Homocysteine, interleukin‑1β, and fasting blood glucose levels as prognostic markers for diabetes mellitus complicated with cerebral infarction and correlated with carotid intima‑media thickness
- Authors:
- Published online on: December 13, 2019 https://doi.org/10.3892/etm.2019.8326
- Pages: 1167-1174
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Copyright: © Dai et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
Diabetes mellitus (DM) is a metabolic disease characterized by hyperglycemia, and its chronic complications can cause patient death and disability (1). There are about 415 million patients with DM worldwide, and the number has been increasing annually (2). Currently, about 193 million of the patients have not been diagnosed. Chronic DM that is untreated induces many complications and the incidence rates are still on the rise even after blood glucose is controlled (3). The long-term development of DM causes pathological changes of vascular structure, and then leads to microvascular and macrovascular complications (4). Previous findings have shown that DM is an independent risk factor for cerebral infarction (CI). The development of CI is closely related to severe metabolic dysfunction, and early CI is caused by arterial occlusion (5,6). The mortality of patients with diabetes mellitus complicated with cerebral infarction (DMCI) is very high. The pathological basis of the disease is atherosclerosis and the pathological change is thrombosis (7). Therefore, the timely detection and control of macroangiopathy is of great significance to prevent and for treatment of DMCI.
Carotid intima-media thickness (CIMT) is an early manifestation of atherosclerosis, and changes in its value reflect the severity of atherosclerosis. It is practical, easy to operate, and conducive to assessing the risk of cerebrovascular diseases (8). Homocysteine (Hey) level plays an important role in the development and progression of DM. Its high level causes atherosclerosis and cardio-cerebrovascular diseases through damaging vascular endothelium, inducing thrombosis, and promoting the proliferation of vascular smooth muscle cells (9). DM is a chronic low-grade inflammation and is characterized by the excessive secretion of interleukin-1β (IL-1β) and other pro-inflammatory cytokines, which enhances inflammatory signals and then results in complications such as vasculopathy (10,11). Previous studies have reported that systolic blood pressure (SBP), diastolic blood pressure (DBP), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) are major risk factors for CI (12–14). However, there are currently few studies on the diagnostic values of Hey, IL-1β, and fasting blood glucose (FBG) levels for DMCI, or whether IL-1β is a risk factor for CI.
Therefore, the roles and significance of Hey, IL-1β, and FBG levels in patients with DMCI were explored in this study.
Patients and methods
General information
Altogether 124 patients with DMCI (the DMCI group) and 103 patients with DM (the DM group) admitted to the People's Hospital of Liuhe District of Nanjing from February 2016 to January 2019 were enrolled in this study. The DMCI group consisted of 65 males and 59 females aged 46–78 years with an average age of 60.9±9.7 years. The DM group consisted of 53 males and 50 females aged 43–75 years with an average age of 60.1±9.5 years. A further 100 healthy controls undergoing physical examinations during the same period (the HC group) were also enrolled. The group comprised 59 males and 41 females aged 39–70 years with an average age of 58.4±8.6 years. The research subjects were informed and signed an informed consent form. This study did not violate ethics or morality and was approved by the Ethics Committee of the People's Hospital of Liuhe District (Nanjing).
Inclusion and exclusion criteria
Inclusion criteria for the study were: patients in the DMCI and DM groups met the diagnostic criteria for DM from the American Diabetes Association (ADA) in 2017 (15), and their diabetes was type II diabetes mellitus. Patients in the DMCI group met the diagnostic criteria for CI from the American Heart Association (AHA) / the American Stroke Association (ASA) in 2018 (16), and their CI was confirmed by cranial imaging, MRI, or CT. The age range of the patients in the two groups were >38 years, but <78 years, and they had complete clinical data. Exclusion criteria were: those complicated with severe hepatic and renal dysfunction, cardiogenic CI, heart failure, thyroid dysfunction, diabetic nephropathy, autoimmune diseases, severe infections, or malignant tumors; those with cognitive disorders or mental illness; those who had taken immunosuppressants or anti-inflammatory drugs in the previous one month. The inclusion and exclusion criteria were applied to the DMCI and DM groups. The healthy controls were in the HC group.
CIMT examination
Carotid artery ultrasound was performed using a Philips E33 Color Doppler Ultrasonic Diagnosis Apparatus (Koninklijke Philips Electronics N.V). All subjects were examined by the same physician. The subjects laid down for 15-min rest and then their necks were fully exposed. Next, the common carotid artery, internal carotid artery, and carotid bifurcation were successively examined at 7.5 MHz. The vertical distance between the lumen intima and the media-adventitia, which was measured at 1 cm before and after the carotid bifurcation, was the CIMT value. The value was measured 3 times to obtain the average value.
Detection of markers
The subjects fasted for 3 h. In the morning the next day, their venous blood (5 ml) was extracted, placed in vacuum blood collection tubes, and centrifuged at 1,450 × g for 10 min at 4°C with a radius of 10 cm, so as to separate and store the upper layer of the serum for later use. The levels of serum Hey (enzymatic cycling method) and FBG (glucose oxidase method) (Beijing Bioassay Technologies Co., Ltd.; batch no. 301, 401) were detected by the AU5800 fully automatic biochemical analyzer (Beckman Coulter, Inc.). The reference ranges of Hey and FBG were 5–15 µmol/l and 3.33–5.55 mmol/l, respectively. The detection was carried out with reference to the instructions of the corresponding kits and instruments. Serum IL-1β level was detected by enzyme-linked immunosorbent assay (ELISA) (17), with steps carried out with reference to the instructions of human IL-1β ELISA kit [Gelatin & Protein Co., Ltd., batch no. JK-(a)-4956]. Standard wells, sample wells to be tested, and blank control wells (without samples and enzyme-labeled reagents) were set up. The standard wells in the enzyme-labeled plate that was coated were accurately added with standard substances (50 µl), while the sample wells to be tested were added with sample diluent (40 µl) and then the samples to be tested (10 µl) (the final dilution of the sample was 5 times). After that, the plate was coated, incubated at 37°C for 30 min, and then patted dry after liquid in the wells was discarded. The plate was repeatedly washed 5 times. Each well, except the blank control wells, was added with the enzyme-labeled reagents (50 µl), coated, and then incubated at 37°C for 30 min. Next, each well was added with substrate A and then substrate B (50 µl each), and colored at 37°C for 10 min in the dark after the substrates were mixed well. Finally, each well was added with stop solution (50 µl) to cease the reaction. Optical density (OD) values of each well were sequentially measured at 450 nm using a SpectraMax iD5-multifunctional microplate reader (Molecular Devices), to calculate the IL-1β level.
Statistical analysis
SPSS 22.0 (IBM Corp.) was used for statistical analysis. Enumeration data were expressed by the number of cases/percentage [n (%)], and the comparison of the data between groups was analyzed by Chi-square test. Measurement data were expressed by mean ± standard deviation (mean ± SD), and comparison of the data between groups was analyzed by independent samples t-test. One-way ANOVA was used for the comparison of means between multiple groups. LSD t-test was used for pairwise comparison between groups. Pearson's test was used to analyze the correlations of Hey, IL-1β, and FBG levels with CIMT value. Receiver operating characteristic (ROC) curves were plotted to calculate the area under the curve (AUC), to determine the cut-off values of Hey, IL-1β, and FBG for diagnosing DMCI, and to calculate their sensitivity and specificity. Multivariate Logistic regression was used to analyze risk factors for DMCI. P<0.05 indicates a statistically significant difference.
Results
General information
There were significant differences between the DMCI, DM, and HC groups in terms of hemoglobin Alc (HbAlc), SBP, DBP, HDL-C, LDL-C, triglyceride (TG), apolipoprotein AI (apoAI), and apolipoprotein B (apoB) (P<0.05), but not in sex, age, body mass index (BMI), years of smoking, history of drinking, place of residence, coronary heart disease (CHD), platelet (PLT) count, and total cholesterol (TC) (P>0.05). There were significant differences between the DMCI and DM groups in terms of SBP, DBP, HDL-C, LDL-C, TG, apoAI, and apoB (P<0.05), not in course of disease, HbAlc, the use of insulin, and CHD (P>0.05) (Table I).
Levels of Hey, IL-1β, and FBG and CIMT value
The levels of Hey, IL-1β, and FBG and the CIMT value in the DMCI and DM groups were significantly higher than those in the HC group (P<0.001). The levels and the value in the DMCI group were significantly higher than those in the DM group (P<0.001) (Fig. 1).
Correlations of Hey, IL-1β, and FBG levels with CIMT value in DMCI group
According to the Pearson's correlation analysis, Hey level was positively correlated with CIMT value (r=0.542, P<0.001). IL-1β level was positively correlated with CIMT value (r=0.522, P<0.001). FBG level was positively correlated with CIMT (r=0.402, P<0.001) (Fig. 2).
Diagnostic values of Hey, IL-1β, and FBG levels for DMCI
The ROC curves of Hey, IL-1β, and FBG levels for diagnosing DMCI were plotted. The AUC of Hey for the diagnosis was 0.909 (95% CI, 0.872–0.945) and the cut-off value was 13.53 µmol/l, with the sensitivity of 86.29 and the specificity of 80.58%. The AUC of IL-1β was 0.842 (95% CI, 0.793–0.892) and the cut-off value was 38.67 pg/ml, with the sensitivity of 68.55 and the specificity of 86.41%. The AUC of FBG was 0.837 (95% CI, 0.784–0.889) and the cut-off value was 7.89 pg/ml, with the sensitivity of 69.35 and the specificity of 88.35% (Table II and Fig. 3).
Multivariate logistic regression analysis of risk factors for DMCI
The multivariate Logistic regression analysis was performed on factors with differences between the DMCI and DM groups. The results showed that SBP (P=0.007), DBP (P=0.009), HDL-C (P=0.001), LDL-C (P=0.041), Hey (P<0.001), IL-1β (P=0.003), FBG (P=0.049), and CIMT (P=0.006) were independent risk factors for DMCI (P<0.05) (Tables III and IV).
Discussion
DM is the main cause of macroangiopathy and its incidence has been increasing year by year. With the improvement of living standards and the development of economy, increasing number of young people have developed DM (18). The pathological basis of CI is atherosclerotic plaques, which lead to luminal stenosis, then microthrombus, and finally hypoxia and ischemia of the brain tissue (19). As a long-term chronic result, DMCI has no obvious clinical signs and symptoms during this period (20). Therefore, to diagnose DMCI in time and analyze its risk factors is of great significance.
CIMT predicts the risk of coronary artery stenosis in asymptomatic patients. Related to the severity of atherosclerosis, its value is significantly higher in patients with type II DM than that in healthy people (21). As an intermediate metabolite of sulfur amino acids, Hey activates the coagulation system and promotes deposition on vascular walls, thus affecting vasodilation (22). IL-1β is a pro-inflammatory cytokine that plays an important role during atherothrombosis. IL-1β-mediated inflammation functions in the deterioration of islet β cell function, atherogenesis, and plaque progression (23). In this study, the levels of Hey, IL-1β, and FBG and the CIMT value in the DMCI and DM groups were significantly higher than those in the HC group; the levels and the value in the DMCI group were significantly higher than those in the DM group. This indicates that patients with DMCI have severe atherosclerosis, and that Hey, IL-1β, and FBG are involved in the development and progression of DMCI. Moreover, Hey, IL-1β, and FBG levels were positively correlated with CIMT value, which shows that the three levels may affect CIMT, so Hey, IL-1β, and FBG are expected to be indicators for evaluating the severity of DMCI. In a study by Matsumoto et al (24), the CIMT value in the DMCI group is significantly higher than that in the CI group. The probability of CI in patients with DM increases by 1.8 times every time CIMT increases by 0.1 mm. HbAlc and age are independently related to CIMT. In a study by Eikelboom et al (25), Hey is closely associated with the pathological changes of arteries, and its level is positively correlated with vascular stenosis and arteriosclerosis, so high Hey level is an independent risk factor for CI. In a study by Huang et al (26), large glucose fluctuations are related to CI and the poor short-term prognosis of patients with the disease. The results of this study showed that SBP, DBP, HDL-C, LDL-C, Hey, FBG, and CIMT were independent risk factors for DMCI, which is similar to the findings of previous studies (27–29). Whether IL-1β can be used as an independent risk factor for DMCI has been rarely studied. According to a previous study, IL-1β release in the cerebral cortex of Fischer rats increases after permanent middle cerebral artery occlusion, while blocking IL-1β with anti-IL-1β antibody reduces the scope of CI, and relieves neurological and behavioral dysfunction (30). Thus, IL-1β may play an important role in CI. The results of the present study showed that IL-1β was an independent risk factor for DMCI. The massive release of Hey damages the vascular endothelial function and unbalances the coagulation and fibrinolytic systems, thereby causing a prethrombotic state (31). Vascular inflammatory responses accelerate the formation of unstable plaques. Hyperglycemia causes acidosis of brain cells through lactic acid accumulation during cerebral ischemia. It also causes brain cell damage through the destruction of mitochondrial function, the promotion of free radical generation, and the enhancement of lipid peroxidation (32,33). Therefore, the development and progression of DMCI may be the result of synergy between Hey, IL-1β, and hyperglycemia. There are currently few studies on the diagnostic values of Hey, IL-1β, and FBG levels for DMCI. According to the ROC curves in this study, the three levels had good predictive values for DMCI, and the cut-off values of the three for diagnosing the disease were 13.53 µmol/l, 38.67 pg/ml, and 7.89 mmol/l, respectively. The observation of the cut-off values was helpful to identify DM and DMCI. Therefore, Hey, IL-1β, and FBG levels can be monitored and intervened, which is conducive to reducing cervical atherosclerosis, delaying the progression of atherosclerosis, and preventing DMCI.
This study confirms the roles of Hey, IL-1β, and FBG in the development and progression of DMCI, but it still has deficiencies. The changes in the three levels during treatment were not observed. Basic experiments were not carried out. The regulatory mechanisms of Hey, IL-1β, and FBG in the development and progression of DMCI were not fully explored. These deficiencies need to be supplemented in future studies to corroborate the conclusions of this study.
In summary, patients with DMCI have severe atherosclerosis. Hey, IL-1β, and FBG are involved in the development and progression of DMCI, so they can be used as predictive markers for the disease. Hey, IL-1β, FBG, and CIMT are independent risk factors for patients with DMCI.
Acknowledgements
Not applicable.
Funding
This study was supported by Value of Grass-roots Hospital's Green Channel in the Treatment of Acute Cerebral Infarction of The Project Fund of Nanjing Health Committee (no. YKK17241).
Availability of data and materials
The datasets used and/or analyzed during the present study are available from the corresponding author on reasonable request.
Authors' contributions
ZD was the major contributor in writing the manuscript and carried out all experiments. YJ analyzed and interpreted the patient general data. QF and AQ performed ELISA. LX and JL were responsible for analysis of the observation indicators. All the authors read and approved the final manuscript.
Ethics approval and consent to participate
The study was approved by the Ethics Committee of the People's Hospital of Liuhe District of Nanjing. Patients who participated in this research, signed an informed consent and had complete clinical data.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
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