The Insulin Resistance Atherosclerosis Study
Elevated serum levels of acute-phase proteins, indicating chronic subclinical inflammation, have been associated with cardiovascular disease as well as the insulin resistance syndrome. Chronic inflammation may also be a risk factor for developing type 2 diabetes. We studied the concentrations of C-reactive protein (CRP), fibrinogen, and plasminogen activator inhibitor-1 (PAI-1) in 1,047 nondiabetic subjects in relation to incident diabetes within 5 years in the Insulin Resistance Atherosclerosis Study. Subjects with diabetes at follow-up (n = 144) had higher baseline levels of fibrinogen (mean ± SD; 287.8 ± 58.8 vs. 275.1 ± 56.0 mg/dl; P = 0.013) as well as of CRP (median [interquartile range]; 2.40 [1.29, 5.87] vs. 1.67 mg/l [0.75, 3.41]; P = 0.0001) and PAI-1 (24 [15, 37.5] vs. 16 ng/ml [9, 27]; P = 0.0001) than nonconverters. The odds ratio (OR) of converting to diabetes was significantly increased with increasing baseline concentrations of the inflammatory markers. In contrast to PAI-1, the association of CRP and fibrinogen with incident diabetes was significantly attenuated after adjustment for body fat (BMI or waist circumference) or insulin sensitivity (SI), as assessed by a frequently sampled intravenous glucose tolerance test. In a logistic regression model that included age, sex, ethnicity, clinical center, smoking, BMI, SI, physical activity, and family history of diabetes, PAI-1 still remained significantly related to incident type 2 diabetes (OR [95% CI] for 1 SD increase: 1.61 [1.20–2.16]; P = 0.002). Chronic inflammation emerges as a new risk factor for the development of type 2 diabetes; PAI-1 predicts type 2 diabetes independent of insulin resistance and other known risk factors for diabetes.
Address correspondence and reprint requests to Steven M. Haffner, MD, the University of Texas Health Science Center at San Antonio, 7703 Floyd Curl Dr., MC 7873, San Antonio, TX 78228-3900. E-mail:.
Received for publication 10 May 2001 and accepted in revised form 17 December 2001.
AIR, acute insulin response; CRP, C-reactive protein; CV, coefficient of variation; IGT, impaired glucose tolerance; IRAS, Insulin Resistance Atherosclerosis Study; NGT, normal glucose tolerance; OR, odds ratio; PAI, plasminogen activator inhibitor; SI, insulin sensitivity index.