Effects of Endocrine Metabolic Factors on Hemocyte Parameters, Tumor Markers, and Blood Electrolytes in Patients with Hyperglycemia

Objective This study was designed to investigate the effect of endocrine metabolic factors on hemocyte parameters, tumor markers, and blood electrolytes in patients with hyperglycemia. Methods In this study, 1791 patients with hyperglycemia were recruited and grouped according to different testing indexes, and their medical records and laboratory indexes were recorded and analyzed. Results In adult patients with hyperglycemia, we found that high-density lipoprotein cholesterol (HDL-C) was negatively correlated with white blood cell (WBC) and could exert an effect on WBC; triglyceride (TG) level was positively associated with lymphocyte (LYM#); age, TG, and P affected the level of LYM#; and uric acid (UA) level was positively related to eosinophil (EO#). Besides, age was positively correlated with red blood cell distribution width-coefficient of variation (RDW-CV) level; fasting blood glucose (FBG) and serum phosphorus (P) were negatively correlated with RDW-CV level; and age, creatinine (Cre), FBG, HDL-C, and P were influencing factors of RDW-CV level in adult hyperglycemic patients. HDL-C was negatively correlated with fibrinogen (Fib) level, and age, HDL-C, serum kalium (K), serum sodium (Na), and body mass index (BMI) were the influencing factors of Fib levels. TG was positively associated with neuron-specific enolase (NSE) level and affected the NSE level. Serum magnesium (Mg) was negatively related to carcinoembryonic antigen (CEA) level, and sex, age, FBG, Mg, and BMI could have an effect on CEA level. As well, age and FBG were positively associated with carbohydrate antigen 50 (CA50) levels, UA was negatively correlated with CA50 levels, and age, aspartate aminotransferase (AST), UA, and FBG were the influencing factors of CA50 levels. FBG was negatively related to Mg levels; K, serum zinc (Zn), and fasting C-peptide (C-P) were positively correlated with Mg levels; and FBG, K, Zn, and C-P had an effect on Mg levels. Conclusion Endocrine metabolic factors are closely related to hemocyte parameters, tumor markers, and blood electrolytes in patients with hyperglycemia.


Introduction
In recent years, the incidence of hyperglycemia in China has been increasing year by year, and diabetes and its complications have become a serious threat to the health of patients. Endocrine metabolic factors are closely related to blood cell parameters, tumor markers, and blood electrolytes. It has been reported that the physiological changes occurring in the hyperglycemic state may lead to adverse outcomes [1]. Elevated blood glucose levels impair neutrophil function and lead to the overproduction of reactive oxygen species, free fatty acids, and inflammatory mediators [2]. These pathophysiological changes directly lead to cellular damage and vascular and immune dysfunction [3,4]. Therefore, this study is conducted to investigate whether blood cell parameters, tumor markers, and blood electrolytes of patients with Table 1: Comparison of clinical data of patients in the WBC ≤ 4 × 10 9 /L and WBC > 44 × 10 9 /L groups.

Items
WBC ≤ 4 × 10 9 /L (n = 90) WBC > 4 × 10 9   hyperglycemia are affected by endocrine metabolic indicators to provide a reference for the clinical diagnosis and treatment.

Methods
All procedures were approved by the Ethics Committee of First Affiliated Hospital of Kunming Medical University (approval no. kmmu2021426), and the application for the exemption from informed consent was approved. The study was conducted in accordance with the principles of the Declaration of Helsinki.

Patients.
Patients with hyperglycemia hospitalized in the Department of Endocrinology, the First Affiliated Hospital of Kunming Medical University, from January 2016 to September 2020 were recruited in the study. Inclusion criteria were that patients met the diagnostic criteria of hyperglycemia, including prediabetic and diabetic patients who met the 1999 World Health Organization diagnostic criteria. Exclusion criteria were as follows: (1) patients who did not meet the diagnosis of diabetes mellitus or impaired glucose regulation; (2) patients who were under 18 years of age; (3) patients with incomplete clinical data; and (4) patients with diseases that affect the white blood cell (WBC) count and lymphocyte count, such as leukemia.

Influencing Factors of RDW-CV.
Compared with the RDW − CV ≤ 12:90 g/L group, the average age, male, HDL-C, Na, and Cl levels were remarkably increased, and the female, FBG, TG, and P levels were significantly decreased  Journal of Diabetes Research in the RDW − CV > 12:90 g/L group of patients with hyperglycemia (P < 0:05); no statistically significant difference was observed in the AST, ALT, Cre, UA, TC, F-CHOL, LDL-C, K, Ca, Mg, Zn, and BMI between the groups (Table 4 and Figure 4). Spearman analysis demonstrated that age

Effect of Endocrine Metabolic
Factors on Fib Levels. The age, Cre, FBG, and serum K levels were significantly higher in the Fib > 4 g/L group, and AST, ALT, HDL-C, Na, Cl, P, and Zn levels were decreased, compared with Fib ≤ 4 g/L group (P < 0:05, Table 5

Influencing Factors of CA50 Levels.
It was shown that the average age, CA50, and FBG levels were obviously higher in the CA50 > 7:20 U/mL group, while the UA and serum P levels were lower in comparison with the CA50 ≤ 7:20 U/mL

Discussion
In this study, we investigated the correlation of endocrine metabolic indicators with blood cell parameters, tumor markers, and blood electrocytes in adult patients with hyperglycemia.
Our findings demonstrated that HDL-C levels were higher in the WBC ≤ 4 × 10 9 /L group than in the WBC > 4 × 10 9 /L group of adult patients with hyperglycemia, and there was a significant negative correlation between WBC and HDL-C, which is consistent with the findings in the physical examination population [5][6][7][8], the population with impaired glucose regulation [9], type 2 diabetes mellitus (T2DM) population [10], and elderly population [11]. In addition, the BMI of the WBC ≤ 4 × 10 9 /L group was lower than that of the WBC > 4 × 10 9 /L group, and there was a positive correlation between WBC and BMI, which is generally consistent with the results of previous studies [12]. A correlation analysis of clinical data from 11526 medical examiners found that WBC was positively correlated with BMI after controlling for age [9]. It has been reported that there was a correlation between BMI and WBC in 215 elderly patients with hypertension [13].
Peripheral blood lymphocytes are an important component of cellular immunity, and their decrease often indicates that the body is in an immunosuppressed state, which may cause disease progression and complications [14]. In this study, the TG levels in the LYM#≤1:10 × 10 9 /L group were lower than that in the LYM#>1:10 × 10 9 /L group of adult patients with hyperglycemia, and a markedly positive correlation was exhibited between TG levels and LYM#. In addition, TG levels in adult patients with hyperglycemia had an effect on LYM#. Lymphopenia occurs in a variety of conditions, such as systemic lupus erythematosus (SLE) [15]. However, the causes of lymphopenia in patients with SLE are not fully clarified, and the possible mechanisms include the increase in lymphocyte destruction or apoptosis increased destruction or apoptosis of lymphocytes mediated by anti-lymphocyte antibodies, anti-Ro52 antibodies, abnormalities in the complement system associated with increased lymphocyte apoptosis, changes in lymphocyte subpopulations prompted by decreased IL-2 levels contributing to lymphopenia in SLE, and the application of infections, hormones, and immunosuppressive agents can suppress immunoreactive cells, especially lymphocytes [16]. Currently, there are fewer reports concerning the factors affecting lymphocytes in people with hyperglycemia, and it deserves further study. We also found that the serum P levels were lower in the LYM#≤1:10 × 10 9 /L group and positively correlated with LYM#, and the serum P levels were the risk factor of LYM#≤1:10 × 10 9 /L. Our findings are consistent with previous studies in patients with bloodstream infections [17]. It was proved that age, the existence of tumors, and hypophosphatemia were independent influencing factors of  [17]. The cause of decreased lymphocytes may be related to lymphocyte apoptosis, and hypophosphatemia accompanied by lymphocyte reduction, suggesting that hypophosphatemia may be associated with abnormal immune function [17].
Eosinophilia is one of the common features of hypersensitivity reactions caused by the sequential release of antigen-activated Th2 cells and key cytokines, including the release of key cytokines such as IL-5, which trigger eosinophil proliferation, accumulation, and function. Hypersensitivity reactions are one of the causes of eosinophilia in patients with chronic kidney disease (CKD). Medications, infections, and autoimmune diseases may also contribute to eosinophilia in patients with acute interstitial nephritis. The higher the CKD stage in patients with heart disease, the higher the prevalence of eosinophilia, which may be associated with subclinical cholesterol embolism, drug allergy, and contrast nephropathy [18]. In the present study, our findings indicated that UA levels in the EO#>0:14 × 10 9 /L group were higher than in the EO#≤0:14 × 10 9 /L group of patients with hyperglycemia, and UA was significantly positively correlated with EO#. Moreover, our regression analysis revealed that UA levels were a risk factor of EO#, which was slightly different from the previous research in patients with CKD. Huanying et al. found that eosinophil counts were negatively correlated with estimated glomerular filtration rate and positively correlated with urea, Cre, cystatin C, and retinol-binding protein, and eosinophil counts were positively correlated with UA but were not yet statistically significant and needs to be analyzed a larger sample size [18]. At present, the relationship between blood AU and EO# in patients with hyperglycemia is less reported and requires further investigation. In the study, the age of the RDW − CV > 12:90 g/L group was significantly higher than that of the RDW − CV ≤ 12:90 g/L group, and there was a positive correlation between age and RDW-CV. Currently, most studies on the effect of age on RDW-CV have focused on coronary heart disease (CHD) [19,20], hypertension [21], cerebral infarction [22], and hemodialysis [23] populations, with fewer studies related to hyperglycemic populations. A retrospective study found that age was an independent and positively correlated risk factor affecting the REW-CV of patients with peritoneal dialysis [24]. It has also been demonstrated in another retrospective study of esophageal cancer patients that the increased risk of RDW-CV was 2.989 times higher in patients over 60 years of age than in patients under 60 years of age, and age was positively correlated with RDW-CV [25]. The results of the present study are consistent with these studies, both suggesting a positive correlation between age and RDW-CV. Moreover, FBG was decreased in the RDW − CV > 12:90 g/L group than in the RDW − CV ≤ 12:90 g/L group and was significantly and negatively correlated with RDW-CV levels. It has been proved that RDW-CV was positively correlated with FBG in over 200 patients with T2DM [26,27]. It has also been shown that RDW was negatively correlated with FBG in 256 patients with cerebral infarction [28]. Besides, it was found that there was no correlation between RDW and FBG in patients with metabolic syndrome [29]. Since the research on the correlation between RDW-CV and FBG is less, the results are not yet consistent, and the correlation is not yet clear, so the sample size needs to be expanded for further studies.
At present, there have been few studies and inconsistent results regarding the effect of HDL-C on Fib levels. Regression analysis of studies on patients with CHD has found a negative correlation between Fib levels and HDL-C [30]. In addition, it was found that there is a negative correlation between HDL-C and plasma Fib levels by comparing the physical examination of people with Fib > 4 g/L and those with Fib < 4 g/L [31]. The results of the present study showed that HDL-C levels in the group with Fib > 4 g/L were 13 Journal of Diabetes Research lower than HDL-C levels in the group with fibrinogen ≤ 4 g /L and were significantly negatively correlated with Fib levels, and the results of the present study were consistent with the above studies. However, it has been reported that in the clinical data of inpatients with a primary diagnosis of T2DM, regression analysis of the relationship between plasma Fib and age, disease duration, and metabolic indicators of patients showed that other independent variables such as HDL-C did not enter the regression model, which is different from the results of the present study [32]. It may be related to the selection of the study group and the sample size, and the sample size can be expanded to analyze subgroups of the population with different degrees of elevated blood glucose in further study.
In this study, we found that the TG level in the NSE ≤ 16:3 ng/mL group was lower than that in the NSE > 16:3 ng /mL group of adult patients with hyperglycemia, and there was a positive correlation between TG and NSE levels. It has been reported that increased TG was positively associated with NSE levels in patients with ischemic stroke with NSE hyperplasia (NSE > 13 μg/mL), and TG and NSE levels were positively correlated in elderly lung cancer patients without surgery and chemotherapy [33,34], which is similar to the results of the present study. Currently, the correlation between blood TG levels and blood NSE levels is poorly reported and has not been reported in hyperglycemic populations. The mechanism of the effect of TG on NSE levels is unclear and needs to be further investigated.
In the present study, Mg levels in the CEA > 5:0 ng/mL group were lower and negatively correlated with CEA levels, while FBG levels in the CEA > 5:0 ng/mL group were lower and positively correlated with CEA levels, compared with Comparison of AST and ALT levels between the groups. (d) Comparison of Cre and UA levels between the groups. The levels of UA in CA50 ≤ 7:2 U/mL group were significantly higher than that in CA50 > 7:2 U/mL group. (e) The CA50 in CA50 ≤ 7:2 U/mL group was significantly lower than that in CA50 > 7:2 U/mL group. (f) Comparison of F-CHOL between the groups. (g) Comparison of BMI of patients between the groups. (h) The average age of patients in CA50 ≤ 7:2 U/mL group was significantly lower than in CA50 > 7:2 U/mL group.
14 Journal of Diabetes Research the CEA ≤ 5:0 ng/mL group. There are findings showing a significant positive correlation between CEA and FBG in the T2DM population and nonalcoholic steatosis patients [35][36][37], which is consistent with the results of the present study. However, there was a study reported that no correlation was found between the FBG and CEA levels in a population study of 150 T2DM patients; it may be limited by the small sample size of that study, which needs to be further analyzed after expanding the sample size [38]. In addition, as no literature reports on the correlation between Mg and CEA levels have been retrieved, the mechanism of the effect of Mg on CEA levels is unclear and needs to be further investigated.
Our findings demonstrated that compared with CA50 ≤ 7:20 U/mL, UA was lower and FBG was higher in the CA50 > 7:20 U/mL group; there was a significant negative correlation between UA and CA50 levels and a positive correlation between FBG and CA50 levels. It has not been reported on the correlation between CA50 and UA, and the mechanism by which UA affects CA50 levels is unclear and needs to be further investigated. Nevertheless, there is less literature on the correlation between CA50 and FBG; it was reported that high and low levels of CA50 in patients with T2DM were not associated with FBG levels [39], which is inconsistent with our findings. Notably, only 76 patients with T2DM were included in the above study; the results may be related to the small sample size; HbA1c is closely associated with FBG, which needs to be further verified by expanding the sample size.
It has been reported that Mg levels were significantly negatively correlated with FBG in T2DM patients [40,41] and acute cerebrovascular patients [42]. There is a positive correlation between K and Mg levels in the patients with nonketotic DM combined with hypokalemia [42], and a positive correlation between Zn and Mg was observed in the physical examination population of 2122 children [43]. It has been found that the Mg level was positively correlated with C-P in 196 gestational diabetes patients [31]. Our findings suggested that FBG was significantly negatively correlated with Mg levels, and C-P, K, and Zn levels were significantly positively correlated with Mg levels, which were consistent with the previous studies. However, there are fewer studies on the relationship between Mg and C-P, and the conclusions are inconsistent. Jinquan et al. found that Mg level was not correlated with C-P in the 80 patients in the intensive care unit, but the sample size of this study was small and further studies with larger sample sizes are required for validation [44].
However, the study has some limitations. This is a single-center retrospective study with limited sample size, and due to incomplete or limited exclusion criteria, it is possible that patients with other comorbidities [45] that may affect blood glucose and patients who may be using medications that may cause hyperglycemia or changes in examination levels [46,47] were included in this study.

Journal of Diabetes Research
Moreover, insulin-like growth factor-(IGF-) 1 and adipokines like leptin have been known to be involved in the context of obesity. Investigations of the two factors in this study were absent; thus, further studies require to link them with other factors in hyperglycaemia from the perspective of pathophysiology.

Conclusions
In summary, endocrine metabolic factors are closely related to hemocyte parameters, tumor markers, and blood electrolytes in patients with hyperglycemia. Our findings provide great referential values for further clinical studies.