C-Reactive Protein And Fibrinogen In Type 2 Diabetes Mellitus*

Introduction. Chronic,low-grade inﬂ ammation is important in the development and progression of type 2 diabetes mellitus (T2DM). Indicators of increased inﬂ ammatory activity include elevated values of circulating acute phase proteins like C-reactive protein (CRP) and ﬁ brinogen. The aim of the study was to test sex-related differences in CRP and ﬁ brinogen blood levels in T2DM patients. Patients and Methods. The cross-sectional study included 40 T2DM patients, both sexes (19 males and 21 females), median age 70 (36-90) years. Patients were hospitalized at the Clinic of Endocrinology, Clinical Center University of Sarajevo. The fasting glucose levels, glycated haemoglobin, ﬁ brinogen and CRP in the blood of T2DM patients were determined by standard laboratory methods. The data were analysed by statistical software SPSS 19. Results. The median values of CRP and ﬁ brinogen in blood were not statistically different between female and male T2DM patients, although values had tendency to be higher in female patients [17.30 mg/L (3.40-61.35) vs. 9.60 mg/L (3.50-28.90); p=0.573]; [5.70 g/L (4.20-6.35) vs. 3.80 g/L (3.60-6.00); p=0.078]. A positive correlation between CRP and ﬁ brinogen was found in samples from female T2DM patients (rho=0.606;p<0.01). Conclusion. Elevated CRP and ﬁ brinogen indicate the presence of inﬂ ammation in T2DM patients. Female patients had higher values of both inﬂ ammatory markers in blood in comparison to males, but we did not prove statistically signiﬁ cant sex-related differences.

One of important factors in the pathogenesis of type 2 diabetes mellitus (T2DM) is a state of subclinical chronic inß ammation. 1It is considered that inß ammation is a key factor in insulin resistance. 2 Except for the disease development, chronic low-grade inß ammation is important in the progression of T2DM.Hyperglycemic condition and proinß ammatory state in T2DM patients are responsible for the development of a wide spectrum of atherosclerotic complications. 3 Indicators of increased inß ammatory activity are elevated values of circulating acute phase proteins like Creactive protein (CRP) and Þ brinogen.These proteins play a signiÞ cant role in initiation, aggravation and progression of atherosclerosis in diabetic patients. 46][7][8] In addition, CRP further contributes to the progression of atherosclerosis by stimulation of monocyte interleukin-6 production. 9There are several mechanisms by which Þ brinogen increases cardiovascular risk such as stimulation of platelet aggregation, promotion of Þ brin formation and increase in plasma viscosity. 10,11Sex-related differences exist in CRP and Þ brinogen blood values among the healthy population. 12Accordingly, our aim was to examine if sex-related differences in CRP and Þ brinogen blood levels also exist in T2DM patients.

Patients and Methods
Patients.Forty (n=40) T2DM patients hospitalized at the Clinic of Endocrinology, Clinical Center University of Sarajevo were included in the study.Patients were divided in sex-based groups: T2DM-males (n=19) and T2DM-females (n=21).The median age of T2DM patients was 70 (36-90) years.All data were taken from patients' medical histories.
Clinical examinations and laboratory measurements.Systolic and diastolic blood pressures were determined by standard protocol using mercury manometer.Body mass index (BMI) was calculated as weight in kilograms divided by height in meters squared.Glucose hexokinase method (Dimension RXL, Siemens, Munich, Germany) was used for fasting blood glucose measurement (reference range 3.3-6.1mmol/L).CRP and HbA1c were analysed by immunoturbidimetric methods on the Dimension Xpand Plus Analyzer (Siemens, Munich, Germany).The CRP reference range was 0-5 mg/L and values less than 6% for HbA1c were considered normal.Fibrinogen measurement was done using immunonephelometric method using BN II nephelometer (Siemens, Munich, Germany) (reference range 1.8-3.5 g/L).

Statistical analysis.
Results of descriptive statistics are presented by median with range from Þ rst to third quar-tile.Differences of parameters between two groups were analysed using non-parametric Mann-Whitney U test because the criteria of normal data distribution were not sat-isÞ ed.Spearman's correlation test was used to analyse the association between studied parameters.For data analysis, we used SPSS Statistics software version 19.0 (SPSS Inc, Chicago, IL, USA).P values less than 0.05 were considered statistically signiÞ cant. 1.There were no age-related differences between T2DM patients of both sexes.We found that type 2 diabetic patients were overweight with a poor control of glycaemia.No statistically signiÞ cant differences were found with regard to glucose and HbA1c levels, duration of disease and blood pressure among men and women.Concentrations of CRP and Þ brinogen in blood were increased in both male and female T2DM patients.The median blood values of CRP and Þ brinogen had tendency to be higher in female T2DM compared to male patients, without statistical signiÞ cance.

Characteristics of clinical and biochemical parameters of type 2 diabetes mellitus patients are presented in Table
Analyses of CRP and Þ brinogen correlation and association of inß ammatory markers with glycemic control parameters in the blood of male and female patients are presented in Table 2. SigniÞ cant positive correlation was found between inß ammatory markers in females while glucose and CRP correlated signiÞ cantly in male diabetic patients.The in-signiÞ cant correlations were found between inß ammatory markers and glycemic control parameters in female patients.In male T2DM patients, no signiÞ cant correlations were observed between blood values of CRP and Þ brinogen and between Þ brinogen and HbA1c (Table 2).

Discussion
Poorly controlled diabetes with elevated CRP and Þ brinogen was found in the patients studied.Analysis of sex-related difference in achieving glycemic control has shown that male patients had a higher glucose values than females.A poorer long-term glycemic control was noted in female patients but sex-related differences were not statistically different.A separate analysis of CRP and Þ brinogen in females and males has revealed a higher value in female patients.Gender related differences in CRP and Þ brinogen were insigniÞ cant, but positive correlations between CRP and Þ brinogen values in females (p<0.01) and glucose and CRP in males (P<0.05) were found.The mechanisms associated with insulin resistance and accelerated atherosclerosis development in patients with T2DM include impaired vasodilatation, increased oxidative stress, low-grade inß ammation and thrombus formation, just to name a few. 13ß ammation markers are indicators of risk for cardiovascular complications development in diabetic patients.CRP and Þ brinogen are hallmarks of the chronic inß ammation and indicators of adipose dysfunction and insulin resistance. 14There are published data that the relative risk for cardiovascular disease onset is more pronounced in female diabetic patients compared to male. 15Lakoski and associates have shown a higher blood value of high sensitivity CRP (hs-CRP) in women compared with men and this gender difference was maintained across all ethnic subgroups. 12The results of Lai and associates and Ahonen and coauthors studies have shown the existence of stronger association of elevated hs-CRP concentration and metabolic syndrome in women. 16,17A higher circulating levels of CRP in women are well established and can be related to differences in visceral and subcutaneous fat and oestrogen levels. 18,12,19,20Study of Ili and associates have shown that women with T2DM and clinically manifest coronary artery disease have more prominent lipid and inß ammatory disorder and they are more susceptible for cardiovascular complication development. 14A reduced susceptibility to plasmin degradation and increase of Þ brinogen synthesis rate are possible mechanisms of elevated Þ brinogen in diabetic patients. 21Study of Alzahrani and associates found higher values of Þ brinogen in female T2DM patients compared to male patients.They have shown the existence of variant type of clots with compromised Þ brinolysis in female T2DM patients.There was gender speciÞ c association between clotting parameters and cardiometabolic risk factors in this population. 22e results obtained implicate the need for further evaluation of gender difference in these markers by larger study group and use of high sensitivity immunoassays.The Þ ndings in this study showed that the presence of elevated CRP and Þ brinogen indicates the existence of inß ammation in T2DM patients as possible risk factors for complication development.Female patients had tendency for higher values of both inß ammatory markers in the blood, but the differences were not statistically signiÞ cant.

Table 1 .
Clinical and biochemical parameters of type 2 diabetic patients Abbreviations: T2DM-type 2 diabetes mellitus; BMI-body mass index; STA-systolic blood pressure; DTA-diastolic blood pressure; FBGfasting blood glucose;HbA1c-glycated haemoglobin; CRP-C-reactive protein; n-number of the patients included in the study; P-probability; † -biochemical parameters which are out of the reference range.