Q J Med 2000; 93: 231-236
© 2000 Association of Physicians
Determinants of raised C-reactive protein concentration in type 1 diabetes
From the Department of Clinical Biochemistry, Hull Royal Infirmary, Hull, 1 Department of Clinical Biochemistry, Wythenshawe Hospital, Manchester, 2 Department of Clinical Biochemistry, Royal Preston Hospital, Preston, and 3 Department of Clinical Biochemistry, and 4 The Diabetes Unit, Gartnavel General Hospital, Glasgow, UK
Received 19 November 1999 and in revised form 18 January 2000
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Summary |
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As a marker of systemic inflammation, raised C-reactive protein (CRP) concentrations which are still within the normal range have been associated with an increased incidence of coronary heart disease (CHD) in non-diabetic subjects. This study aimed to establish potential determinants of raised CRP concentrations in type 1 diabetic patients. We used a sensitive assay to measure ‘low-level’ CRP concentrations in 167 type 1 patients (93M, 74F, median age 30 years, range 13–67). Stepwise multivariate analysis was used to relate these CRP levels to known cardiovascular risk factors and demographic data. Only six patients had established CHD (median CRP 3.34 mg/l vs. 0.83 mg/l, p=0.032). In subjects without overt CHD, multivariate analysis showed increases in subject age (p=0.0025), BMI (p=0.001) and HbA1 (p=0.012) to be associated with a higher CRP concentration, as was female sex (p=0.026) and a history of CHD in a first-degree relative (p=0.018, n=57). The duration of diabetes, current smoking status, presence of microvascular complications, lipid status and presence of hypertension were unrelated. This study suggests that some of the risk factors associated with CHD in type 1 patients are also independently predictive of high CRP concentrations. The reasons for this, and whether intervention would prove useful, require further investigation.
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Introduction |
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Cardiovascular disease is the main cause of morbidity and mortality in patients with diabetes. The reason for this increase in atherosclerosis is multifactorial, but is in excess of that which would be expected when account is taken of traditional coronary heart disease (CHD) risk factors such a smoking, hyperlipidaemia and hypertension.1–4
Atherosclerosis has been described as an inflammatory disease.5 Measurement of the acute-phase reactant C-reactive protein (CRP) has been routinely used to detect and monitor inflammatory changes in patients with sepsis or connective tissue diseases. Recently, the use of highly sensitive assays has indicated that variations of CRP within the ‘normal range’ i.e. <5 mg/l, are a potent risk indicator for coronary heart disease in non-diabetic subjects.6–10 Intervention may also be successful in reducing CRP levels10 and coronary events.7,9
This study aimed to determine factors which predispose to high CRP concentrations in patients with type 1 diabetes.
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Methods |
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Patients with type 1 diabetes (n=167, 93M, 74F, median age 30 years, range 13–67) attending the Diabetes Unit, Gartnavel General Hospital, Glasgow, participated in the study following written informed consent and approval by the local Ethical Committee. None had overt evidence of infection or connective tissue diseases, and all participants had negative urinalysis for nitrite and leukocytes. All patients also had a baseline ECG performed at the time of diagnosis or referral if aged >35 years.
Each had low-level CRP measured using a modified latex-enhanced immuno-turbimetric assay (Bio-Stat Diagnostics). Between-batch precision (CV) for the assay was 5.6%, 6.9% and 8.2% at CRP concentrations of 5.3, 2.2 and 1.0 mg/l, respectively. The locally-derived median reference value was 0.73 mg/l (0.95 interfractile reference interval 0.2–6.4 mg/l, n=77).11
Log10 CRP in the patients without known CHD was related by univariate regression and by forward stepwise multiple regression to the following variables: age, sex, duration of diabetes, presence of microvascular complications (retinopathy defined as early background diabetic retinopathy or worse when examined by an experienced examiner using direct ophthalmoscopy through dilated pupils; known microalbuminuria defined as a consistent overnight timed urine albumin excretion rate >20 µg/min, neuropathy defined as peripheral neuropathy using DCCT clinical criteria12), body mass index (kg/m2), current HbA1, current smoking status, current spot early-morning urine microalbumin concentration (mg/l), current non-fasting cholesterol/triglyceride/HDL-cholesterol, hypertension (on treatment or current blood pressure >140/90) and first-degree family history of cardiovascular disease.
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Results |
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Table 1
lists the characteristics of the diabetic patients who participated in the study. Figure 1 shows the log-normal distribution of CRP values found in these patients.
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Only six patients had overt coronary heart disease (Table 1
). In these patients CRP concentrations were higher than in unaffected patients (median CRP 3.34 mg/l vs. 0.83 mg/l, p=0.032 using Mann-Whitney).
Table 2 shows the univariate correlations between all the variables in the study, while Table 3 shows those which remain significantly associated with log10CRP when the data is subjected to a forward stepwise multivariate regression.
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Discussion |
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Independent studies have shown that the measurement of baseline concentrations of CRP as a marker of systemic inflammation can predict the risk of future myocardial infarction in non-diabetic subjects.6–9 In one such study, healthy subjects in the upper quartile of the CRP distribution (
2.11 mg/l) who were not taking aspirin were four times as likely to experience a myocardial infarction than those in the lowest (
0.55 mg/l).7 Of importance, this excess risk was reduced substantially by aspirin treatment, leading to the speculation that the cardioprotective action of the drug may be due to its anti-inflammatory action as well as its anti-platelet effect. The effect of the HMGCoA reductase inhibitor, pravastatin, was similar.9 It is thought that this theory of low-grade inflammation and atherosclerosis could therefore bring together, in one unifying hypothesis, the apparently disparate cardiovascular risk markers of fibrinogen, ferritin and white blood cell count, since they are all acute-phase reactants.
Our study has sought to establish some of the determinants of raised CRP concentrations in type 1 diabetic patients. Univariate analysis (Table 2) has shown that some of the strongest established predictors of CHD in type 1 diabetic patients (age, BMI, duration of diabetes, albumin excretion, serum triglyceride)13 are also the measurements which are predictive of a raised CRP concentration. These findings are in agreement with previous studies involving only non-diabetic subjects.8,14 Additionally, female sex, a family history of cardiovascular disease and a high current glycated haemoglobin value are also related to rises in CRP. However, when these factors are adjusted for each other by stepwise multiple regression, only the variables in Table 3 (age, sex, family history of CHD, BMI and current HbA1) are found to be independently associated with C-reactive protein concentrations.
The female/male difference may simply be associated with an increased prevalence of subclinical urinary infection in women. However, compared to diabetic men, diabetic women have a higher relative risk of ischaemic heart disease than their non-diabetic counterparts.1,4 Only one previous study of CRP in non-diabetic individuals has included or commented on women, and no difference was found.8
There remains considerable debate as to whether poor glycaemic control can lead to an increase in CHD in diabetic patients. In the Diabetes Control and Complications Trial (DCCT), the cardiovascular event rate was low because of the age of the type 1 patients recruited, but there was still an excess of macrovascular events in the conventionally-treated compared to the intensively-treated group (40 vs. 23), although this just failed to reach statistical significance (p=0.08).15 In the United Kingdom Prospective Diabetes Study (UKPDS), the event rate amongst the type 2 patients was higher, but the HbA1c separation between the two groups was lower, and again the findings were statistically suggestive but not conclusive (p=0.052 for myocardial infarction).16 However, recent analysis has shown that when the whole range of UKPDS patient HbA1c concentrations is taken into account, there is a highly significant relationship between HbA1c and coronary heart disease risk in these patients.17 It is thus of interest that this study has found that glycated haemoglobin is an independent predictor of CRP levels, even though it is only the patients' current value.
Our data on smoking is consistent with previous studies, in finding no relationship between current smoking and CRP.6,14,18 However, two of these studies did find a relationship with pack-years smoked14,18 (an index not collected by ourselves), indicating that the effect of smoking on CRP may be long-lasting.
The lack of association between CRP and hypertension may reflect the low prevalence of raised or treated blood pressure (6% of patients) found in this study, presumably because of the young mean age (30 years) of participants. Nevertheless, in studies with non-diabetic subjects, no blood pressure/CRP associations have been noted either.6,14 However, it must be regarded as surprising that although the cholesterol, triglyceride and HDL cholesterol of our patients were related to several factors such as HbA1, duration of diabetes and microvascular complications, none of these lipid parameters were independently related to CRP levels.
Given all the associations found with CRP in this study, the reasons why inflammation is present at all remains speculative. Some authors believe CRP values may reflect the intrinsic inflammation and tissue damage within arterial lesions themselves, with severe atheroma resulting in both raised CRP levels and an increased risk of coronary occlusion.8 Others believe high levels may be consequent on chronic infection with potentially atherogenic organisms such as C. pneumoniae or H. pylori.19,20
An attractive alternative possibility is related to the fact that CRP production by hepatocytes is stimulated by inflammatory cytokines.21 One such cytokine, tumour necrosis factor 
(TNF) has also been implicated in the pathogenesis of obesity-associated insulin resistance.22 Plasma TNF levels correlate positively with percentage body fat and body mass index (BMI).23 Since BMI is known to relate to increasing subject age,24 it may help to explain some of the associations found here. Also, women have a larger percentage body fat than men for a given BMI,25 so they may produce relatively more TNF, thereby explaining their higher CRP values. Low-level CRP measurements in this situation may thus partly be a surrogate marker for circulating TNF concentrations.
Of clinical relevance to diabetic patients, studies in non-diabetic subjects have shown that aspirin and statin treatment specifically reduce the increased cardiovascular risk associated with high CRP values.7,9 If applied to the asymptomatic diabetic patients in our study, it would suggest that it is the older, female, poorly controlled, overweight patient with a bad family history of heart disease who is most likely to benefit from such treatment, since they tend to have the highest CRP levels.
In summary, this study has found that factors already known to be associated with cardiovascular risk in type 1 diabetes are also indicative of raised CRP concentrations. However, the mechanisms involved in these relationships require further investigation.
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Notes |
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Address correspondence to Dr E.S. Kilpatrick, Department of Clinical Biochemistry, Hull Royal Infirmary, Anlaby Road, Hull HU3 2JZ. e-mail: eric\|[hyphen]\|kilpatrick{at}hotmail.com
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