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Published online March 19, 2007
Diabetes Care 30:1627-1629, 2007
DOI: 10.2337/dc06-2531
© 2007 by the American Diabetes Association
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Cardiovascular and Metabolic Risk
Brief Report

C-Reactive Protein Is Independently Associated With Glucose but Not With Insulin Resistance in Healthy Men

Anne G. Niehoff, MD1,2, Timon W. van Haeften, MD, PHD3, N. Charlotte Onland-Moret, PHD1,2, Clara C. Elbers, MSC1,2, Cisca Wijmenga, PHD2 and Yvonne T. van der Schouw, PHD1

1 Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, the Netherlands
2 Complex Genetics Section, DBG-Department of Medical Genetics, University Medical Center Utrecht, the Netherlands
3 Department of Internal Medicine, University Medical Center Utrecht, the Netherlands

Address correspondence and reprint requests to Yvonne T. van der Schouw, PhD, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Room 6.131 Stratenum, P.O. Box 85500, 3508 GA Utrecht, Netherlands. E-mail: y.t.vanderschouw{at}umcutrecht.nl

Abbreviations: CRP, C-reactive protein • HOMA-IR, homeostasis model assessment of insulin resistance


   INTRODUCTION
TOP
 INTRODUCTION
RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 References
 
Recent studies have shown that low-grade inflammation is linked both to insulin resistance (1,2) and the metabolic syndrome (3,4) and may even predict the development of type 2 diabetes (5–8).

However, adipose tissue might play an important role in these relationships. There is still controversy about whether low-grade inflammation is an intermediate factor between obesity and insulin resistance or whether it has an independent effect on the development of type 2 diabetes through a mechanism separate from obesity.

The aim of this study was to explore whether low-grade inflammation (measured by plasma C-reactive protein (CRP) levels) was related to insulin resistance and to parameters of metabolic syndrome, independent of obesity.


   RESEARCH DESIGN AND METHODS—
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
RESULTS--
 CONCLUSIONS--
 References
 
We conducted a cross-sectional, single-center study on 400 men aged between 40 and 80 years. The subjects, methods of recruitment, study procedures and anthropometrical and laboratory measurements have been described elsewhere (9). Twenty-one participants had prevalent diabetes and were excluded from the study; 13 participants were excluded because their level of CRP was above 10 mg/l and 2 because blood samples had been taken in a nonfasting state. Our final study population comprised 364 participants.

Various measures of obesity were obtained: weight, BMI, waist circumference, waist-to-hip ratio, visceral and subcutaneous fat using ultrasound measurement (10), and total body fat mass using dual-energy X-ray absorptiometry.

Information on prevalent diseases, medication use, and lifestyle factors was available. Peripheral blood pressure was measured. Physical activity was assessed using the Voorrips score (11).

High-sensitivity–CRP, HDL cholesterol, triglycerides, glucose, and insulin were measured in fasting blood samples. Details about the precision of the assays have been reported (9,12,13). Insulin sensitivity was determined with the homeostasis model assessment of insulin resistance (HOMA-IR): [fasting insulin (mU/l) x fasting glucose (mmol/l)]/22.5. The presence of metabolic syndrome was defined according to the National Cholesterol Education Program criteria (14).

Statistical analysis
Subjects were divided into quartiles according to their CRP level. Linear regression analysis was used to estimate the relation of CRP with insulin resistance and the individual components of metabolic syndrome. The P value for linear trend was calculated with the median of the CRP level in each quartile. Multivariate analyses were adjusted for age, smoking, and physical activity. To explore the relationship between CRP and insulin resistance and between CRP and metabolic syndrome independently of markers of obesity, the models were also adjusted for various different body composition parameters. Statistical analyses were performed using SPSS, version 12.0.1 for Windows.


   RESULTS—
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
CONCLUSIONS--
 References
 
In general, men with higher CRP levels were older, scored higher on markers of obesity, were less physically active, and had higher glucose levels and insulin resistance. They also fulfilled the criteria for metabolic syndrome more often (Online Appendix Table 1 [available at http://dx.doi.org/10.2337/dc06-2531]).

After adjusting for confounders (age, smoking, and physical activity), insulin resistance was significantly higher in the 4th quartile of CRP compared to the 1st, but after adjusting for the various parameters of obesity, the difference in HOMA-IR between the quartiles of CRP was no longer evident (Table 1). However, adjustment for subcutaneous fat attenuated the relationship between CRP and HOMA-IR to a lesser extent than the other parameters of obesity.


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  		Table 1— Relationship between CRP (in quartiles) and insulin resistance as assessed by HOMA-IR and between CRP (in quartiles) and glucose, with the first quartiles as reference

 
Of the individual components of metabolic syndrome, waist circumference, glucose, and HDL-cholesterol showed a statistically significant association with CRP (data not shown). When we further adjusted the relationship between CRP and the individual components of metabolic syndrome for measures of obesity, only glucose remained statistically significantly higher in the 4th quartile of CRP compared to the 1st quartile (Table 1).


   CONCLUSIONS—
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
References
 
CRP was not related to insulin resistance after adjustment for parameters of body composition, whereas CRP was independently associated with glucose, but not with the other components of metabolic syndrome.

Recently Kahn et al. (15) showed that the relationship between CRP and the number of components of metabolic syndrome markedly attenuated and became nonsignificant after adjusting for BMI in drug-naive type 2 diabetes patients. Because all the patients in their study satisfied the glucose criteria of metabolic syndrome by definition, this criterion did not contribute to the correlation between CRP and components of metabolic syndrome. Our study therefore broadens what is known about this topic, since it shows that CRP is associated with plasma glucose, independently of obesity. Furthermore, in healthy elderly men we confirmed Kahn et al.'s finding that CRP is not independently related to other components of metabolic syndrome.

Conflicting results have been found regarding the correlation between CRP and insulin resistance (2,16–20). However most of these studies did not have the prime aim of exploring the underlying pathways. Some of these studies did not therefore adjust for parameters of obesity at all, while others did not investigate the effect of a separate adjustment for obesity.

A limitation of our study is its cross-sectional design, and, therefore, we can only suggest, but not prove, the causality of the observed relationships. We used HOMA-IR and ultrasound instead of hyperinsulinemic-euglycemic clamp and computed tomography scan, respectively, for assessing insulin sensitivity and visceral and subcutaneous fat. However, these measurements have proven to be strongly correlated with the gold standards (correlation coefficients –0.82 and 0.81, respectively) (10,21)

Our data point to an obesity-independent mechanism which relates CRP and glucose. One explanation might be the proinflammatory effects of glucose: In itself, glucose is proinflammatory (22), and it can increase IL (interleukin)-6, tumor necrosis factor-{alpha}, and IL-18 release in healthy subjects and persons with impaired glucose tolerance (23). Furthermore, prolonged hyperglycemia and the accompanying production of excess amounts of advanced glycation end products can activate nuclear factor-{kappa}B (24). This will lead to an inflammatory reaction, independently of adipose tissue.

In conclusion, our findings strongly point to low-grade inflammation as an intermediate factor in the relationship between adipose tissue and insulin resistance. The independent association of glucose with CRP suggests an additional mechanism by which glucose and CRP are related, independent of obesity.


   Acknowledgments
 
We thank Jackie Senior for critically reading the manuscript. This work was supported by an Innovatieve Onderzoeks Programma's (Innovative Research Programs) grant from the Dutch Ministry of Economic Affairs (grant no. IGE05012).


   Footnotes
 
Published ahead of print at http://care.diabetesjournals.org on 19 March 2007. DOI: 10.2337/dc06-2531.

Additional information for this article can be found in an online appendix at http://dx.doi.org/10.2337/dc06-2531.

C.W. is currently affiliated with the Department of Genetics, University Medical Center Groningen, Groningen, the Netherlands.

A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C Section 1734 solely to indicate this fact.

Received for publication December 14, 2006. Accepted for publication March 9, 2007.


   References
TOP
 INTRODUCTION
 RESEARCH DESIGN AND METHODS--
 RESULTS--
 CONCLUSIONS--
 References
 

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This Article
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