https://orcid.org/0000-0001-7306-5233
Abstract
Aim
Hemogram indices were proposed as novel inflammatory markers in chronic conditions and inflammation has substantial role in the pathogenesis of type 2 diabetes mellitus (T2DM). We aimed to observe hemogram parameters of type 2 diabetic male subjects with various age groups in well and poorly controlled subsets.
Methods
Data of type 2 diabetic men enrolled to the study were recorded from patient files of the institution. Study population were grouped into three according to the age. Group A was consisted of patients younger than 55 years, Group B was consisted of patients aged between 55 and 64 years, and Group C was consisted of patients aged 65 years or older. Data of the study groups were compared.
Results
Study population was consisted of 130 subjects; 44 in Group A and 43 in each of Groups B and C. Median red cell distribution width (RDW) (p = .04), mean RDW to platelet ratio (RPR) (p = .006), median mean platelet volume to platelet ratio (MPR) (p = .02) levels of the study groups were statistically different. HbA1c level was significantly and positively correlated with RDW (r = 0.45, p < .001), neutrophil to lymphocyte ratio (NLR) (r = 0.47, p < .001), mean platelet volume to lymphocyte ratio (MLR) (r = 0.35, p < .001), MPR (r = 0.26, p = .003), and RPR (r = 0.37, p < .001) levels.
Conclusion
Elevated RDW, NLR, MLR, MPR, and RPR levels in diabetic men should trigger the measurement of HbA1c since each were strongly correlated with HbA1c level. Moreover, elevated RDW, NLR, MLR, and RPR could be marker of worse diabetic control in men with T2DM.
Introduction
Type 2 diabetes mellitus (T2DM) is one of the most common chronic diseases in the world. The disease itself and its complications cause enormous functional and fiscal burden annually to the world societies [Citation1].
Inflammation has substantial role in the pathogenesis of T2DM. Apoptosis of pancreatic beta cells are driven by interleukin-1 beta, which is stimulated by elevated plasma glucose levels [Citation2,Citation3].
Recently, the indices that derived from the routine hemogram test are proposed as novel inflammatory markers and predictors of outcome in chronic conditions. Some of these markers are red cell distribution width (RDW), mean platelet volume (MPV), neutrophil count to lymphocyte count ratio (NLR), platelet count to lymphocyte count ratio (PLR), MPV to lymphocyte count ratio (MLR), MPV to platelet count ratio (MPR), and RDW to platelet count ratio (RPR). Many of the hemogram parameters could interact with pathological processes of conditions that are characterized with prominent or subtle amount of inflammation. Associations between these indices and inflammatory diseases have been well established [Citation4–13]. Moreover, T2DM or its complications have been suggested to be related with novel inflammatory hemogram parameters in literature [Citation14–20]. However, to the best of our knowledge, the association between these parameters and T2DM in different age groups has not been studied yet.
In present retrospective analysis, we aimed to observe RDW, MPV, NLR, PLR, MLR, MPR, and RPR levels of type 2 diabetic male subjects with various age groups in well and poorly controlled subsets. We also aimed to study possible association between those indices and diabetic regulation.
Methods
The present study was conducted in Internal Medicine department of Abant Izzet Baysal University Hospital. After obtaining approval of local ethics committee (2019/128), type 2 diabetic men were enrolled to the study and their data were recorded from patient files of the institution. Exclusion criteria were as follows: patients with other types of diabetes mellitus other than T2DM, active infectious diseases, malignant tumors, or inflammatory conditions; such as rheumatoid arthritis, inflammatory bowel diseases, etc.
Age, height, weight, waist circumference of the participants were recorded. The body mass index (BMI) was calculated by division of weight (kg) by the square of height (m).
Duration of the T2DM, existence of accompanying diseases (i.e. hypertension, cardiovascular diseases, heart failure, renal disease, chronic obstructive pulmonary disease), treatment of T2DM (either monotherapy with an oral anti-diabetic or combination/insulin treatment), the presence of diabetic retinopathy, nephropathy or neuropathy, and smoking habit were noted. Diabetic patients were all on standard diabetic diet that was recommended by diet department of our clinic.
Serum urea, creatinine, uric acid, total cholesterol, LDL cholesterol, HDL cholesterol, triglyceride, fasting blood glucose, and glycated hemoglobin (HbA1c) levels were recorded. While subjects with an HbA1c lower than 7% were defined as well controlled T2DM, others were grouped into poorly controlled T2DM group.
White blood cell count (WBC), neutrophil count, lymphocyte count, hemoglobin (Hb), hematocrit (Htc), RDW, platelet count (PLT), and MPV values of the subjects were obtained from database and recorded. NLR, PLR MLR, MPR, and RPR were calculated as division of neutrophil count by lymphocyte count, PLT by lymphocyte count, MPV by lymphocyte count, MPV by PLT, and RDW by PLT, respectively.
Study population were grouped into three according to the age. Group A was consisted of patients younger than 55 years, Group B was consisted of patients aged between 55 and 64 years, and Group C was consisted of patients aged 65 years or older.
Statistics were held with SPSS software (SPSS 15.0 for Windows, IBM Co., Chicago, IL, USA). Distribution of variables were conducted with Kolmogorov–Smirnov test. Variables with normal distribution were compared with One-Way ANOVA test between groups and expressed as mean ± standard deviation. Variables without normal distribution were conducted with Kruskal–Wallis test and expressed as median (Min–Max). Correlation between HbA1c and study parameters were done with Pearson’s correlation analysis. Sensitivity and specificity of study parameters in determining well diabetic control and presence of microvascular complications were held with ROC analysis. A p value lower than .05 was considered as statistically significant.
Results
Study population was consisted of 130 subjects; 44 in Group A and 43 in each of Groups B and C. Ages of Groups A, B, and C were 48 (2–54) years, 59 (55–64) years, and 71 (65–85) years, respectively (p < .001).
Body weight (p = .49), waist circumference (p = .44), BMI (p = .17), and diastolic blood pressure were not significantly different among the study groups. However, duration of T2DM was significantly longer in Group C (10 (1–30) years) compared to Groups A (5 (1–30) years) and B (4 (1–15) years) (p = .005).
Serum levels of urea (p = .83), creatinine (p = .26), fasting glucose (p = .18), LDL cholesterol (p = .30), HDL cholesterol (p = .60), HbA1c (p = .12), and blood WBC (p = .82), PLT (p = .06), MPV (p = .10), NLR (p = .07), PLR (p = .49), and MLR (p = .054) levels were not significantly different among the study groups.
Mean RPR of Groups A, B, and C was 6 ± 1.5%, 7 ± 1.7%, and 7.5 ± 1.8%, respectively. The difference between groups was statistically significant (p = .006).
Median MPR of Groups A, B, and C was 3 (2–5)%, 3 (2–8)%, and 4 (2–7)%, respectively. The difference between groups was statistically significant (p = .02).
Median RDW of Groups A, B, and C was 15 (13–20)%, 15.5 (13–18)%, and 16 (13–19)%, respectively. The difference between groups was statistically significant (p = .04).
Presence of comorbidities in Groups A, B, and C was 39%, 3%, and 44%, respectively (p = .11).
About 33% of patients in Group A, 18% in Group B, and 14% in Group C had well controlled T2DM. Although there was a difference in the rate of well controlled T2DM between the groups, this difference could not reach the statistically significance level (p = .08).
The rate of microvascular complications in Groups A, B, and C was 50%, 49%, and 54%, respectively (p = .90). Similarly, the rate of smoking patients in Groups A (34.1%), B (34.9%), and C (32.6%) was not statistically different (p = .34).
The HbA1c level was significantly and positively correlated with RDW (r = 0.45, p < .001), NLR (r = 0.47, p < .001), MLR (r = 0.35, p < .001), MPR (r = 0.26, p = .003), and RPR (r = 0.37, p < .001) levels. Neither MPV nor PLR was correlated with HbA1c levels.
A ROC analysis revealed that RPR values greater than 6.2% was 75% sensitive and 57% specific for determining poorly controlled T2DM.
A ROC analysis revealed that RDW values greater than 15% was 75% sensitive and 54% specific for determining poorly controlled T2DM.
A ROC analysis revealed that NLR values greater than 1.64 was 67% sensitive and 57% specific for determining poorly controlled T2DM.
In subgroup analysis according to the age group, NLR (p = .03) and RDW (p = .008) were significantly higher in poorly controlled compared to well controlled T2DM subjects in Group A. RPR (p = .049) was significantly higher in poorly controlled compared to well controlled T2DM subjects in Group B. NLR (p = .04) and MLR (p = .02) were significantly higher in poorly controlled compared to well controlled T2DM subjects in Group C.
Discussion
The main outcomes of present study are as follows: (i) RDW, NLR, MLR, MPR, and RPR are reliable markers of inflammatory state which are positively correlated with HbA1c levels in men with T2DM, (ii) although duration of T2DM was different, the rate of well controlled disease, the presence of microvascular complications, and HbA1c levels were not different in elderly men compared to younger men, (iii) RPR, NLR, and RDW have considerable sensitivity and specificity in the determination of worse diabetic regulation in men with T2DM.
Despite RPR, MPR, and RDW were significantly higher in Group C compared to Groups A and B, significant increase in poorly controlled T2DM subjects compared to well controlled diabetics was demonstrated only for RDW in only Group A. Groups B and C were lack of such association. Testosterone increases the mass of skeletal muscle and it gradually decrease in men by aging [Citation21]. One can assume that control of T2DM should be better in younger compared to older diabetic men, since testosterone has protective effect in progression of prediabetes to overt T2DM [Citation22]. Present study was lack of such association, however, diabetic control could be predicted by RDW in Group A, by NLR in Groups A and C, by RPR in Group B, and by MLR in Group C. Testosterone is an anabolic steroid hormone that have substantial effects on hematopoiesis in bone marrow [Citation23]. In literature, it has been shown that testosterone has beneficial effects on obesity markers; which is closely associated with insulin resistance and even T2DM [Citation24]. Possibly, higher testosterone levels in Group A and lower in Group C were responsible of the association of different hematological parameters and diabetic control in the present study.
Another important hormone for skeletal system is vitamin D. Authors have reported that lower vitamin D levels were associated with erectile dysfunction in diabetic men [Citation25], which could also be related with low testosterone levels. Remaining at home for longer duration in daytime is a more common issue in elderly and is associated with lower vitamin D levels. Vitamin D deficiency is associated with higher NLR levels [Citation26]. Therefore, distinct hematological parameters were associated with diabetic control in each one of study subgroups in the present study.
Possible different testosterone levels in groups of the present study could be the underlying reason of association between NLR and diabetic control, because, androgen therapy has important effects on inflammatory markers and blood glucose levels [Citation27]. Aging causes reduction in circulating testosterone levels men, therefore, different age groups of diabetic men could have different amount of inflammatory burden caused by diabetes mellitus. In the literature, elevated NLR was associated with T2DM and correlated with HbA1c strongly, in general population [Citation28]. Similar to the literature, present study showed its association with diabetic control in Groups A and C and its correlation with HbA1c.
Moreover, elevated RDW was also suggested to be a risk factor for the development of macrovascular and microvascular complications in T2DM [Citation29]. In the present study, it was associated with diabetic control in T2DM patients in Group A and it had great sensitivity and specificity in the determination of poor controlled disease.
Physicians tend to follow tight blood glucose control more strictly in younger than older diabetic subjects, since accompanying comorbidities are affected by hypoglycemia during tight control. Indeed, nocturnal hypoglycemia was suggested to be linked with fasting glucose levels [Citation30]. To the best of our knowledge, RPR has not been studied in T2DM, previously. Nevertheless, it has been reported to be increased in hepatic fibrosis, another inflammatory condition [Citation31]. In the present study, elevation of RPR was associated with poorly controlled T2DM.
Underlying cause of elevated hemogram indices in men with T2DM could include several possible mechanisms. Inflammatory burden caused by poorly regulated diabetes mellitus may cause elevation in circulating inflammatory cytokines, such as c-reactive protein, interleukin-1, and tumor necrosis factor alpha. These cytokines may interact in hematopoiesis in bone marrow and cause an increase in inflammatory hemogram indices such as NLR, RRP, RDW, MLR, and MPR.
There are three limitations in the present study; first, since only diabetic men were enrolled to the study and exclusion criteria were strict, study cohort was relatively small. Second, retrospective design of the study which may make our result difficult to interpret. Third, lack of measurement of serum testosterone and vitamin D levels again due to the retrospective nature of the study. However, the results of our report emphasized that the role of hematologic parameters in diabetic control in men with T2DM are very important.
In conclusion, elevated RDW, NLR, MLR, MPR, and RPR levels in diabetic men should trigger measurement of HbA1c since each were strongly correlated with HbA1c level. Moreover, elevated RDW, NLR, MLR, and RPR could be marker of worse diabetic control in men with T2DM.
Disclosure statement
No potential conflict of interest was reported by the authors.
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