Relationship of C-Reactive Protein, Metabolic Syndrome and Diabetes Mellitus

26 Nov
2009

Relationship of C-Reactive Protein, Metabolic Syndrome and Diabetes Mellitus

The incidence of obesity is increasing in the American population. This inarguable fact is a cause of concern for politicians and industrial leaders, whose firms carry the cost of healthcare, as well as for physicians, who will be increasingly burdened with the long-term health consequences of this demographic trend. The public health implications of the increase in obesity are formidable; almost 10% of the U.S. healthcare budget is related to direct costs of obesity and physical inactivity. For African Americans, the cost may be even greater, as obesity is a primary contributor to the high prevalence of hypertension, and obesity and hypertension are both related to the risk of diabetes mellitus. In fact, type-2 diabetes is about twice as prevalent in African Americans as in whites. Of note is that more than three-quarters of African-American women >20 years of age are overweight, and almost half are considered obese.

C-Reactive Protein as a Marker

Excess weight contributes to an elevation in markers of inflammation, which we now understand play a significant role in the development and progression of cardiovascular disease (treating certain kinds of angina) (CVD). Although these markers are considered novel with respect to their use in predicting CVD, our knowledge of them dates from 1929, when researchers discovered that a serum fraction from patients with pneumonia had the ability to bind to the C-polysaccharide of the pneumococcal cell wall. This fraction was named C-reactive protein (CRP) and is considered to be the first acute-phase protein. For decades, CRP has been used as a marker for systemic inflammation caused by infection, cancer or autoimmune diseases. However, its clinical use was greatly limited by its poor predictive value, and it is only recently that the development of a high-sensitivity assay for CRP (hsCRP) has given this marker new importance.

Ample evidence now exists that elevated hsCRP levels alone are a strong independent risk factor for cardiovascular events. Levels of <1, 1-3 and >3 mg/L have been proposed to define low-risk, moderate-risk and high-risk groups, respectively. Most evidence indicates that the hsCRP level adds predictive information to the Framingham risk score. For example, in the Women’s Health Study of 27,939 apparently healthy women, the incidence events was calculated across the full range of baseline hsCRP levels and was adjusted for the Framingham risk score. After a nine-year follow-up period, the rate of cardiovascular events increased in a linear fashion from the very lowest to the very highest levels of hsCRP. Even very low (<0.5 mg/L) and very high (10.0 mg/L) levels of hsCRP provided important prognostic information on the risk of cardiovascular (is used for treating high blood pressure) events across a full range of Framingham risk scores.

CRP is related to the development of atherosclerotic disease through several mechanisms. Atherosclerosis, including initiation, development and plaque vulnerability, is now known to be associated with an inflammatory response to injury of the vessel wall. Diverse CVD risk factors, such as smoking, high blood pressure, dyslipidemia and hyperglycemia, are proinflammatory triggers that initiate endothelial dysfunction—a precursor to atherosclerosis. These risk factors promote the secretion of leukocyte-soluble adhesion molecules, which facilitate the attachment of monocytes to endothelial cells, and of chemotactic factors that promote migration of monocytes into the intima. CRP plays a role in all these processes. In addition, at levels associated with vascular events, CRP attenuates production of nitric oxide (NO) and decreases expression of endothelial NO synthase, triggers oxidation of low-density-lipoprotein cholesterol (LDL-C) and induces expression of plasminogen activator inhibitor-1 (PAI-1). Moreoever, by stimulating the release of matrix met-alloproteinase-1 (MMP-1), which degrades collagen, CRP plays a direct role in destabilizing the fibrous cap of the atheromatous lesion. Thus, as well as serving as a risk marker, CRP appears to play an important direct role in atherothrombosis.

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