(-1)), estimated by a frequently sampled intravenous glucose tolerance test and the minimal model and fasting plasma insulin concentration, to microalbuminuria (albumin-to-creatinine ratio > or = 2 mg/mmol) in 982 nondiabetic subjects aged 40-69 years. Altogether, 15% of the subjects had microalbuminuria, and 32% had hypertension. Subjects with microalbuminuria had a lower degree of insulin sensitivity (means +/- SE, 1.70 +/- 0.11 vs. 2.25 +/- 0.07, P = 0.003) and higher fasting insulin concentrations (17.4 +/- 1.1 vs. 15.7 +/- 0.5 mU/l, P = 0.059) compared with subjects without microalbuminuria. In logistic regression analysis, an increasing degree of insulin sensitivity was related to a decreasing prevalence of microalbuminuria (odds ratio = 0.86, 95% CI: 0.79-0.94, P < 0.001). Although this relationship attenuated after adjustment for age, sex, ethnicity, hypertension, fasting glucose, and BMI, it still remained significant. The association between insulin sensitivity and microalbuminuria was shown not to be different between normotensive and hypertensive subjects. Our results suggest a relationship between insulin resistance and microalbuminuria in nondiabetic subjects that is partially dependent on blood pressure, glucose levels, and obesity.