Home Metformin can alleviate the symptom of patient with diabetic nephropathy through reducing the serum level of Hcy and IL-33
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Metformin can alleviate the symptom of patient with diabetic nephropathy through reducing the serum level of Hcy and IL-33

  • Ling Zhang EMAIL logo , Jiansheng Niu , Xiumei Zhang and Wanxia He
Published/Copyright: August 31, 2019
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Open Medicine
From the journal Open Medicine Volume 14 Issue 1

Abstract

Background

Interleukin-33 (IL-33) and homocysteine (Hcy) were found to be up-regulated in patients with diabetic nephropathy (DN), and the present study aimed to investigate whether metformin (MT) can influence the serum levels of IL-33 and Hcy in patients with DN.

Methods

Sixty patients with type 2 diabetes mellitus (DM) were divided into DM group (albumin: Alb <20 mg/L), DN group (Alb >20mg/L), and DN+ MT treatment group, with 20 cases in each group. Patients in each group were treated with insulin for 3 months, and patients in DN+MT group was treated with insulin+MT for 3 months. The serum levels of IL-33, urinary microalbumin excretion rate (UAE), body mass index (BMI), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C), creatinine (Cr), cystatin C (CysC) and Hcy were measured before and after medication. Twenty normal subjects were involved as control.

Results

BMI, Hcy and TC were reduced and HDL-C was increased of patients had been treated with metformin and insulin. UAE, Cr, Ccr and CysC had no differences before and after treatment. The serum level of IL-33 significantly up-regulated in patients with DN, and MT treatment significantly decreased the serum level of IL-33 in patients with DN.

Conclusion

Metformin could alleviate the symptom of patient with DN through decreasing the serum level of IL-33 and Hcy.

Keywords: Metformin; IL-33; Hcy; Diabetic nephropathy

1 Introduction

Diabetes mellitus (DM) is one of the leading causes of chronic kidney disease worldwide. Based on data from the American diabetes association, in the U.S., there are about 17.5 million diabetic patients, suggesting that diabetes has become a big threaten to the health of human beings. DM can lead to the incidence of other diseases and even increase the chance of mortality worldwide [1]. Diabetic nephropathy (DN) is a common DM-related disease, and it can be observed among 30 to 40% of patients with either type 1 or type 2 diabetes [2]. At current stage, the management of DN is a painful process to the patients, not only because of the long course of the disease, but also the psychological burden and low quality of life caused to the patients [3, 4]. Therefore, it is urgent to explore more effective methods for treating DN.

The pathogenesis of DN remains largely unclear. Hcy is the intermediate production of methionine, it has been proved that the plasma level of Hcy is significantly up-regulated in patients with DN, which was mainly due to the decrease of excretion. Recently, a new member of interleukin (IL) that belongs to the IL-1 family, IL-33, is presented in cisplatin-induced nephropathy. Accumulating evidence suggested that IL-33 is one of the most important cytokines in the pathogenesis of various disorders, including autoimmune diseases, myocardial infarction, heart failure, and allergic pulmonary diseases [5, 6, 7]; however, in current literature, the data regarding the role of IL-33 in DN is limited. Thus, to confirm the specific roles of IL-33 and Hcy in DN is in a great need, which may help scientists and physician to develop novel therapies for improved therapeutic efficacy of current methods for the management of DN.

In current clinical applications, different treatment modalities have been applied to treat DN. Melatonin (MT) is one of the first-line medications the for the treatment of DN; however, the role of MT in patients with DN still requires further investigation. Hence, in the present study, we sought to determine whether MT can reduce the level of IL-33 in patients with DN and exert its therapeutic effects.

2 Material and methods

2.1 Patients

Sixty type 2 DM patients that hospitalized in Chongqing General Hospital between Jan 2016 and Feb 2017 were selected for this study. The study was approved by the Ethics Committee of Chongqing General Hospital. All of the participants signed informed consent before research. The patients were divided into DM group (Alb <20 mg/L), DN group (Alb >20mg/L), and DN+MT treatment group, with 20 cases in each group. It was the first therapy for all the patients. Patients in each group were treated with insulin, and patients in DN+ MT group was treated with insulin+MT, and the fasting blood glucose (FPG) of patients was controlled at ≤7mmol/L for a course of 3 months. Meanwhile, 20 healthy subjects who received the physical examination in our hospital during the same period were selected as the controls. The general data such as age and sex in each group showed no statistical significance (p>0.05).

2.2 Collection and detection of clinical specimens

Blood samples of 10 ml venous blood were collected in the morning from all patients and the healthy volunteers. After centrifugation at room temperature (1,000 rpm, 10 minutes), the supernatants were collected and then stored at −80°C. Some of the serum samples were directly sent to the clinical laboratory for the measurement of TG, TC, HDL-C, Cr, CysC, Hcy using automatic biochemistry analyzer (olympus, Japan) before and after medication; the serum levels of IL-33 (Cat no. ab223865; Abcam, USA) in each candidate was determined by using ELISA kit according to the manufacturer’s instructions; the urine of the patients was also collected at 8:00 a.m., and the levels of UAE in the urine of each patient was measured.

2.3 Statistical analysis

Data analysis was performed using SPSS software (Version 17.0, SPSS Inc., Chicago, Ill, USA). Data were presented as the mean ± standard deviation (SD). ANOVA was used to compare the mean value of each parameter among the groups. P <0.05 was considered statistically significant.

3 Results

3.1 Comparison of BMI, Hcy, TC, and HDL-C in different groups

Before the drug intervention, BMI, Hcy, TC and HDL-C in each group of diabetic patients shows no significant differences. After drug intervention, the BMI, Hcy, TC were significantly decreased in DN+MT group. Moreover, MT treatment also induced significant increase in the content of HDL-C in DN+MT group (Table 1-4, p<0.05).

Table 1

Comparison of BMI in different groups.

Group Before drug intervention (kg/m2) After drug intervention (kg/m2)
DM 22.9 ± 5.2 23.7 ± 2.6
DN 23.5 ± 1.7 22.5 ± 6.2
DN+MT 24.6 ± 4.4 18.7 ± 1.9*
Control 20.5 ± 2.3 21.4 ± 1.2

  1. *p<0.05 v.s. before drug intervention.

Table 2

Comparison of Hcy in different groups

Group Before drug intervention (μmol/ L) After drug intervention (μmol/ L)
DM 12.1 ± 5.2 10.7 ± 4.8
DN 11.5 ± 3.4 11.5 ± 3.2
DN+MT 12.7 ± 5.6 9.3 ± 2.9*
Control 10.2 ± 1.1 11.4 ± 1.3

  1. *p<0.05 v.s. before drug intervention.

Table 3

Comparison of TC in different groups

Group Before drug intervention (mmol/ L) After drug intervention (mmol/ L)
DM 4.82 ± 2.0 4.71 ± 1.5
DN 4.94 ± 1.4 4.56 ± 2.1
DN+MT 5.35 ± 1.9 4.23 ± 1.9*
Control 3.11 ± 1.1 3.24 ± 1.8

  1. *p<0.05 v.s. before drug intervention.

Table 4

Comparison of HDL-C in different groups

Group Before drug intervention (mmol/ L) After drug intervention (mmol/ L)
DM 1.08 ± 0.13 1.11 ± 0.07
DN 0.94 ± 0.21 1.05 ± 0.13
DN+MT 1.05 ± 0.08 1.22 ± 0.24*
Control 0.99 ± 0.11 1.05 ± 0.16

  1. *p<0.05 v.s. before drug intervention.

3.2 Comparison of UAE, CysC and Ccr in each group

Before the intervention, there was no significant difference between the serum level of UAE, CysC, Ccr among patients with diabetes. After drug intervention, the serum levels of UAE CysC, and Ccr in different groups had no significant changes (Table 5-7, p>0.05).

Table 5

Comparison of UAE in different groups

Group Before drug intervention (μg/ min) After drug intervention (μg/ min)
DM 12.08 ± 3.13 13.11 ± 5.64
DN 111.98 ± 6.21 108.14 ± 6.13
DN+MT 113.07 ± 7.01 112.29 ± 7.24
Control 10.42 ± 4.13 11.01 ± 3.76
Table 6

Comparison of Ccr in different groups

Group Before drug intervention (ml/min) After drug intervention (ml/min)
DM 97.36 ± 1.72 98.59 ± 1.65
DN 99.65 ± 1.33 101.25 ± 1.47
DN+MT 103.12± 1.29 95.29 ± 0.97
Control 80.14 ± 7.13 81.23 ± 6.59
Table 7

Comparison of CysC in different groups.

Group Before drug intervention (mg/ L) After drug intervention (mg/ L)
DM 1.94 ± 0.41 2.07 ± 0.48
DN 2.05 ± 0.21 1.92 ± 0.51
DN+MT 2.13 ± 0.28 1.87 ± 0.35
Control 1.13 ± 0.13 1.28 ± 0.16

3.3 Comparison of the serum level of IL-33 in different groups

Compared with the control group, the serum level of IL-33 was significantly increased in DM, DN and DN+MT groups. Either insulin or insulin+ MT treatment could decrease the serum level of IL-33 in different groups, and the effect of MT on the serum level of IL-33 in DN+MT group was more significant (Table 8, p<0.05).

Table 8

Comparison of the serum level of IL-33 in different groups.

Group Before drug intervention (ng/L) After drug intervention (ng/ L)
DM 107.12 ± 9.41 96.23 ± 7.51
DN 111.31 ± 8.72 91.85 ± 6.34*
DN+MT 108.74 ± 9.15 72.53 ± 9.21**
Control 41.02 ± 5.31 43.52 ± 4.83

  1. *p<0.05, ***p<0.01v.s. before drug intervention.

4 Discussion

In the present study, the therapeutic effect of metformin for the treatment of DN was evaluated. We proved that metformin could alleviate the symptom of patient with DN by decreasing the serum levels of IL-33 and Hcy.

Metformin, as a first-line drug for the treatment of type 2 diabetes, will have an impact on the process of DN, and still remains doubtful. Hcy is the intermediate production of methionine during tissue metabolism substance, and it is also an endogenous pathogenic factor which has cellular and genetic cytotoxicity, which can play the role in the process of vascular damage through a variety of pathways. In patients with DN, especially with hyperinsulinemia, the elevated plasma level of Hcy is mainly due to the decrease of excretion [8]. Moreover, the levels of high external insulin can affect the activities of enzymes during the process of Hcy metabolism (such as MTHFR, MS, etc), which can also cause the increase of blood Hcy [9]. High Hcy can lead to oxidative stress and promote the repairing process of low density lipoprotein. On the other hand, it can also cause endothelial cell aging, reduce the synthesis of nitric oxide (NO), and increase secretion of vascular pseudohemophilia factor (VWF) and other cells. Hcy can also activate protein kinase C, promoting the expression of proto oncogene c-fos and c-myb in vascular smooth muscle cells [10, 11, 12]. Therefore, Hcy may be induced by oxidative stress and endothelial damage. The results of this study showed that Hcy level significantly enhanced in patients with type 2 DM compared with the control group, and MT treatment induced significant decrease in the expression of Hcy in patients with DN, and also altered the expression of Hcy-related molecules TC and HDL-C. Taken together, these results suggested that Hcy was involved in the process of MT-induced therapeutic effects.

IL-33 is possible to promote cell proliferation and inhibit apoptosis via activation of various pathways such as STAT3, MAPK, and/or NF-κB signaling in different types of cells [13]. Autocrine production of IL-33 has been suggested to contribute to human cancer cell survival, migration and resistance to chemotherapy, through the up-regulation of anti-apoptotic proteins including Bcl-2, and via ST2/STAT3 [14, 15]. In the field of DN-related studies, reports on the functions of IL-33 in the pathogenesis of the disease is rare. In the present study, we focused on the role of IL-33 in the management of DN using MT. It has been observed that compared with the control group, the serum level of IL-33 was significantly increased in DM and DN groups. Either insulin or insulin+ MT treatment could decrease the serum level of IL-33 in DN patients, and the effect of MT on the serum level of IL-33 in DN+MT group was more significant.

In conclusion, our results indicated that metformin could alleviate the symptom of patient with DN through reducing the serum level of IL-33. Our data has provided novel evidence for the application of IL-33 as an index for evaluating the therapeutic efficacy of MT for the treatment of DN.

  1. Declaration of interests: The authors report no competing financial interests

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Received: 2018-11-28
Accepted: 2019-05-13
Published Online: 2019-08-31

© 2019 Ling Zhang et al., published by De Gruyter

This work is licensed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

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https://doi.org/10.1515/med-2019-0071
Keywords for this article
Metformin; IL-33; Hcy; Diabetic nephropathy
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BY-NC-ND 4.0

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  56. Comparison of laparoscopy and open radical nephrectomy of renal cell cancer
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  63. Nasointestinal tube in mechanical ventilation patients is more advantageous
  64. The change of endotracheal tube cuff pressure during laparoscopic surgery
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  66. Case Report
  67. Primary angiosarcoma of the kidney: case report and comprehensive literature review
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  73. Indications and outcomes of splenectomy for hematological disorders
  74. Expression of CENPE and its prognostic role in non-small cell lung cancer
  75. Barbed suture and gastrointestinal surgery. A retrospective analysis
  76. Using post transplant 1 week Tc-99m DTPA renal scan as another method for predicting renal graft failure
  77. The pseudogene PTTG3P promotes cell migration and invasion in esophageal squamous cell carcinoma
  78. Lymph node ratio versus TNM system as prognostic factor in colorectal cancer staging. A single Center experience
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  89. microRNA-27a-3p down-regulation inhibits malignant biological behaviors of ovarian cancer by targeting BTG1
  90. PYCR1 is associated with papillary renal cell carcinoma progression
  91. Prediction of recurrence-associated death from localized prostate cancer with a charlson comorbidity index–reinforced machine learning model
  92. Colorectal cancer in the elderly patient: the role of neo-adjuvant therapy
  93. Association between MTHFR genetic polymorphism and Parkinson’s disease susceptibility: a meta-analysis
  94. Metformin can alleviate the symptom of patient with diabetic nephropathy through reducing the serum level of Hcy and IL-33
  95. Case Report
  96. Severe craniofacial trauma after multiple pistol shots
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  101. Review Article
  102. Oncological outcomes and quality of life after rectal cancer surgery
  103. Research Article
  104. MiR-638 repressed vascular smooth muscle cell glycolysis by targeting LDHA
  105. microRNA-16 via Twist1 inhibits EMT induced by PM2.5 exposure in human hepatocellular carcinoma
  106. Analyzing the semantic space of the Hippocratic Oath
  107. Fournier’s gangrene and intravenous drug abuse: an unusual case report and review of the literature
  108. Evaluation of surgical site infection in mini-invasive urological surgery
  109. Dihydromyricetin attenuates inflammation through TLR4/NF-kappaB pathway
  110. Clinico-pathological features of colon cancer patients undergoing emergency surgery: a comparison between elderly and non-elderly patients
  111. Case Report
  112. Appendix bleeding with painless bloody diarrhea: A case report and literature review
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  114. Protective effects of specneuzhenide on renal injury in rats with diabetic nephropathy
  115. PBF, a proto-oncogene in esophageal carcinoma
  116. Use of rituximab in NHL malt type pregnant in I° trimester for two times
  117. Cancer- and non-cancer related chronic pain: from the physiopathological basics to management
  118. Case report
  119. Non-surgical removal of dens invaginatus in maxillary lateral incisor using CBCT: Two-year follow-up case report
  120. Research Article
  121. Risk factors and drug resistance of the MDR Acinetobacter baumannii in pneumonia patients in ICU
  122. Accuracy of tumor perfusion assessment in Rat C6 gliomas model with USPIO
  123. Lemann Index for Assessment of Crohn’s Disease: Correlation with the Quality of Life, Endoscopic Disease activity, Magnetic Resonance Index of Activity and C- Reactive Protein
  124. Case report
  125. Münchausen syndrome as an unusual cause of pseudo-resistant hypertension: a case report
  126. Research Article
  127. Renal artery embolization before radical nephrectomy for complex renal tumour: which are the true advantages?
  128. Prognostic significance of CD276 in non-small cell lung cancer
  129. Potential drug-drug interactions in acute ischemic stroke patients at the Neurological Intensive Care Unit
  130. Effect of vitamin D3 on lung damage induced by cigarette smoke in mice
  131. CircRNA-UCK2 increased TET1 inhibits proliferation and invasion of prostate cancer cells via sponge miRNA-767-5p
  132. Case report
  133. Partial hydatidiform mole and coexistent live fetus: a case report and review of the literature
  134. Research Article
  135. Effect of NGR1 on the atopic dermatitis model and its mechanisms
  136. Clinical features of infertile men carrying a chromosome 9 translocation
  137. Review Article
  138. Expression and role of microRNA-663b in childhood acute lymphocytic leukemia and its mechanism
  139. Case Report
  140. Mature cystic teratoma of the pancreas: A rare cystic neoplasm
  141. Research Article
  142. Application of exercised-based pre-rehabilitation in perioperative period of patients with gastric cancer
  143. Case Report
  144. Predictive factors of intestinal necrosis in acute mesenteric ischemia
  145. Research Article
  146. Application of exercised-based pre-rehabilitation in perioperative period of patients with gastric cancer
  147. Effects of dexmedetomidine on the RhoA /ROCK/ Nox4 signaling pathway in renal fibrosis of diabetic rats
  148. MicroRNA-181a-5p regulates inflammatory response of macrophages in sepsis
  149. Intraventricular pressure in non-communicating hydrocephalus patients before endoscopic third ventriculostomy
  150. CyclinD1 is a new target gene of tumor suppressor miR-520e in breast cancer
  151. CHL1 and NrCAM are primarily expressed in low grade pediatric neuroblastoma
  152. Epidemiological characteristics of postoperative sepsis
  153. Association between unstable angina and CXCL17: a new potential biomarker
  154. Cardiac strains as a tool for optimization of cardiac resynchronization therapy in non-responders: a pilot study
  155. Case Report
  156. Resuscitation following a bupivacaine injection for a cervical paravertebral block
  157. Research Article
  158. CGF treatment of leg ulcers: A randomized controlled trial
  159. Surgical versus sequential hybrid treatment of carotid body tumors
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