Original Article
Cross-sectional associations of C-reactive protein with vascular risk factors and vascular complications in the DCCT/EDIC cohort

https://doi.org/10.1016/j.jdiacomp.2007.02.003Get rights and content

Abstract

Objective

To determine the relationships between C-reactive protein (CRP) levels and features of Type 1 diabetes.

Research Design and Methods

Serum CRP was measured by nephelometry in a cross-sectional study of the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort (n=983) and nondiabetic subjects (n=71).

Results

CRP levels [geometric mean (95% CI)] were higher in diabetic than in control subjects, 1.6 (1.5–1.7) vs. 1.2 (1.1–1.5) mg/l, P=.019. CRP was higher in diabetic women (n=438) than in men (n=545) [2.0 (1.8–2.3) vs. 1.3 (1.2–1.5), P<.001]. Diabetic subjects formerly in the DCCT intensive treatment group had higher CRP levels than those who were randomized to the conventional treatment group [1.8 (1.6–1.9), n=479 vs. 1.5 (1.3–1.6), n=456, P=.010], attributable to greater BMI in the prior intensive group. In diabetes, CRP correlated with HbA1c (r=0.13, P<.0001) and with insulin resistance traits: BMI (r=0.34, P<.0001), waist-to-hip ratio (WHR; males: r=0.35, P<.0001; females: r=0.22, P<.0001), diastolic blood pressure (r=0.07, P=.025), triglycerides (r=0.19, P<.0001), apoB (r=0.22, P<.0001), LDL particle concentration (r=0.26, P<.0001), and LDL particle size (r=−0.22, P<.0001). CRP was not associated with complications. Significant independent predictors of CRP in diabetes were gender, BMI, WHR, concurrent HbA1c, and oral contraceptive pill use.

Conclusions

CRP was elevated relative to nondiabetic subjects, and in diabetes was higher in females. Elevated CRP in Type 1 diabetes was associated with poor glycemic control, larger body habitus, and other factors that comprise the insulin resistance syndrome. Nevertheless, CRP levels were not associated with complications. Longitudinal studies are warranted.

Introduction

Elevated C-reactive protein (CRP), determined by high sensitivity assay, is a risk factor for vascular disease in nondiabetic subjects (Ridker, 1999, Ridker et al., 2000, Rohde et al., 1999, Strandberg & Tiluis, 2000) and for Type 2 diabetes (Freeman et al., 2002). Significant correlations have been reported between this marker of inflammation and other vascular risk factors, including age, body mass index (BMI), blood pressure, total cholesterol, triglycerides, apolipoprotein B (ApoB), lipoprotein(a) [Lp(a)], smoking, and homocysteine (Ford, 1999, Ford & Giles, 2000, Mendall et al., 1996, Visser et al., 1999).

People with diabetes are at risk for retinopathy and nephropathy, as well as accelerated atherosclerosis. Several risk factors, for example, hypertension and dyslipidemia, are common to micro- and macrovascular disease in diabetes (American Diabetes Association, 1996, Jenkins et al., 2004, Pyorala, 1989). Inflammation may also increase complication risk. We conducted a cross-sectional study in Type 1 diabetic subjects, enrolled in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) cohort (The Diabetes Care and Complications Trial (DCCT), 1993, Epidemiology of Diabetes Interventions and Complications (EDIC), 1999), to assess associations of CRP with vascular disease risk factors, and with indices of micro- and macrovascular disease.

Section snippets

Research design and methods

The DCCT/EDIC cohort and methods used in the study for clinical and biochemical assessment are described elsewhere (The Diabetes Care and Complications Trial (DCCT) Research Group, 1987, The Diabetes Care and Complications Trial (DCCT), 1993, The Diabetes Control and Complications Trial (DCCT) Research Group, 1995, Epidemiology of Diabetes Interventions and Complications (EDIC), 1999, Epidemiology of Diabetes Interventions and Complications (EDIC) Research Group, 1999). In 1996, a collaborative

Results

CRP levels were higher in diabetic subjects than in controls; geometric mean (95% CI), 1.6 (1.5–1.7) vs. 1.2 (1.1–1.5) mg/l, P=.02. This effect was stronger in women [2.0 (1.8–2.3), n=438 diabetic subjects vs. 1.4 (1.0–1.9), n=36 controls, P=.03] than in men [1.3 (1.2–1.5), n=545 vs. 1.0 (0.7–1.5), n=35, P=.15] for diabetic vs. nondiabetic subjects, respectively. Among diabetic women, CRP levels were higher in those taking than in those not taking the oral contraceptive pill (OCP): 2.6

Discussion

In this cross-sectional analysis of the DCCT/EDIC cohort, we evaluated the relationship between serum CRP, risk factors for vascular disease, and complications. The well-described, large, DCCT/EDIC cohort provides a valuable opportunity to evaluate this inflammatory marker as a risk factor for the complications of Type 1 diabetes. CRP levels were higher in diabetic subjects than in controls, were higher in females compared with males with diabetes, and were increased in association with OCP

Acknowledgments

Funding was provided by the National Institutes of Health (PO1 HL55782), the Juvenile Diabetes Research Foundation International (Grants: 41998272, 996001), the American Diabetes Association, and the Diabetes Research and Wellness Foundation. AJJ received a National Heart Foundation (Australia) Fellowship. MR was funded by the MUSC Summer Undergraduate Program. DCCT/EDIC center coordinators and Eunsil Yim are gratefully acknowledged. James Otvos, Ph.D., (LipoScience Inc. Raleigh, NC, USA)

References (74)

  • L.E.P. Rohde et al.

    Survey of C-reactive protein and cardiovascular risk factors in apparently healthy men

    American Journal of Cardiology

    (1999)
  • D. Streja et al.

    Associations between inflammatory markers, traditional risk factors, and complications in patients with type 2 diabetes mellitus

    Journal of Diabetes and its Complications

    (2003)
  • C.M. Albert et al.

    Prospective study of C-reactive protein, homocysteine, and plasma lipid levels as predictors of sudden cardiac death

    Circulation

    (2002)
  • American Diabetes Association

    Diabetes complications

  • M.E. Atabek et al.

    Evidence for an association between type 1 diabetes and premature carotid atherosclerosis in childhood

    Pediatric Cardiology

    (2006)
  • S. Bhakdi et al.

    Complement and atherogenesis: Binding of CRP to degraded, nonoxidized LDL enhances complement activation

    Arteriosclerosis, Thrombosis, and Vascular Biology

    (1999)
  • H.M. Colhoun et al.

    C-Reactive protein in type 1 diabetes and its relationship to coronary artery calcification

    Diabetes Care

    (2002)
  • T. Costacou et al.

    The prospective association between adiponectin and coronary artery disease among individuals with type 1 diabetes. The Pittsburgh Epidemiology of Diabetes Complications Study

    Diabetologia

    (2005)
  • S. Devaraj et al.

    Increased monocytic activity and biomarkers of inflammation in patients with type 1 diabetes

    Diabetes

    (2006)
  • Epidemiology of Diabetes Interventions and Complications (EDIC)

    Design, implementation, and preliminary results of a long-term follow-up of the Diabetes Control and Complications Trial cohort

    Diabetes Care

    (1999)
  • Effect of intensive diabetes treatment on carotid artery wall thickness in the Epidemiology of Diabetes Interventions and Complications

    Diabetes

    (1999)
  • E.J. Erlandsen et al.

    Reference interval for serum C-reactive protein in healthy blood donors using the Dade Behring N Latex CRP mono assay

    Scandinavian Journal of Clinical and Laboratory Investigation

    (2000)
  • E.S. Ford

    Body mass index, diabetes, and C-reactive protein among U.S. adults

    Diabetes Care

    (1999)
  • D.J. Freeman et al.

    C-Reactive protein is an independent predictor of risk for the development of diabetes in the West of Scotland Coronary Prevention Study

    Diabetes

    (2002)
  • A.I. Fyfe et al.

    Association between serum amyloid A proteins and coronary artery disease: Evidence from two distinct arteriosclerotic processes

    Circulation

    (1997)
  • W.T. Garvey et al.

    Effects of insulin resistance and type 2 diabetes on lipoprotein subclass particle size and concentration determined by nuclear magnetic resonance

    Diabetes

    (2003)
  • M. Giese et al.

    2003 update on the Hypertension Initiative of South Carolina. Bringing South Carolina from “worst to first” in cardiovascular health

    Journal of the South Carolina Medical Association

    (2003)
  • M. Gunn et al.

    Significant association of sera positive Helicobacter pylori strains with risk of premature myocardial infarction

    Heart

    (2000)
  • R. Hayaishi-Okano et al.

    Elevated C-reactive protein associates with early-stage carotid atherosclerosis in young subjects with type 1 diabetes

    Diabetes Care

    (2002)
  • M.K. Heliovaara et al.

    Improved glycaemia in type 1 diabetes results in decreased levels of soluble adhesion molecules with no change in serum adiponectin or most acute phase proteins

    Experimental and Clinical Endocrinology & Diabetes

    (2006)
  • G.S. Hotamisligil et al.

    Increased adipose tissue expression of tumor necrosis factor-alpha in human obesity and insulin resistance

    Journal of Clinical Investigation

    (1995)
  • A.J. Jenkins et al.

    Serum lipoproteins in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Intervention and Complications cohort: Associations with gender and glycemia

    Diabetes Care

    (2003)
  • A.J. Jenkins et al.

    Lipoproteins, glycoxidation and diabetic angiopathy

    Diabetes/Metabolism Research and Reviews

    (2004)
  • W.B. Kannel et al.

    Diabetes and cardiovascular disease. The Framingham Study

    Journal of the American Medical Association

    (1979)
  • E.S. Kilpatrick et al.

    Determinants of raised C-reactive protein concentration in type 1 diabetes

    Quarterly Journal of Medicine

    (2000)
  • R.L. Klein et al.

    Fibrinogen is a marker for nephropathy and peripheral vascular disease in type 1 diabetes: Studies of plasma fibrinogen and fibrinogen gene polymorphism in the DCCT/EDIC cohort

    Diabetes Care

    (2003)
  • W. Koenig

    Fibrin(ogen) in cardiovascular disease: An update

    Thrombosis and Haemostasis

    (2003)
  • Cited by (22)

    • Association of reduced glyoxalase 1 activity and painful peripheral diabetic neuropathy in type 1 and 2 diabetes mellitus patients

      2013, Journal of Diabetes and its Complications
      Citation Excerpt :

      The results of the present study however did not confirm any correlations with CRP. This difference could be explained by the slightly elevated CRP values in both the painful and painless DN groups due to poor metabolic control, which had been associated with an elevated CRP in both type 1 (Jenkins et al., 2008) and type 2 (Arnalich et al., 2000) diabetes mellitus. It should be pointed out that the pathogenesis of type 2 diabetes mellitus is considerably heterogeneous and both glycation stress and inflammation-related processes could be cooperatively driving forces in the development of late complications of diabetes mellitus.

    • Increased methionine sulfoxide content of apoA-I in type 1 diabetes

      2008, Journal of Lipid Research
      Citation Excerpt :

      Urine specimens used to calculate AER were obtained in the EDIC year that preceded the collection of the serum used to measure Met(O) oxidation levels (Table 1). Other measures of apolipoproteins, inflammation, oxidative stress, and advanced glycation end products were performed in the authors' laboratories as described previously (34–39). Lipoprotein subclasses were measured by NMR (LipoScience, Raleigh, NC) (33).

    View all citing articles on Scopus
    1

    These authors contributed equally.

    2

    Box NDIC/EDIC, Bethesda, MD 20892, USA.

    View full text