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CRP and Metabolic Dysfunction
In 1988, Reaven proposed that insulin resistance is causally linked to hypertension and associated with atherogenic dyslipidemia [elevated triglycerides, decreased high-density lipoprotein cholesterol (HDL-C) and small LDL particles] and impaired glucose tolerance. These conditions are diagnostic criteria for a cluster of lipid and metabolic abnormalities formerly called the insulin resistance syndrome or syndrome X, and, with the addition of abdominal obesity, now known as metabolic syndrome. According to the Third Report of the National Cholesterol Education Program Adult Treatment Panel (NCEP ATP III), the term metabol ic syndrome describes a high-risk population that is defined as having >3 of the following characteristics: abdominal obesity, hypertriglyceridemia, low HDL-C, hypertension and/or abnormal glucose (Table 1). It should be noted that the World Health Organization has a slightly different definition of metabolic syndrome, which emphasizes insulin resistance rather than central obesity. Both definitions, however, recognize CVD as the primary outcome of metabolic syndrome. Both recognize too that metabolic syndrome increases risk for type-2 diabetes, a major risk factor for CVD.
Table 1. Clinical identification of metabolic syndrome
|Risk Factor||Defining Level|
|Abdominal Obesity||Waist Circumference|
|Men||> 102 cm (>40in)|
|Women||>88 cm (>35 in)|
|Blood pressure||>130/85 mmHg|
|Fasting glucose||>110 mg/dL|
Each of the characteristics of metabolic syndrome is also independently associated with increased levels of CRP. The relationship of obesity to CRP as well as to other inflammatory markers, such as the proinflammatory cytokine interleukin-6 (IL-6), has been the subject of intense scrutiny. CRP is synthesized primarily by hepatocytes and is chiefly regulated by circulating levels of IL-6, which is secreted by subcutaneous adipose tissue. A recent study found that human coronary artery smooth-muscle cells can also synthesize CRP after stimulation by inflammatory cytokines, although this locally produced CRP is less robust than that produced by the liver.
In a study that examined CRP in healthy subjects, levels of CRP and IL-6 were found to be related to insulin resistance, blood pressure, HDL-C and endothelial dysfunction. These data support the concept that a low level of chronic inflammation may induce insulin resistance and endothelial dysfunction, which links them with obesity and CVD. In the Insulin Resistance Atherosclerosis Study (IRAS), investigators studied 1,008 nondiabetic individuals, a third of whom had impaired glucose tolerance and none of whom had clinical coronary artery disease (CAD). Strong associations were identified between
CRP levels and body mass index (BMI), waist circumference and fasting insulin—all of which are diagnostic criteria for metabolic syndrome.
Evidence is also accumulating implicating inflammation in the pathogenesis of type-2. A recent study examined the database of the West of Scotland Coronary Prevention Study to determine the ability of CRP to predict the development of diabetes in the 5,245 enrolled men for whom baseline CRP measurements were available; 127 of these men were newly diagnosed with type-2 diabetes during the study period. CRP was found to be a predictor of diabetes (actos diabetes treat type II of diabetes) independent of any other clinical predictors, including baseline BMI, fasting triglycerides and serum glucose concentrations. In addition, there was a graded increase in risk over CRP quintiles, with a three-fold increase in risk between the lowest and highest quintiles at five years.
The association between CRP and the incidence of type-2 diabetes among middle-aged men was examined in the Augsburg cohort of the Monitoring of Trends and Determinants (MONICA) epidemiologic study. A total of 2,052 nondiabetic men aged 45-74 years participated and were followed for an average of 7.2 years, during which 101 cases of incident diabetes occurred. Adjusted for age, men with CRP in the highest quartile (>2.91 mg/L) had a 2.7 times higher risk of developing diabetes compared with men in the lowest quartile (<0.67 mg/L).
Over a four-year follow-up period in the Women’s Health Study, 188 women developed type-2 diabetes and were matched by age and fasting serum status with 362 disease-free subjects. Baseline levels of IL-6 and CRP were significantly higher in the women who developed diabetes than in the controls (P<0.001). The data support a role for inflammation in the development of type-2 diabetes.
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