Sympathetic Nervous System Activity in Patients with
Metabolic Syndrome, Type 2 Diabetes Mellitus and
Chronic Kidney Disease. Role of Renalase and Alpha
Amylase

Hernandez LE; Hernandez GP; Sanchez DCV; Garcia AG; Aguilar CA

Research Article

J Dis Markers. 2021; 6(1): 1039.

Sympathetic Nervous System Activity in Patients with Metabolic Syndrome, Type 2 Diabetes Mellitus and Chronic Kidney Disease. Role of Renalase and Alpha Amylase

Hernández LE¹, Hernández GP², Sánchez DCV³, García AG³ and Aguilar CA^2,4*

¹Family Medicine Unit No. 80, Mexican Institute of Social Security (IMSS) Morelia, Michoacán, México

²Faculty of Medical and Biological Sciences “Dr. Ignacio Chávez”, Michoacán University of San Nicolás de Hidalgo. Morelia, Michoacán, México

³Division of Clinic Research. Biomedical Research Center of Michoacán, IMSS. Morelia, Michoacán, México

⁴Medical Research Assistant Coordination in Health of the IMSS, Morelia, Michoacán, México

*Corresponding author: Cleto Alvarez Aguilar, Medical Research Assistant Coordination in Health of the IMSS, Morelia, Michoacán, México

Received: May 01, 2021; Accepted: May 20, 2021; Published: May 27, 2021

Abstract

Aim: To evaluate serum renalase and salivary alpha amylase concentrations and their relationship with plasma catecholamine levels in patients with Metabolic Syndrome (MS), Type 2 Diabetes Mellitus (T2DM), and End-Stage Renal Disease (ESRD).

Method: In cross-sectional study 163 patients were enrolled; 43 patients with MS, 93 withT2DM, 13 with ESRD, and 14 healthy subjects (control group). All patients had their ascription to the UMAA/UMF No. 75, in Morelia, Michoacan, Mexico. Glucose, creatinine, cholesterol, triglycerides, HDL, and renalase were measurement in serum, and Dopamine (DA), Epinephrine (E) and Norepinephrine (NE) in plasma. An aliquot of saliva was collected for alpha amylase determination.

Results: High plasma concentrations of DA, E and NE (p<0.0001) was founded in T2DM and ESRD patients. Renalase was lower in ESRD compared to MS and T2DM patients (p<0.0001). High concentrations of alpha amylase were found in MS, T2DM, and ESRD patients in comparison with control group (p<0.0001). Catecholamines correlated positively with alpha amylase and diabetes evolution.

Conclusion: Sympathetic hyperactivity in MS, T2DM and ESRD patients was founded. Renalase could be proposed as biomarker of renal function and salivary alpha amylase as sympathetic hyperactivity. Additional studies are required to evaluate the pathophysiological mechanisms involved of SNS in CKD development.

Keywords: Renalase; Alpha amylase; Sympathetic activity; Metabolic syndrome; Type 2 diabetes mellitus; Chronic kidney disease

Introduction

Metabolic Syndrome (MS) is defined as a cluster of metabolic abnormalities that increase the risk for the development of Cardiovascular Diseases (CVD) and diabetes, including abdominal obesity, elevated plasma glucose and triglycerides, reduction in High- Density Lipoproteins (HDL) and high blood pressure levels [1]. MS is becoming one of the main public health problems of the 21^st century, as it is strongly associated with a 5-fold increase in the prevalence of Type 2 Diabetes Mellitus (T2DM) and a 2-3-fold increase in CVD [2,3].

The American Diabetes Association defines T2DM as a metabolic disorder characterized by chronic hyperglycemia related to disturbances in the carbohydrate, fat and protein metabolism, that translate into defects in the secretion and action of insulin [4]. Epidemiological data show that T2DM is a risk factor for CVD morbidity and mortality [5].

The National Kidney Foundation (NKF), Kidney Diseases Outcomes Quality Initiative (KDOQI) (NKF-KDOQI) in its clinical practice guidelines defines Chronic Kidney Disease (CKD) as kidney damage or Glomerular Filtration Rate (GFR) ≤60 ml/min/1.73m2SC that lasts for 3 or more months, regardless of the cause [6]. Diabetes [7] and Hypertension [8] are responsible for up to two thirds of CKD cases, although there are other risk factors such as age, family history, race, low educational and socioeconomic levels, other chronic systemic diseases, and drug toxicity [9].

Renalase is produced and secreted mainly by glomerular and tubular cells in the kidney. One function of renalase is to regulate blood pressure and cardiovascular function through circulating catecholamine degradation [10]. Renalase is also expressed in heart, musculoskeletal tissue, and small intestine [11,12] and its concentration is regulated by renal function, renal perfusion, and catecholamine concentrations [13]. Renalase has been referred as a new candidate for DM2diagnosis [14] and as a therapeutic target in the prevention of cardiorenal syndrome, as it was suggested by Yin et al. [15] inan experimental model of nephrectomizedrats, in which renalase absence protected against renal injury and cardiac remodeling.

Alpha Amylase is an endoamylaserelated to carbohydrate digestion that is mainly expressed in pancreas and salivary glands. Amylase catalyzes the hydrolysis of α, 1-4 glycosidic bonds in the inner part of glycogen and starch chains, ultimately producing monosaccharides [16]. Human studies provided direct evidence of alpha amylase sensitivity in adrenergic activity, specifically related to psychological stress, mediated through beta receptors [17]. Recently, alpha amylase has been proposed as a non-invasive biomarker of chronic psychosocial stress, in which its activity is found elevated [18].

Sympathetic nerve activity is increased in CKD patients as a result of increased vascular resistance and blood pressure, which in turn leads to an increase in circulating catecholamine levels [Dopamine (DA), Epinephrine (E) and Norepinephrine (NE)] due to a reduction in glomerular filtration [19]. However, there is controversy in relation toplasma levels of catecholamines in patients with T2DM and CKD and their possible implications in the pathogenesis and complications of this disease [20]. Therefore, the objective of this study was to evaluate serum renalase and salivary alpha amylase concentrations and their relationship with plasma catecholamine levels in patients with MS, T2DM, and End-Stage Chronic Disease (ESRD) secondary to diabetes.

Material and Methods

A total of 163 patients were enrolled in a prospective, crosssectional study; from them, 43 patients with MS diagnosis (MS), 93 patients with T2DM, 13 with ESRD and 14 healthy subjects as control group, recruited from Outpatient Medical Unit (UMAA)/Family Medicine Unit No. 75 (UMF No. 75) (UMAA/UMF No. 75), of the Instituto Mexicano of Seguro Social (IMSS) in Morelia Michoacán, Mexico.

The inclusion criteria for all groups were: age ≥20 years, both genders, without inflammatory, infectious pathology or bleeding in the oral cavity. For T2DMgroup a diagnosis older than 6 months was considered, according to the American Diabetes Association criteria [21]. Finally, for ESRD patients in replacement treatment of renal function with hemodialysis, were included. All subjects were informed of the purpose of the study before giving their consent. MS diagnosis was made according to International Diabetes Federation (IDF) criteria, estimating central obesity by an abdominal circumference ≥94 cm in men, ≥80 cm in women, plus one or two of the following risk factors: blood pressure ≥130/85 mmHg, triglycerides ≥150 mg/ dL, HDL-C<40 mg/dL in men, <50 mg/dL in women and fasting glucose between 100 to 125 mg/dL, as oral glucose tolerance curve is suggested but not essential to MS diagnosis [22].

Ablood sample of approximately 12 ml was taken from all participants. In control group, MS and T2DM, sample was taken from antecubital vein of left arm in a supine position, after 10 hours of fasting. In ESRD group, blood was taken fromarterial line before hemodialysis. Saliva sample was collected in10 hours fasting, without eating, drinking, chewing gum, or cleaning their mouth for at least 60 minutes prior to sample. Blood samples were centrifuged at 3,500 rpm for 10 minutes in a refrigerated centrifuge and serum/ plasma obtained was stored at -70^oC (SANYO Biomedical Freezer Mod. Allegra X-22) until processing. Serum was used for glucose, creatinine, total cholesterol, triglycerides and HDL-c determination (Automated Clinical Chemistry equipment, Vitros 5.1 FSSANYO, Series 34001004). Renalase was assessed by ELISA commercial kit (BioAssay^TM ELISA Kit Human). Plasma catecholamines (DA, E and NE) were measured by HPLC (WatersTM Mod. 2487, Milford, USA).Whereas salivary Alpha amylase was determined by ELISA commercial kit (USBiological^TMAmylase Alpha Bioassay ELISA Kit Human), with a detection range of 0-400 U/mL. The eGFR was estimated using the Chronic Kidney Epidemiology Collaboration (CKD-EPI) equation [23].

This study protocol was approved by Local Research and Health Research Ethics Committee #1602 of IMSS in Morelia, Michoacán, México.

Statistical analysis

Results are shown as mean ± standard deviation. The normality of the variable distribution was verified using the Kolmogorov-Smirnov test. Mean differences were evaluated with Kruskal-Wallis test and U de Mann Whitney. Spearman’s correlation coefficient was used for the assessment of correlation between variables. All variables were analyzed in statistical package SPSS.V21 for PC. Statistical significance was considered p <0.05.

Results

Table 1 resumes the results of clinical and biochemical variables in studied population. BMI, SBP, DBP, MAP, and eGFR in MS, T2DM and ESRD were statistically different compared to control group (p<0.01). ESRD had the highest serum creatinine concentrations. Also, a decrease in eGFR was observed in DM2 patients in relation to control group and MS (p<0.01). In SNS activity parameters, higher plasma concentrations of DA (p<0.01), E (p<0.05), and NE (p<0.001) was found in the patients with ESRD and T2DM compared to control group.

Table 1: Renalase and alpha amylase concentration in study groups.




  
    Variables 
    Control Group 

      n=14 
    MS Group 

      n=43 
    DM2 Group 

      n=93 
    ESRD Group 

      n=13 
  
  
    Gender (M/F) 
    6/8 
    17/26 
    31/62 
    7/6 
  
  
    Age (years) 
    49±11 
    50±10 
    59±10* 
    50±17 
  
  
    BMI (kg/m2) 
    22.8±1.9 
    29.8±3.8* 
    29.6±4.4* 
    27.7±5.2*** 
  
  
    BPS (mm/hG 
    113±6 
    129±15** 
    140±19* 
    166±13* 
  
  
    BPD (mm/Hg) 
    75±6 
    84±11** 
    86±11** 
    101±7* 
  
  
    MBP (mm/Hg) 
    88±4 
    98±10*** 
    104±11* 
    117±6* 
  
  
    Diabetes evolution    (years) 
    ------ 
    ------ 
    7±6 
    20±3d
  
  
    Glucose (mg/dL) 
    86.2±8.3 
    104.0±9.6*** 
    135.7±45.3* 
    97.5±21.8 
  
  
    eGFR (ml/min/m2 BS)
    104.8±105.9
    87.6±15.9**
    77.6±18.1*
    5.6±1.5*
  
  
    TC (mg/dL)
    165.7±32.8
    175.2±34.2
    167.1±42.4
    146.7±31.2
  
  
    TG(mg/dL) 
    118.7±51.8 
    183.2±76.7*** 
    171.4±76.7*** 
    167.3±39.2*** 
  
  
    c-HDL (mg/dL) 
    47.8±10.9 
    37.8±7.1*** 
    40.1±11.3*** 
    38.1±8.7 
  
  
    Dopamine (pg/mL) 
    11.4±2.6 
    21.1±10.6 
    25.7±15.3** 
    61.8±14.7* 
  
  
    Epinephrine 
    14.2±3.3 
    23.1±14.6 
    33.1±28.2*** 
    105.9±32.6* 
  
  
    (pg/mL) 
  
  
    NE (pg/mL) 
    40.2±9.1 
    150.4±88.4** 
    198.4±111.2* 
    438.4±114.6* 
  
  
    Results are expressed in media±SD; MS Group:    Metabolic Syndrome Group; DM2 Group: Diabetes mellitus 2 Group; ESRD Group:    End-stage renal disease; BMI: Body Mass Index; SBP: Systolic Blood Pressure;    DBP: Diastolic Blood Pressure; MBP: Mean blood pressure (DBP+1/3 of    difference SBP-DBP); eGFR= Estimated Glomerular Filtration Rate; TC=Total    Cholesterol; TG: Triglycerides; c-HDL: High Density Lipoprotein; NE=    Norepinephrine; *p<0.0001; **p<0.01; ***p<0.05;    Control group vs MS, T2DM and ESRD    group; dp<0.0001 T2DM vs ESRD group.



Table 1: Renalase and alpha amylase concentration in study groups.

Interestingly, renalase concentrations were lower in ESRD compared to T2DM and MS (p<0.0001) while higher concentrations of salivary alpha amylase were found in MS, T2DM, and ESRD patients compared with control group (p<0.0001) (Figure 1).

Figure 1: Renalase and alpha amylase concentration in study groups.

    
    
    Figure 1: Renalase and alpha amylase concentration in study groups.

Table 2 show the univariate analysis of serum renalase and salivary alpha amylase with other variables analyzed. We found an inverse correlation between serum renalase, blood pressure, and diabetes evolution. While positive correlation was found with serum glucose, and GFRe. Moreover, salivary alpha amylase had a negative correlation with eGFR and a positive correlation with BP, serum glucose, and plasma DA, E and NE.

Table 2: Correlation between renalase, alpha amylase, clinical and biochemical variables of the studied population.




  
    Variables 
    Renalase 
    Salivary alpha amylase 
  
  
    Spearman    test 
    P
    Spearman    test 
    P
  
  
    Age (yr) 
    0.104 
    0.391 
    0.104 
    0.197 
  
  
    BMI (m2) 
    0.3 
    <0.0001 
    0.136 
    0.09 
  
  
    SBP (mm/hg) 
    -0.193 
    0.014 
    0.499 
    <0.0001 
  
  
    DBP (mm/hg) 
    -0.238 
    0.002 
    0.472 
    <0.0001 
  
  
    MBP (mm/hg) 
    -0.22 
    0.005 
    0.488 
    <0.0001 
  
  
    Diabetes evolution    (years) 
    -0.328 
    <0.001 
    0.19 
    0.054 
  
  
    Glucose (mg/dL) 
    0.216 
    0.006 
    0.241 
    0.002 
  
  
    Total Cholesterol (mg/dL) 
    0.092 
    0.242 
    -0.173 
    0.12 
  
  
    Triglycerides (mg/dL) 
    0.166 
    0.035 
    0.097 
    0.227 
  
  
    eGFR (ml/min/m2SC) 
    0.188 
    0.016 
    -0.422 
    <0.0001 
  
  
    Dopamine pg/mL) 
    -0.095 
    0.229 
    0.574 
    <0.0001 
  
  
    Epinephrine (pg(mL) 
    -0.151 
    0.054 
    0.614 
    <0.0001 
  
  
    Norepinephrine (pg/mL) 
    -0.153 
    0.051 
    0.684 
    <0.0001 
  
  
    BMI: Body Mass Index; SBP: Systolic Blood    Pressure; DBP: Diastolic Blood Pressure; MBP: Mean blood pressure (DBP+1/3 of    difference SBP-DBP); eGFR: Estimated Glomerular Filtration Rate.



Table 2: Correlation between renalase, alpha amylase, clinical and biochemical
variables of the studied population.

Figure 2 report important correlations between diabetes evolution and MBP (r=0.351; p<0.0001), DA (r=0.296 p=0.0002), E (r=0.474, p=<0.0001), NE(r= 0.443, p<0.0001), salivary alpha amylase (r=0.256, p=0.009) and eGFR (r=-0.604, p<0.0001). Additionally, correlations between eGFR and DA (r=-0.629, p<0.0001), E (r=-0.662, p<0.0001), NE (r=-0.635, p<0.0001) and MBP (r=-0.480, p<0.0001) are represented in Figure 3.

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Citation:Hernández LE, Hernández GP, Sánchez DCV, García AG and Aguilar CA. Sympathetic Nervous System Activity in Patients with Metabolic Syndrome, Type 2 Diabetes Mellitus and Chronic Kidney Disease. Role of Renalase and Alpha Amylase. J Dis Markers. 2021; 6(1): 1039.

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