The aim of the present study was to investigate the possible contribution of leukocyte subgroups to future hypertension, T2DM, and MetS as well as its components in Taiwan citizens. This study also demonstrated a potential age-dependent association between total leukocyte count, monocyte count and risk of developing the three diseases mentioned above. Our results revealed that total leukocyte count and monocyte count were positively correlated with future MetS, hypertension, and T2DM in middle-aged participants. In addition, the significant association between total leukocyte count and monocyte count with MetS components had been identified.
In the present study, the significant association between the total leucocyte, neutrophil and lymphocyte with MetS was consistent with previous studies with a smaller cohort of participants (1, 17, 18). Furthermore, our study indicated the fact that elevated total leukocyte count was significantly and positively correlated with WC, SBP, DBP, fasting glucose, and TG while negatively correlated with HDL-C. The above relationship supported by previous longitudinal study (19) had demonstrated the important role for total leukocyte count playing in MetS components.
Multiple risk factors contributing to CVD such as diabetes, obesity, hypertension, and dyslipidemia has been well established (20). It is well established that the prevalence of MetS, hypertension and T2DM all rise from young to old ages (21–24). As far as the author reviewed, there were few reports focusing on the relationship between total/subtype leukocyte counts and risk of future MetS, hypertension, and T2DM by age distribution. Both studies done by Nakanishi et al and Nilsson et al (25, 26) revealed the positive correlation of total leukocyte count in adult age for MetS. However, this trend could only be identified in the subjects categorized into young-old group ( ≧ 65 and < 75) then disappear in older age subjects according to Chuang et al, 2015 (1). Our results also demonstrated similar evidence that total leukocyte count showed no significant correlation in both multivariate models of older age subjects.
The biological mechanisms for higher total leukocyte count causing increasing risk for MetS might be explained through high inflammatory activities. White blood cell, high- sensitivity C-reactive protein (hs-CRP), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) levels were all significantly elevated in the MetS group according to previous research (27). Produced by activated macrophages within adipose tissue, aforementioned inflammatory cytokines, especially TNF-α, takes an important part in obesity-linked insulin resistance (28). Composed of enlarged dead adipocytes surrounded by numerous activated macrophages, these crown-like structures had been recognized as characteristic histological pattern for dysfunction of adipose tissue(29). Moreover, as a possible systemic manifestation of adipose tissue dysfunction, MetS had been prooved to play a key role in lots of pathophysiological mechanisms including insulin resistance, systemic inflammation, and endothelial dysfunction (30, 31).
In the present study, we identified that elevated total leukocyte count with the possibility of predicting future T2DM for both young and middle-aged subjects, which was consistent with previous research (1, 32, 33). For the close relation between MetS and T2DM, it is reasonable to discover these positive associations.
Considered as a chronic inflammatory process, atherosclerosis centers in the pathophysiological pathway leading to hypertension (34, 35). Serving as a biomarker of chronic inflammation, it is not surprising that total leukocyte count showed positive association with hypertension in prior research, which was all in line with our results (36, 37).
As far as we know, this research is the first to investigate the role for monocyte count playing in predicting future MetS, hypertension, and T2DM according to age distribution. Analogous to total leukocyte count, monocyte count holds prospective associations with the above three diseases in middle-aged participants. While for young subjects, the aforementioned association between monocyte count and future T2DM vanished.
By means of either acting directly on macrophages to shift polarization or prime human monocyte differentiation into anti-inflammatory M2 macrophages for healthy individual, Adiponectin is an adipokine with multiple effects on cytokine secretion, metabolism of lipids, and direct insulin sensitizing activity (38, 39). As a cluster of risk factors for CVD and diabetes, MetS is well considered to be a proinflammatory state (36). Infiltration of macrophage and lymphocyte in adipose tissue may hold the key to pathogenesis of obesity-mediated metabolic disorders through crosstalk and release of various biomediators that promote inflammation (40). Increased systemic oxidative stress derived from MetS is associated with adiponectin deficiency, which drives monocytes toward M1 rather than M2 phenotype of macrophages in the circulation of MetS subjects (41, 42).
Dysregulation of M1 and M2 phenotype of macrophages as well as increasing amounts of circulating monocytes also exist in T2DM subjects (43, 44). Previous studies demonstrated an acute proceeding cytokine-mediated response initiated by both the innate and adaptive immune system which comes along with T2DM. In the tissues where they are generated, cytokines such as IL-6, IL- 1β, and TNF-α hold the capability of promoting insulin resistance and then influence other locations through circulation including cardiac and skeletal muscle as well as endothelium of vascular walls(45, 46).
An article published in the Cellular and Molecular Life Sciences in 2016 reported a novel concept about “trained immunity” in patients with diabetes, a theory that long-term functional reprogramming of monocytes and macrophages, result from hyperglycemia, centers in the phenomenon of hyperglycemic memory leading to atherosclerotic plaques development and subsequent macrovascular complications (47).
Localizing to district of injury, infection or stress, innate immune cells serve as part of the inflammatory process through reacting to chemokine and adhesion molecules such as monocyte chemoattractant protein-1 (MCP- 1) and vascular cell adhesion molecule-1 (VCAM-1). It is still uncertain about how monocyte promote hypertension, a consequence of low-grade inflammation. The possible pathophysiology relationship between monocytes and hypertension can be summarized into the following: (1) expression of functional Angiotensin II and mineralocorticoid receptors on monocytes leads to production of reactive oxygen species (ROS) via activation of reduced nicotinamide adenine dinucleotide (NADPH) oxidase; (2) tissue damage via the CC chemokine receptor 2 (CCR2) expressed on monocytes, which results from chemotaxis of monocytes and macrophages by increased MCP-1 (48).
The main strength of the present study is that this is the first longitudinal study to identify the value of monocyte count as predictors for future MetS, hypertension, and T2DM in different age subgroups. Moreover, the role of total leukocyte count on the risk of MetS and its components as well as development of the aforementioned diseases were also demonstrated. Nevertheless, several limitations still existed in the present research. First, the participants of our study were not from a general population, but from a health promotion center located in the capital city of Taiwan, which means they may fail to represent the general population for relatively higher socio-economic status. Second, insulin resistance, as the central concept of MetS, was not measured through glucose tolerance test in the current research. Third, cytokines (such as IL-6 and TNF-α) were not measured in this research on account of budget shortage. Fourth, our study lacked information on drug use such as antidiabetic, anti-hypertensive, or statin medication, which could affect hematological parameters or metabolism, should be recorded in specific details for risk stratification in further research. At last, we did not gain available data of cardiovascular event or all-cause mortality, which might cause considerable interference in the interpretation of our results. Future studies with plasma insulin levels, circulating levels of cytokines, detailed record of medication usage and incidence of all-cause mortality and/or cardiovascular events would provide further aid and insights to our current discoveries.
In conclusion, our results explore the promising value of total leukocyte count and monocyte count to recognize the high-risk subjects, especially meddle-aged ones, having MetS, hypertension, and T2DM in the present or the future. Elevated levels of these easily measured hematologic parameters might take crucial parts in these modern diseases, which special attention should be paid by healthcare providers, from the present into the future.