Abstract
In recent years, there has been renewed interest in hematological parameters as predictors of endothelial dysfunction and inflammation. The aim of our study is to evaluate the relationship between HbA1c and hematological indices, and to evaluate the relationship between these parameters and microvascular complications of diabetes. Three hundred and seven diabetic patients (124 male, 183 female; mean age 50.8±8.5), and 187 controls (76 male, 111 female; mean age 51.1±10.1) were included in the study. In the diabetic group, mean platelet volume (MPV), plateletcrit (PCT), platelet distribution width (PDW), white blood cell count (WBC), platelet count, platelet to lymphocyte ratio (PLR) and neutrophil to lymphocyte ratio (NLR) were significantly higher than the control group (P<0.05). Diabetic patients were divided into two group according to their HbA1c levels (Group 1; HbA1c <7 (n=82) and group 2; HbA1c ≥7 (n=225)). Mean platelet volume, PCT and PDW levels were significantly increased in group 2. Mean platelet volume was significantly increased in diabetic patients with retinopathy compared to those without retinopathy (P=0.006). The neutrophil to lymphocyte ratio and PLR levels were significantly higher in patients with nephropathy (P=0.004, P=0.004 respectively). There was statistically significant difference of lymphocyte count between patients with and without neuropathy. In correlation analysis, positive correlation between HbA1c and PCT (rs=0.192, P<0.001), HbA1c and PDW (rs=0.305, P<0.001), HbA1c and MPV (rs=0.352, P<0.001) were determined. In binary logistic regression analysis; WBC, PDW and PLR levels were found to be independently associated with diagnosis of diabetes while WBC, MPV, PLR and NLR levels were found to be independently associated with impaired glucose regulation. This study demonstrates that altered hematological indices are closely associated with HbA1c levels in individuals with and without diabetes and some of these parameters are associated with diabetic microvascular complications. These associations may be explained by connection between these easy accessible and inexpensive hematological indices and inflammation, tendency to coagulation and thrombosis in patients with diabetes.
Keywords: Hematological parameters, diabetes mellitus, HbA1c, microvascular complications
Introduction
Diabetes is a disease of metabolism clinically expressed by chronic hyperglycemia and blood lipid and protein disorders that have been extensively reported as linked to several complications that cause morbidity and mortality. Diabetes and uncontrolled hyperglycemia are known to play a significant role in the development of cardiovascular disease (CVD) since Framingham study [1,2]. Additionally, besides the diabetes and classical risk factors, the presences of microvascular complications are also predictor of coronary heart events [3]. In addition to atheroma formation, the combination of hypercoagulability, impaired fibrinolysis and impaired vasodilation likely further increases the risk of vascular occlusion and cardiovascular events in diabetes [4].
In recent years, there has been renewed interest in hematological parameters such as white blood count (WBC), mean platelet volume (MPV), platelet distribution width (PDW), plateletcrit (PCT), platelet count, platelet to lymphocyte ratio (PLR) and neutrophil to lymphocyte ratio (NLR) and are designated as predictors of endothelial dysfunction and inflammation.
Elevated white blood cell count (WBC) is a classical inflammatory marker and is associated with several cardiovascular disease risk factors and diabetes [5-9]. The association of increased MPV, PDW, PCT and platelet count with diseases related to endothelial dysfunction and inflammation as metabolic syndrome, diabetes, coronary artery disease and malignancy have been shown [10-19]. In the last decades, PLR and NLR were introduced as potential markers to determine inflammation in cardiac and non-cardiac disorders [19-27].
In the light of mentioned studies, the aim of present study is to evaluate the relationship between HbA1c and hematological indices, and to evaluate the relationship between these parameters and microvascular complications of diabetes.
Material and methods
Patient population and study design
Three hundred and seven diabetic patients and a control group of 187 healthy people enrolled in this cross-sectional prospective study. Diabetic group was divided into two according to their HbA1c levels as group 1; HbA1c <7 (n=82) and group 2; HbA1c ≥7 (n=225). Patients with hematologic diseases, hepatic failure, renal failure, heart failure, acute illness, chronic diseases like chronic infections, alcohol abuse, that are on medication altering the platelet function, and atherosclerotic diseases except for arterial hypertension were not included in the study.
Evaluation of demographical and clinical specifications
Patients’ blood pressure, height and weight measurements, age, gender, accompanying disease history, smoking habits, medication history and medical history were recorded. Body mass index (BMI) was calculated by using Quetlet index with weigh/height² formula. In addition, patients with DM were evaluated regarding metabolic regulation, nephropathy, retinopathy and neuropathy. Retinopathy diagnosis was made based on the findings of at least two microaneurysms and/or retinal hemorrhage and/or retinal damage in the records [28]. The quantitative urine albumin/creatinine ratio in morning spot urine samples were used for standard albuminuria determination and diagnosis of nephropathy.
Diabetic neuropathy symptom score were queried to determine the presence of diabetic peripheral neuropathy in all diabetic patients [29].
Biochemical and hematologic evaluation
Serum glucose levels were calculated with glucose oxidase technique, creatinine levels with Jaffe method, total cholesterol (TC), and triglyceride (TG), High Density Lipoprotein Cholesterol (HDL-C) with enzymatic colorimetric method of HDL and low density Lipoprotein Cholesterol (LDL-C) with Friedewald formula. HbA1c was studied with HPLC method. NLR and PLR were calculated as the ratio of neutrophils to lymphocytes and platelets to lymphocytes respectively. Simultaneous complete blood count results were used to obtain data of WBC, MPV, PDW, PCT, neutrophil and lymphocyte counts. NLR and PLR were calculated as the ratio of neutrophils to lymphocytes and platelets to lymphocytes respectively.
Statistical analysis
Statistical analyses were carried out using the Statistical Package for Social Sciences, Windows version 20.0 (SPSS, Chicago, IL, USA). Descriptive statistics for each variable were determined. Normality of the data distribution was assessed with the Kolmogorov-Smirnov test. Results for continuous variables were demonstrated as mean ± standard deviation. Results for continuous variables without normal distribution were demonstrated as median [inter quartile range (IQR)]. Statistical significant differences between the groups were determined by chi-square test for categorical variables. For continuous variables, nonparametric statistics (Mann-Whitney U), and parametric statistics (t test) were all used, as appropriate. Associations between the variables were explored using the Spearman’s rho (for data that was not normally distributed). Binary logistic regression analysis was also performed to define variables associated with diabetes in whole group and impaired glucose regulation in diabetic patients. A P value less than 0.05 was considered significant.
Results
A total of 307 patients (124 male, 183 female; mean age 50.8±8.5) and 187 controls (76 male, 111 female; mean age 51.1±10.1) were selected to the study. Comparison of the groups regarding demographical, clinical, biochemical and hematologic data are shown in Table 1. There were no statistically significant differences between the groups respecting the following variables; age, gender, BMI, waist circumference, systolic blood pressure, diastolic blood pressure, TC, HDL-C, LDL-C, TG and creatinine levels whereas there were statistically significant difference between the groups respecting; MPV, PCT, PDW, WBC, platelet count, PLR, NLR, fasting plasma glucose and HbA1c (P<0.05).
Table 1.
Demographical and laboratory specifications of diabetes and control group
| Parameters | Diabetes Group (n=307) | Control Group (n=187) | P value |
|---|---|---|---|
| Age (year)* | 52 (45-58) | 52 (43-58) | >0.05 |
| Gender (f/m)** | 183/124 | 111/76 | >0.05 |
| BMI (kg/m²)* | 30.8 (27.5-33.6) | 30.7 (27.6-35.2) | >0.05 |
| Waist circumference (cm)* | 102 (97-109) | 103 (96-110) | >0.05 |
| SBP (mmHg)* | 130 (120-140) | 130 (115-135) | >0.05 |
| DBP (mmHg)* | 80 (70-80) | 80 (70-80) | >0.05 |
| TC (mg/dL)* | 206 (174-233) | 209 (177-239) | >0.05 |
| HDL-C (mg/dL)* | 45 (40-50) | 47 (40-52) | >0.05 |
| LDL-C (mg/dL)*** | 126.13±42.81 | 131.20±36.73 | >0.05 |
| TG (mg/dL)* | 164 (118-225) | 144 (110-208) | >0.05 |
| Creatinine (mg/dL)* | 0.71 (0.60-0.85) | 0.71 (0.63-0.85) | >0.05 |
| MPV (fL)* | 9.2 (8.7-9.9) | 8.8 (8.3-9.3) | <0.001 |
| PCT (%)* | 0.232 (0.195-0.269) | 0.212 (0.186-0.238) | <0.001 |
| PDW (fL)* | 16.4 (15-17.8) | 15.4 (14.2-16.5) | <0.001 |
| Platelet count (x103/uL)* | 249 (214-297) | 244 (209-275) | 0.033 |
| FPG (mg/dL)* | 182 (125-243) | 86 (80-92) | <0.001 |
| HbA1c (%)* | 8.6 (6.9-10.4) | 5.3 (5.1-5.5) | <0.001 |
| WBC (x103/uL)* | 7.4 (6.4-8.7) | 6.8 (5.9-7.9) | <0.001 |
| NLR* | 1.75 (1.40-2.27) | 1.58 (1.30-2.00) | 0.001 |
| PLR* | 106.96 (84.96-135.00) | 101.30 (80.70-119.70) | 0.012 |
Mann-Whitney U (Data are given as median (IQR)).
Chi-Square Test.
T-Test (Data are given as mean ± SD).
SBP: Systolic Blood Pressure. DBP: Diastolic Blood Pressure. TC: Total Cholesterol. HDL-C: High Density Lipoprotein Cholesterol. LDL-C: Low Density Lipoprotein Cholesterol. TG: Triglyceride. MPV: Mean Platelet Volume. FPG: Fasting Plasma Glucose. HbA1c: Glycosylated Hemoglobin.
As shown in Table 2, when patients separated in two groups according to HbA1c levels, there were no statistically significant differences between the groups respecting the following variables; age, gender, BMI, waist circumference, systolic blood pressure, diastolic blood pressure, TC, HDL-C, LDL-C, TG, creatinine levels, WBC, platelet count, lymphocyte count, neutrophil count, NLR and PLR while there were statistically significant difference between the groups respecting; disease duration, MPV, PCT, PDW, fasting plasma glucose, HbA1c and albuminuria.
Table 2.
Demographic. clinical and laboratory features of the patients according to HbA1c groups
| Parameters | HbA1c <7 (n=82) | HbA1c ≥7 (n=225) | P value |
|---|---|---|---|
| Age (years)* | 51.5 (45-57.3) | 52 (45-58) | >0.05 |
| Gender (f/m)** | 45/37 | 138/87 | >0.05 |
| BMI (kg/m²)* | 30.9 (28.4-33.7) | 30.7 (27.2-33.6) | >0.05 |
| Waist circumference (cm)* | 103 (98-110) | 102 (97-109) | >0.05 |
| Disease duration (month)* | 48 (24-72) | 72 (36-132) | <0.001 |
| SBP (mmHg)* | 130 (114-140) | 130 (120-140) | >0.05 |
| DBP (mmHg)* | 75 (65-81) | 80 (70-80) | >0.05 |
| TC (mg/dL)*** | 205.40±45.11 | 208.21±48.55 | >0.05 |
| HDL-C (mg/dL)* | 45 (41-52) | 45 (39-50) | >0.05 |
| LDL-C (mg/dL)*** | 124.55±39.16 | 126.71±44.13 | >0.05 |
| TG (mg/dL)* | 164 (131-198) | 164 (112-233) | >0.05 |
| Creatinine (mg/dL)* | 0.72 (0.62-0.85) | 0.70 (0.59-0.85) | >0.05 |
| MPV (fL)*** | 8.9±0.8 | 9.4±0.9 | <0.001 |
| PCT (%)* | 0.222 (0.195-0.258) | 0.237 (0.195-0.280) | 0.039 |
| PDW (fL)* | 16.0 (15.0-17.0) | 16.6 (15.3-18.0) | 0.002 |
| Platelet Count (x103/uL)* | 251 (226-289) | 248 (209-301) | >0.05 |
| FPG (mg/dL)* | 116 (110-121) | 205 (172-255) | <0.001 |
| HbA1c (%)* | 6.5 (6.2-6.8) | 9.5 (8.2-11.1) | <0.001 |
| WBC (x103/uL)* | 7.3 (6.3-8.1) | 7.5 (6.5-8.7) | >0.05 |
| NLR* | 1.92 (1.40-2.34) | 1.71 (1.40-2.23) | >0.05 |
| PLR* | 107.61 (88.29-129.77) | 106.81 (83.50-138.51) | >0.05 |
| Albuminuria (mg/g Cr)* | 8.83 (2.65-19.88) | 18.43 (7.71-224.53) | <0.001 |
Mann-Whitney U (Data are given as median (IQR)).
Chi-Square Test.
T-Test (Data are given as mean ± SD).
SBP: Systolic Blood Pressure. DBP: Diastolic Blood Pressure. TC: Total Cholesterol. HDL-C: High Density Lipoprotein Cholesterol. LDL-C: Low Density Lipoprotein Cholesterol. TG: Triglyceride. MPV: Mean Platelet Volume. FPG: Fasting Plasma Glucose. HbA1c: Glycosylated Hemoglobin.
In the evaluation of association of retinopathy and hematological indices; there were statistically significant difference of MPV levels between patients with (n=67; MPV=9.54±0.88) and without (n=240; MPV=9.20±0.92) retinopathy (P=0.006) while other studied hematological indices were not differ statistically (P>0.05).
In the evaluation of association of nephropathy and hematological indices; there were statistically significant difference of NLR, PLR levels and absolute lymphocyte count between patients with [n=114; NLR=1.99 (1.50-2.62); PLR=116.43 (88.26-150.23); lymphocyte count=2.17 (1.80-2.75)] and without [n=193; NLR=1.68 (1.37-2.16); PLR=102.37 (83.98-127.77); lymphocyte count=2.46 (1.99-2.99)] nephropathy (P=0.004, P=0.004, P=0007 respectively) while other studied hematological indices were not differ statistically (P>0.05).
In the evaluation of association of neuropathy and hematological indices; there was statistically significant difference of lymphocyte count between patients with [n=104; 2.10 (1.81-2.78)] and without [n=203; 2.44 (1.98-2.93)] neuropathy (P=0.046) while other studied hematological indices were not differ statistically (P>0.05).
The correlation between HbA1c and hematological parameters were tested using bivariate correlation analysis. Positive correlation between serum HbA1c and WBC (rs=0.145, P=0.001), HbA1c and PCT (rs=0.192, P<0.001), HbA1c and PDW (rs=0.305, P<0.001), HbA1c and MPV (rs=0.352, P<0.001) were determined.
Binary logistic regression analysis was also performed to define the variables associated with diagnosis of diabetes in whole group (Table 3) and impaired glucose regulation (HbA1c ≥7%) in diabetic patients (Table 4). Age, waist circumference, BMI, creatinine, TC, LDL-C, HDL-C, TG, SBP, WBC, PCT, PDW, MPV, platelet count, NLR and PLR levels were included in this model. White blood cell count, PDW and PLR levels were found to be independently associated with diagnosis of diabetes while WBC, MPV, NLR and PLR levels were found to be independently associated with impaired glucose regulation.
Table 3.
Binary logistic regression of diagnosis of diabetes
| Parameters | Odds Ratio | 95% C.I. | P value | |
|---|---|---|---|---|
|
| ||||
| Lower | Upper | |||
| Age | 0.997 | 0.975 | 1.021 | >0.05 |
| WC | 1.013 | 0.988 | 1.040 | >0.05 |
| BMI | 1.016 | 0.966 | 1.067 | >0.05 |
| Creatinine | 0.905 | 0.260 | 3.147 | >0.05 |
| TC | 0.994 | 0.984 | 1.005 | >0.05 |
| LDL-C | 1.009 | 0.998 | 1.020 | >0.05 |
| HDL-C | 1.002 | 0.975 | 1.029 | >0.05 |
| TG | 1.000 | 0.996 | 1.003 | >0.05 |
| SBP | 0.990 | 0.979 | 1.001 | >0.05 |
| WBC | 0.708 | 0.576 | 0.870 | 0.001 |
| PCT | 23.253 | 0.000 | 1.025E+20 | >0.05 |
| PDW | 0.810 | 0.710 | 0.925 | 0.002 |
| MPV | 0.472 | 0.160 | 1.392 | >0.05 |
| Platelet Count | 0.993 | 0.955 | 1.033 | >0.05 |
| NLR | 1.002 | 0.581 | 1.728 | >0.05 |
| PLR | 0.981 | 0.969 | 0.994 | 0.003 |
WC: Waist Circumference, BMI: Body Mass Index, TC: Total Cholesterol, HDL-C: High Density Lipoprotein Cholesterol, LDL-C: Low Density Lipoprotein Cholesterol, TG: Triglyceride, SBP: Systolic Blood Pressure, WBC: White Blood Cell Count, PCT: Plateletcrit, PDW: Platelet Distribution Width, MPV: Mean Platelet Volume, NLR: Neutrophil to Lymphocyte Ratio: PLR: Platelet to Lymphocyte Ratio.
Table 4.
Binary logistic regression of impaired glucose regulation (HbA1c >7%)
| Parameters | Odds Ratio | 95% C.I. | P value | |
|---|---|---|---|---|
|
| ||||
| Lower | Upper | |||
| Age | 1.012 | 0.978 | 1.046 | >0.05 |
| WC | 0.987 | 0.951 | 1.025 | >0.05 |
| BMI | 0.957 | 0.888 | 1.031 | >0.05 |
| Creatinine | 0.495 | 0.092 | 2.656 | >0.05 |
| TC | 0.997 | 0.983 | 1.012 | >0.05 |
| LDL-C | 1.001 | 0.986 | 1.015 | >0.05 |
| HDL-C | 0.977 | 0.942 | 1.013 | >0.05 |
| TG | 1.002 | 0.997 | 1.006 | >0.05 |
| SBP | 1.012 | 0.998 | 1.026 | >0.05 |
| WBC | 1.637 | 1.165 | 2.300 | 0.004 |
| PCT | 0.000 | 0.000 | 2984029.470 | >0.05 |
| PDW | 1.129 | 0.941 | 1.355 | >0.05 |
| MPV | 7.047 | 1.397 | 35.551 | 0.018 |
| Platelet Count | 1.038 | 0.982 | 1.097 | >0.05 |
| NLR | 0.321 | 0.143 | 0.720 | 0.006 |
| PLR | 1.028 | 1.007 | 1.049 | 0.008 |
WC: Waist Circumference; NLR: Neutrophil to Lymphocyte Ratio; PLR: Platelet to Lymphocyte Ratio; BMI: Body Mass Index; TC: Total Cholesterol; HDL-C: High Density Lipoprotein Cholesterol; LDL-C: Low Density Lipoprotein Cholesterol; TG: Triglyceride; SBP: Systolic Blood Pressure; WBC: White Blood Cell Count; PCT: Plateletcrit; PDW: Platelet Distribution Width; MPV: Mean Platelet Volume; NLR: Neutrophil to Lymphocyte Ratio.
Discussion
There are four main findings of the present study. First, several hematological parameters (MPV, PCT, PDW, WBC, platelet count, PLR and NLR) were significantly different between the normal and diabetic groups. Second, levels of MPV, PCT and PDW were significantly different between the regulated (HbA1c <7%) and unregulated (HbA1c ≥7%) diabetic patients and levels of these parameters were tend to increase in unregulated patients. Third, levels of MPV (in retinopathy), PLR (in nephropathy), NLR (in nephropathy) and lymphocyte counts (in nephropathy and neuropathy) were differ in patients with and without microvascular diabetic complications.
Finally, WBC, PDW and PLR levels were found to be independent predictor of diabetes while WBC, MPV, NLR and PLR levels were found to be independent predictor of impaired glucose regulation in diabetic patients.
Patients with type 2 diabetes mellitus (T2DM) have an increased risk of coagulation abnormalities and thromboembolic events. Platelets have a key role and increased adhesion, activation, and aggregation of platelets due to dysregulation of several signaling pathways and metabolic disturbances including insulin resistance, hyperglycemia, and dyslipidemia have been noted in diabetic patients [30,31]. Systematic inflammation, oxidative stress, impaired calcium metabolism, decreased bioavailability of nitric oxide, increased phosphorylation and glycosylation of cellular proteins are responsible for increased platelet activation and increased release of prothrombotic and proinflammatory agents in diabetes [32]. Larger platelets which can be demonstrated by increased MPV are more active because of elevated prothrombic contents, such as thromboxane A2, thromboxane B2, platelet factor 4, serotonin, and platelet-derived growth factor [33].
Association of increased MPV with prediabetes, diabetes and vascular diabetic complications are stated in the literature [16,34-39]. Moreover, association of MPV and impaired glucose regulation in diabetic patients also reported [12]. As with MPV, increased PDW is also reported to be associated with diabetes and vascular complications [16,17,38,40-42]. Performed studies did not report a relation between increased PCT, diabetes and related complications [16,42,43]. Conflicting results have been reported for the relation of platelet count and diabetes. Several studies reported no relation [12,16,17,42] while some reported positive association [39,44] between diabetes and platelet count.
Inflammation is closely associated with both secretory function of beta cell and insulin resistance [45-47]. Circulating inflammatory molecules can decrease beta cell functions directly by secretory dysfunction or uncontrolled apoptosis [45,46]. As a result glucotoxicity and lipotoxicity occurs and causes enhanced inflammatory process and a vicious cycle [46]. Elevated WBC is a classical inflammatory marker and reveals association of inflammation with impaired glucose metabolism, insulin resistance and DM [5-7]. In recent years PLR and NLR were introduced as novel inflammatory markers in cardiac and non-cardiac disorders [19-27]. Additionally, elevated levels of PLR and NLR were stated in diabetes and diabetic nephropathy [25,26]. Beside the thromboembolic disorders, associations of platelet indices with inflammation, disease activity of inflammatory disorders and response to anti inflammatory therapies have been also shown [33].
Consistent with the literature, our results reveals that inflammation, tendency to coagulation and thrombosis can be detected with these easy accessible and inexpensive hematological indices. Moreover some of these parameters may help to aware clinicians about impaired glucose regulation and vascular diabetic complications. According to our extensive literature, there has been no study researching association of these parameters together with diabetes and diabetic complications.
Our study has some limitations. First, since it involves one single institution, it may not represent the general population. Second, we cannot determine a cause and effect relationship due to the cross-sectional nature of our study. Despite the limitations, the strength of our study is relatively the large cohort of individuals.
Results of the present study reveal that inflammation and tendency to coagulation and thrombosis can be detected with easy accessible and inexpensive hematological indices. However, large scaled studies need to be conducted in order to evaluate its usability and efficiency.
Disclosure of conflict of interest
None.
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