Correlation of high-sensitivity C-reactive protein and plasma fibrinogen with individual complications in patients with type 2 diabetes.
Methods: In 73 patients with type 2 diabetes, we investigated associations between both markers and carotid artery intimal medial complex thickness (IMT), heart rate variability, or urinary albumin excretion (UAE).
Results: Log hsCRP and fibrinogen correlated significantly with each other (r = 0.3701, P = 0.0013). Fibrinogen correlated negatively with the coefficient of variation of RR intervals (C[V.sub.RR]) and positively with log UAE (r = -0.2433, P = 0.0381; r = 0.4815, P < 0.0001), while log hsCRP did not. Furthermore both log hsCRP and fibrinogen did not correlate with IMT.
Conclusion: We concluded that despite their close correlation, fibrinogen compared with hsCRP might be closely associated with diabetic microangiopathy and that both markers might not correlate with IMT as a marker of macroangiopathy.
Key Words: high-sensitivity C-reactive protein, fibrinogen, poorly controlled type 2 diabetes
Atherosclerosis now is considered to reflect chronic inflammation in arterial walls. (1,2) Accordingly, various acute-phase reactants and proinflammatory cytokines have been assessed as possible markers of atherosclerosis. (3-7) In particular, high-sensitivity C-reactive protein (hsCRP) and fibrinogen, acute-phase reactants produced in the liver in response to stimulation by proinflammatory cytokines such as tumor necrosis factor (TNF)-[alpha] and interleukin (IL)-6, have been well studied (3,4) and found to be predictors of cardiovascular events and mortality. (8-11) In addition, CRP itself may have atherogenic effects such as activation of complement (12,13) or enhancement of monocyte chemoattractant protein (MCP)-1 production. (14) On the other hand, fibrinogen, which is elevated in diabetes as well as CRP, (15,16) is not only an acute-phase reactant, but also a coagulation factor, and therefore in diabetes its elevation might be associated with not only macroangiopathy but also microangiopathy, as a result of the increased blood viscosity.
We know of only one report in which associations of diabetic complications with hsCRP and fibrinogen were investigated simultaneously. (17) In that study of patients with moderately controlled diabetes, some differences were found. Therefore the differences between hsCRP and fibrinogen might be expected to include differences in their implications as markers of specific diabetic complications. However, to date, relationships with carotid artery intimal medial thickness (IMT), a marker of systemic atherosclerosis, (18-20) and with neuropathy, a specific form of diabetic microangiopathy, were not assessed.
In the present study of poorly controlled type 2 diabetes, we analyzed associations of hsCRP and fibrinogen with IMT and neuropathy evaluated by heart rate variation. We also considered conventional measures of macroangiopathy such as blood pressure, and serum lipid concentrations, as well as indictors of microangiopathy.
We hypothesized that in patients with poorly controlled diabetes, hsCRP would be associated mainly with macroangiopathy as reflected by the thickened IMT, while fibrinogen would be associated with both macroangiopathy and microangiopathy.
Patients and Methods
We studied 73 Japanese patients with type 2 diabetes who had been admitted because of poor glycemic control. Patients included 38 men and 35 women. Mean age and duration of diabetes in all patients, men and women respectively, were 60.8 [+ or -] 10.7, 62.5 [+ or -] 9.2, and 59.0 [+ or -] 12.0 years and 10.5 [+ or -] 7.8, 9.6 [+ or -] 1.8, and 10.4 [+ or -] 2.4 years. Mean fasting plasma glucose (FPG) and Hb[A.sub.1C] in all patients, men and women, were 192.2 [+ or -] 72.6, 184.2 [+ or -] 68.3, and 200.9 [+ or -] 77.1 mg/dL and 10.0 [+ or -] 2.1%, 9.6 [+ or -] 1.8%, and 10.4 [+ or -] 2.4%, respectively. Body mass index (BMI) in all patients were 23.9 [+ or -] 4.3, 23.6 [+ or -] 3.9, and 24.2 [+ or -] 4.8 kg/[m.sup.2]. Systolic and diastolic blood pressures in all patients, men and women, were 130.9 [+ or -] 18.2, 131.1 [+ or -] 18.6, and 130.7 [+ or -] 17.9 mm Hg, and 74.1 [+ or -] 11.4, 75.6 [+ or -] 11.5, and 72.5 [+ or -] 11.1 mm Hg, respectively. Five patients were treated with dietary modification alone. Fifty patients were receiving sulfonylureas (glibenclamide, gliclazide, or glimepiride) as oral hypoglycemic agents (OHA) in addition to diet. Eighteen patients were managed with diet and insulin injection. Twenty-seven patients took antihypertensive drugs, variously including an angiotensin converting enzyme inhibitor (ACE-I), an angiotension II receptor blocker (ARB), or a calcium channel blocker. Twenty-nine patients were smokers.
Diabetic nephropathy was assessed according to urinary albumin excretion (UAE), which was used to classify patients into three groups: UAE below 30 mg/g of creatinine (Cr)--normal albuminuria (n = 34); UAE of 30 to 300 mg/g of Cr-microalbuminuria (n = 19); and UAE above 300 mg/g Cr-macroalbuminuria (n = 20). Diabetic retinopathy was assessed by each patient's ophthalmologist according to Davis' classification (21): no diabetic retinopathy or NDR (n = 38); simple diabetic retinopathy or SDR (n = 17); and proliferative diabetic retinopathy or PDR (n = 18).
BMI and blood pressure were determined before breakfast in the morning on the day after admission. When BMI was determined, patients were dressed in their underwear.
In the current study, any patient exhibiting evidence of liver or renal dysfunction, and findings or treatments of infections or autoimmune disease, was excluded. In addition, although the upper limit of plasma glucose concentration as inclusion criteria was not made, the patients with evident ketoacidosis were also excluded.
Clinical data for all 73 patients are summarized in Table 1.
Determination of the Coefficient of Variation of RR Intervals (C[V.sub.RR])
We chose C[V.sub.RR] as assessment of heart rate variability. Electrocardiographic (ECG) RR intervals were measured using recordings of 100 consecutive cardiac cycles, usually obtained in the morning. During recording, all subjects were at rest in a supine position and were instructed to maintain a respiratory rate above 9 breaths/min to decrease any effect of respiratory sinus arrhythmia. C[V.sub.RR] was calculated according to the formula, C[V.sub.RR] = (standard deviation of RR/mean RR) X 100. Any patient with arrhythmia was excluded from C[V.sub.RR] analysis.
Measurement of Combined Intimal Medial Thickness (IMT) in the Carotid Artery
IMT was measured once during each patient's admission using ultrasonography (SSD-1200; Aloka, Tokyo, Japan) with a linear pulse echoprobe operating at 7.5 MHz (ASU-35WL-7.5). Axial resolution with this probe was better than 0.1 mm. A suitable portion of the right common carotid artery in the neck was scanned longitudinally from an anterior oblique orientation. Using calipers, IMT was measured at the thickest point with a 1 cm interval on each side in the area scanned (including plaques), as Kawamori et al. (22) have demonstrated. The mean of these three thicknesses was taken as the individual's IMT, as well as our previous study. (23)
Serum hsCRP Assay
Blood was centrifuged at 1,500 rpm for 5 minutes to separate serum from the clot-containing blood cells. Sera were stored at -70[degrees]C until analysis. The BNIIN High-Sensitivity CRP assay (Dade Behring, Marburg, Germany), which has been approved by the US Food and Drug Administration (FDA) for use in evaluating risk of cardiovascular and peripheral vascular disease, was used. The lowest detectable concentration of hsCRP with this assay was 0.05 mg/L. If a patient had an hsCRP value less than 0.05 mg/L, the CRP concentration was taken to be 0.05 mg/L. Intra- and interassay coefficient of variation (CV) was 1.72% and 2.80% in this assay.
Measurement of Plasma Fibrinogen
Plasma fibrinogen was measured by the von claus method.
Measurement of Plasma Glucose, Hb[A.sub.1C], and Serum Lipid Concentrations
Fasting plasma glucose was evaluated by an automated glucose oxidase method (Glucose Auto Stat GA 1160; Arkray, Kyoto, Japan). Hb[A.sub.1C] was measured by high-performance lipid chromatography (HPLC; Hi-auto [A.sub.1C], HA8150; Arkray). With this method, only Hb[A.sub.1C] was detected, and the normal range was 4.3% to 5.8%. Serum total, low-density, and high-density lipoprotein cholesterol (TC, LDL-C, and HDL-C) and also serum triglyceride (TG) concentrations were measured enzymatically.
Measurement of UAE
UAE was measured once during the hospital stay by enzyme immunoassay in a 24-hour urine specimen maintained at 4[degrees]C. Albumin values were corrected for urinary creatinine concentration. Creatinine clearance (Ccr) was assessed using a 24-hour urine specimen.
All venous blood samples for biochemical examinations were collected from patients in the morning following admission after at least 10 hours of overnight fasting.
All subjects gave informed consent to be included in the present study, which was performed according to the guidelines proposed in the Declaration of Helsinki.
All data are presented as the mean [+ or -] standard deviation (SD). The significance of correlations between two variables was determined by a simple regression analysis. For analysis, hsCRP and UAE values were [log.sub.10]-transformed because of skewed distributions. Comparisons between two groups were made using an unpaired t test. For multiple comparisons, significances of individual differences were assessed using the Bonferroni test. Multiple regression analysis with log hsCRP or fibrinogen as the dependent variable was performed using a stepwise regression method. In addition to fibrinogen or hsCRP, independent variables tested initially were age, gender, duration of diabetes, BMI, FPG, Hb[A.sub.1C], TC, TG, HDL-C, SBP (systolic blood pressure), DBP (diastolic blood pressure), and smoking. Among these variables, no combination with a strong correlation (R >0.9) was found. Each variable with an F value of less than 2 then was excluded. A P value less than 0.05 was accepted as indicating statistical significance.
In all 73 patients, (38 men and 35 women), the respective mean hsCRP was 1.52 [+ or -] 2.12, 1.83 [+ or -] 2.56, and 1.20 [+ or -] 1.47 mg/L, showing no significant gender-related difference (P = 0.1981). Mean fibrinogen in all patients was 381.30 [+ or -] 118.0, 364.6 [+ or -] 111.3, and 399.5 [+ or -] 124.0 mg/dL, again with no gender-associated difference (P = 0.2086). A significant elevation in fibrinogen but not hsCRP was evident in patients receiving antihypertensive drugs compared with other patients (P = 0.0474, P = 0.0690, respectively). No significant difference in hsCRP or fibrinogen was noted between smokers and nonsmokers (P = 0.3235, P = 0.7229, respectively).
When patients were assigned to one of three groups according to presence and degree of retinopathy (NDR, SDR, or PDR), mean values for hsCRP and fibrinogen showed no significant differences between these three groups; however, fibrinogen showed a slight tendency to differ between NDR and PDR groups (363.1 [+ or -] 110.6 mg/dL versus 411.4 [+ or -] 138.8 mg/dL, P = 0.1569).
Considering all 73 patients, a significant positive correlation was detected between log hsCRP and fibrinogen (r = 0.3701, P = 0.0013). No correlation was obtained between log hsCRP and IMT, C[V.sub.RR], or log UAE. Fibrinogen showed a significant positive correlation with log UAE and a negative correlation with C[V.sub.RR], while fibrinogen did not correlate with IMT. The coefficients and P values obtained by linear regression analysis for correlations between log hsCRP or fibrinogen and various parameters are summarized in Table 2.
By stepwise regression analysis with log hsCRP as the dependent variable, fibrinogen, age, BMI, Hb[A.sub.1C], and smoking retained a significant association ([beta] = 0.4707, 0.3280, 0.3322, 0.2758, 0.2472, P < 0.0001, 0.0017, 0.0014, 0.0161, 0.0191, respectively).
On the other hand, stepwise regression analysis with fibrinogen as the dependent variable retained log UAE, log CRP, and TG as significant independent variables ([beta] = 0.4923, 0.3154, 0.3042, P < 0.0001, 0.0009, 0.0022, respectively).
In the current study, a significant correlation was found between log hsCRP and fibrinogen, as we had expected. Considering that patients in the current study had poorly controlled diabetes and thus were unlike previously reported non-diabetic (24) and diabetic (25) populations showing this correlation; the two markers appear to have a close association with one another independently of plasma glucose.
We also investigated correlations of hsCRP and fibrinogen with IMT, an established systemic atherosclerosis marker. (18-20) Contrary to our expectation, we failed to find any correlation. Even previous reports finding that patients with relatively high CRP or fibrinogen showed increased IMT demonstrated no actual correlations. (26,27) We concluded that the association between hsCRP or fibrinogen and IMT was likely to be weak because both hsCRP and fibrinogen reflected the degree of inflammation in arterial walls rather than quantitative atherosclerotic changes such as thickening.
We also examined associations of hsCRP and fibrinogen with conventional atherosclerosis markers such as diabetic control, blood pressure, and serum lipid concentrations. Unlike previous results, (28) neither log hsCRP nor fibrinogen correlated with FPG or blood pressure, although log hsCRP had a significant association with Hb[A.sub.1C] in our multiple regression analysis. Although these negative results are difficult to explain, especially those concerning hsCRP and fibrinogen in relation to FPG, patients in the current study all had poor diabetic control and were relatively few in number. This may have revealed a relationship demonstrable in a larger, more diverse clinical sample.
On the other hand, significant associations were demonstrated between fibrinogen and serum lipid concentrations such as TC and TG. This disagrees with a previous study of a large number of nondiabetic subjects, in which hsCRP but not fibrinogen showed a statistically significant correlation with TC and TG. (28) One should consider that many of our patients had albuminuria, which is associated with higher fibrinogen (29) and lipid concentrations. However, a more detailed analysis might be needed to explain these differences.
We also explored associations of hsCRP and fibrinogen with diabetic microangiopathy, including neuropathy. We know of no report simultaneously investigating associations of hsCRP and fibrinogen with diabetic microangiopathy (neuropathy, nephropathy, and retinopathy) in poorly controlled type 2 diabetes. Log hsCRP did not correlate with log UAE or with C[V.sub.RR] but fibrinogen did. As for retinopathy, no difference in mean hsCRP was seen between NDR, SDR, and PDR groups, while fibrinogen concentrations tended to be higher in the PDR group than in the NDR group without attaining statistical significance. Among possible associations between fibrinogen and types of microangiopathy, the strongest was observed between fibrinogen and nephropathy (UAE); this association also was demonstrated as independent by multiple regression analysis. Although this result is difficult to fully explain, hepatic overproduction of fibrinogen in response to nephropathy might have contributed to this strong correlation.
Taking the various results together, hsCRP appears not to have a significant association with microangiopathy in poorly controlled type 2 diabetes. On the other hand, fibrinogen appears to be associated with microangiopathy, particularly nephropathy.
This was a cross sectional study. Therefore, additional prospective studies are needed to investigate the association between hsCRP or fibrinogen and atherosclerosis in patients with type 2 diabetes. This is a major limitation of this study.
In summary, when we explored associations of hsCRP and fibrinogen with complications of poorly controlled type 2 diabetes, log hsCRP and fibrinogen correlated significantly with each other. We could not find any association between log hsCRP or fibrinogen and IMT. On the other hand, unlike hsCRP, fibrinogen had a significant association with UAE (ie, nephropathy) and with C[V.sub.RR] (neuropathy), and also showed a tendency toward association with retinal microangiopathy. We concluded that fibrinogen compared with hsCRP might be closely associated with diabetic microangiopathy and that both markers might not have evident associations with macroangiopathy as reflected by IMT in patients with type 2 diabetes.
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Kohzo Takebayashi, MD, PHD, Mariko Suetsugu, MD, Rika Matsutomo, MD, PHD, Sadao Wakabayashi, MD, PHD, Yoshimasa Aso, MD, PHD, and Toshihiko Inukai, MD, PHD
From the Department of Medicine, Koshigaya Hospital, Dokkyo University School of Medicine, Koshigaya, Japan.
Reprint requests to Kohzo Takebayashi, MD, Department of Medicine, Koshigaya Hospital, Dokkyo University School of Medicine, 2-1-50, Minami-Koshigaya, Koshigaya, 343-8555, Japan. Email: firstname.lastname@example.org
The study was approved by the local ethics committee of Dokkyo University School of Medicine.
Accepted April 4, 2005.
RELATED ARTICLE: Key Points
* We investigated the role of two acute-phase reactants; high-sensitivity C-reactive protein (hsCRP) and fibrinogen, as markers of diabetic complications in patients with type 2 diabetes.
* In the current study, fibrinogen, but not hsCRP had a significant association with diabetic nephropathy or neuropathy. Both hsCRP and fibrinogen did not correlate with IMT as a marker of macroangiopathy.
* We concluded that fibrinogen compared with hsCRP might be closely associated with diabetic microangiopathy and that these might not have a close association with diabetic macroangiopathy.
Table 1. Clinical characteristics of the diabetic subjects Diabetic subjects No. (male/female) 73 (38/35) Age (year) 60.8 [+ or -] 10.7 Duration of diabetes (year) 10.5 [+ or -] 7.8 FPG (mg/dL) 192.2 [+ or -] 72.6 Hb[A.sub.1C] (%) 10.0 [+ or -] 2.1 BMI (kg/[m.sup.2]) 23.9 [+ or -] 4.3 Smoker (n) 29 Therapy (n) Diet 5 OHA 50 Insulin 18 Retinopathy (n) NDR 38 SDR 17 PDR 18 Nephropathy (n) Normo 34 Micro 19 Macro 20 FPG, fasting plasma glucose; BMI, body mass index; OHA, oral hypoglycemic agents; NDR, no diabetic retinopathy; SDR, simple diabetic retinopathy; PDR, proliferative diabetic retinopathy; Normo, normal albuminuria; Micro, microalbuminuria; Macro, macroalbuminuria. Table 2. Correlation between log hsCRP or fibrinogen and various factors in 73 diabetic patients Variant log hsCRP FPG (mg/dL) r = -0.0523 P = 0.6602 Hb[A.sub.1C] (%) r = 0.0916 P = 0.4411 SBP (mmHg) r = 0.0822 P = 0.4893 DBP (mmHg) r = 0.0063 P = 0.9580 TC (mg/dL) r = 0.1340 P = 0.2585 TG (mg/dL) r = 0.1287 P = 0.2781 HDL-C (mg/dL) r = -0.0215 P = 0.8570 LDL-C (mg/dL) r = 0.1493 P = 0.2074 IMT (mm) r = 0.1789 P = 0.1299 Ccr (mL/min) r = -0.1041 P = 0.3809 C[V.sub.RR] (%) r = -0.0459 P = 0.6999 [log.sub.10]UAE (mg/g Cr) r = 0.0575 P = 0.6289 Fibrinogen (mg/dL) r = 0.3701 P = 0.0013* Variant Fibrinogen FPG (mg/dL) r = -0.1310 P = 0.2692 Hb[A.sub.1C] (%) r = -0.0658 P = 0.5804 SBP (mmHg) r = 0.1510 P = 0.2024 DBP (mmHg) r = -0.0661 P = 0.5782 TC (mg/dL) r = 0.3593 P = 0.0018* TG (mg/dL) r = 0.4034 P = 0.0004* HDL-C (mg/dL) r = -0.0088 P = 0.9410 LDL-C (mg/dL) r = 0.0685 P = 0.5649 IMT (mm) r = 0.1349 P = 0.2554 Ccr (mL/min) r = -0.1913 P = 0.1050 C[V.sub.RR] (%) r = -0.2433 P = 0.0381* [log.sub.10]UAE (mg/g Cr) r = 0.4815 P < 0.0001* Fibrinogen (mg/dL) -- -- r, Pearson's correlation coefficient; FPG, fasting plasma glucose; SBP, systolic blood pressure; DBP, diastolic blood pressure, TC: total cholesterol; TG, triglyceride, HDL-C: high density lipoprotein cholesterol; LDL-C, low density lipoprotein cholesterol; Ccr, creatinine clearance; C[V.sub.RR], coefficient of variation of RR intervals; UAE, urinary albumin excretion; IMT, intimal medial thickness. P < 0.05 are defined as statistical significance (* shows statistical significance).
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|Title Annotation:||Original Article|
|Publication:||Southern Medical Journal|
|Date:||Jan 1, 2006|
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