Association of Metabolic Syndrome with Albuminuria in Diabetes Mellitus Type 2

Article history: Received 23 August 2019 Received in revised form 14 October 2019 Accepted 21 October 2019


Introduction
Metabolic syndrome is a major health problem nowadays. International Diabetes Federation (IDF) believes that groups of these factors influence the global epidemic of diabetes mellitus type 2 (DMT2) and cardiovascular disease, the syndrome consists of several risk factors including visceral obesity, dyslipidemia, insulin resistance, impaired glucose tolerance, and increased blood pressure. 1 The disease is related to lifestyle such as physical inactivity, junk food, carbohydrates, and smoking.
Metabolic syndrome affects about 40% of the population above 50 years old in United States and almost 30% in Europe. Tjokroprawiro reported that the prevalence of metabolic syndrome in a population over 40 years old undergoing a medical examination in Surabaya ranged from 32%. In addition, it was reported 43.3% were treated in DMT2 and 59.0% were treated in naïve DMT2 as observed in private clinics, while the prevalence of metabolic syndrome in people with DMT2 with obesity was 81.7% . 2 Metabolic syndrome is closely related to cardiovascular disease (CVD). In addition, recent studies show an association between metabolic syndrome and the risk of chronic kidney disease (CKD) and microalbuminuria. 3 Study of Hao, et al. (2006) explained that there was a significant correlation between metabolic syndrome and the prevalence of microalbuminuria (r = 0.44, p <0.001). 4 Albuminuria is an early marker of CKD which also acts as a predictor of CVD and mortality. People with DMT2 with microalbuminuria, progression to massive proteinuria occurs in 20-40% of cases, while 10-50% of DMT2 patients with proteinuria will have CKD and require renal replacement therapy. 2 The aim of this study was to determine the association between metabolic syndrome and albuminuria in people with DMT2 especially in Surabaya. It could give a Biomolecular  little description of the prevalence and characteristics of metabolic syndrome in the population of type 2 diabetes, especially in Surabaya. In addition, to predict the possibility of diabetes patients with metabolic syndrome that have cardiovascular complications. Thus, the therapy can reduce the possibility of cardiovascular complications as early as possible.

Methods
This was an observational analytic study with cross sectional design. Population of this study was DMT2 patients over the age of 30 years old and less than 80 years old who undergo treatment at a private outpatient clinic Metabolic and Diabetes Endocrinologist Internist Consultant in Surabaya. The sample was 40 people, taken by using non random purposive sampling technique.
Independent variable was components of metabolic syndrom (waist size, triglyceride level, HDL level, systolic pressure, diastolic pressure, and fasting blood glucose level). Dependent variable was albuminuria, divided into normo albuminuria, mikro albuminuria, and makro albuminuria. The data was collected using medical record and was analyzed using Spearman Correlation and Mann-Whitney.

Demographic and Clinical Chracteristic
The number of subjects included this study was 131 DMT2 patients, consisting of 71 men (54.2%) and 62 women (45.8%). The overall clinical characteristics of the subjects were summarized in Table 1 Figure 1.
Characteristics of DMT2 subjects based on classification of metabolic syndrome components are shown in Table 2. Due to the abnormal distribution of the data, non-parametric test calculation were used, and Kruskal Wallis test was chosen to compare more than 2 variables. This study found significant differences in systolic blood pressure with metabolic syndrome component group p=0.000, diastole blood pressure p=0.000, hypertriglyceridemia p=0.000, low HDL p=0.000, and albuminuria p=0.002. Meanwhile, for age, duration of DM, body mass index, waist circumference, fasting blood glucose, post prandial glucose, HbA1C, total cholesterol, LDL, Hb, BUN, and serum creatinine, there were no significant differences.
Due to the significant differences in systolic BP, diastolic BP, hypertriglyceride and low HDL with metabolic syndrome, further tests were performed with Mann-Whitney test to find out where the difference lies, whether in the 3 components group with 4 components, 3 components group with 5 components, or 4 components group with 5 components group of metabolic syndrome. Based on the Mann-Whitney test, there was a significant difference between 3 components group and 4 components of metabolic syndrome, p=0.007 in systolic BP, p=0.000 in diastolic BP, p=0.000 for hypertriglycerides, and p=0.001 for low HDL. Between

Association between metabolic syndrome and albuminuria
The correlation between components of metabolic syndrome and albuminuria can be seen in Table 4. Spearman's test was used to measure the correlation between two unpaired variables. A significant association was found between systolic blood pressure and albuminuria, p=0.000 and r=0.325. Fasting blood glucose with albuminuria, p = 0.01 and r=0.223. On the other hand, no significant association was found between diastolic blood pressure and albuminuria, p=0.153, but a positive r value (r=0.125) means that although there was no statistically significant association, if diastolic blood pressure is higher, albuminuria will increase too. Likewise, between waist circumference with albuminuria, p=0.311 but with a positive r value (r=0.089). The same goes with hypertriglyceridemia with albuminuria, p=0.727 and r=0.031. Even so, association of low HDL and albuminuria found p=0.771 and r value =-0.025 mean that the lower of HDL will increase albuminuria. Characteristics of DMT2 with metabolic syndrome based on albuminuria classification (normoalbuminuria, microalbuminuria, macroalbuminuria) can be seen in Table 3. A significant difference was found in systolic blood pressure with albuminuria (p=0.024). Whereas in age, duration of DM, body mass index (BMI), diastolic blood pressure, waist circumference, fasting blood glucose (FBG), post prandial level, HbA1C, total cholesterol, LDL, triglycerides, HDL, Hb, BUN, and serum creatinine no meaningful difference obtained.
Due to the significant differences found in systolic BP, then further tests with the Mann-Whitney test was carried out. Based on the Mann-Whitney test, there was a significant difference between the normoalbuminuria and microalbuminuria groups (p=0.007). However, between normoalbuminuria and macroalbuminuria groups, there was no significant difference (p=0.362). Likewise, for microalbuminuria and macroalbuminuria groups, no significant difference was found (p=0.435).   6 The prevalence of metabolic syndrome is influenced by factors that can or cannot be modified. Many of these factors are interrelated, including age, gender, ethnicity/ race, obesity and fat distribution, diet and physical activity patterns, birth weight, genetics, endocrine factors, menopause or hormone replacement therapy, inflammation, alcohol, and comorbid factors (such as diabetes, hypertension, coronary artery disease). Nevertheless, the prevalence of metabolic syndrome can be increased due to the increasing prevalence of obesity and central obesity. 7 Jorgenson examined the prevalence of metabolic syndrome in a population over 35 years old, found two different figures using different criteria, using WHO criteria the prevalence was 20.7%, while using NCEP-ATP III criteria the prevalence was 17.9%. 8  The proportion for each component of metabolic syndrome in this study found 52.6% subjects with hypertension, 56.4% subjects with hypertriglyceridemia, 54.9% subjects with low HDL cholesterol, 100% central obesity, and 100% diabetes mellitus. This study shows that all subjects have central obesity, this is because in determining the metabolic syndrome this research used IDF criteria in 2006 where a person is said to have metabolic syndrome if he/she has central obesity marked by waist circumference > 90 cm in men and > 80 cm for women, plus 2 or more than 4 other components of metabolic syndrome. All subjects in this study also had diabetes mellitus because the subject population was taken from people with DMT2.

Albuminuria in DM type 2
The results from 133 DMT2 patients, 65.4% of patients have normoalbuminuria, 27.1% microalbuminuria, and 7.5% macroalbuminuria. It is in line with research by Tseng on 549 DMT2 patients, which found 45.7% DMT2 patients with normoalbuminuria, 44.1% patients with microalbuminuria, and 10.2% patients with macroalbuminuria, 12 meanwhile the study by Chiowanich of 2231 DMT2 patients, found 63.4% patients with normoalbuminuria, 27.5% patients with microalbuminuria, and 9% patients with macroalbuminuria. 13 Microalbuminuria can be an etiology or complication of vascular disease. STENO hypothesis said that leakage of albumin into the urine is a reflection of extensive vascular damage. This hypothesis links endothelial dysfunction with vascular albumin leakage. In some ways, the kidneys are the window to the body's vascular system. Renal leakage can reflect the permeability of the overall vascular system. 14 A significant difference was found in systolic blood pressure with albuminuria p = 0.024. Whereas in age, duration of DM, body mass index (BMI), diastolic blood pressure, waist circumference, fasting blood glucose (FBG), post prandial glucose level, HbA1C, total cholesterol, LDL, triglycerides, HDL, Hb, BUN, and serum creatinine no meaningful difference obtained. Based on the Mann-Whitney test, there was a significant difference in systolic blood pressure between the normoalbuminuria and microalbuminuria groups, p = 0.007. However, between normoalbuminuria and macroalbuminuria groups, there was no significant difference. Likewise, for microalbuminuria and macroalbuminuria groups, no significant difference was found.
Published data from cross sectional studies show the prevalence of microalbuminuria in hypertensive populations ranging from 4.7% to 40%, depending on the severity of hypertension and comorbidity. Research by de Melo 15 confirmed the Nogueira study, which showed that there was an association between blood pressure changes and the incidence of diabetes mellitus with an increase of albuminuria in individuals with hypertension. This suggests that efforts to achieve adequate blood pressure and glycemic control must be sought, with the aim of reducing albuminuria excretion and consequently preventing evolution towards target organ damage and decreasing morbidity and mortality. 15

Correlation between metabolic syndrome and albuminuria
This study found a significant association between systolic blood pressure and albuminuria, p = 0.000 and r = 0.325. Fasting blood glucose with albuminuria, p = 0.01 and r = 0.223. This is consistent with the results shown by research conducted by Hao,et al. 4 as well as by Palaniappan, et al. 16 Whereas in diastolic blood pressure, waist circumference, low HDL, and hypertriglyceridemia, there was no significant association.
Study by Hao, et al. showed a significant relationship between metabolic syndrome and albuminuria. This study also stated that blood pressure and obesity individually have an association with ural microalbumin. 4 In the study of Palaniappan, et al., a strong positive relationship was found between the components of metabolic syndrome and microalbuminuria in both male and female populations. From this research it shows that high glucose levels and blood pressure are the most influential components on the occurrence of microalbuminuria. 16 Study by Tseng showed that TG levels increased with increasing albuminuria. TG levels differed significantly between the three groups of albuminuria and correlated with albuminuria (ACR) for the entire albuminuria range. 12 Numerous studies have shown that lipid abnormalities can initiate glomerular injury and increase the development of existing glomerular disease. The final pathway for most of these diseases is generally the development of glomerulosclerosis. The mechanism that associate hypercholesterolemia with the development of glomerular disease is thought to be the same as the influence of high cholesterol levels which cause atherosclerosis. 17 Glomerular cells have LDL receptors, mesangial, and glomerular epithelial cells that can internalize atherogenic lipoproteins through receptor or non-receptor intermediate mechanisms. Infiltration of atherogenic lipoproteins into glomerular endothelium and mesangial cells can initiate a cascade of events including expression of adhesion molecules, production of monoattractant monocytes, and reactive release of oxygen species, resulting in initial glomerular injury. 12 In the study of Zoppini with a large 5-year cohort study involving 1987 outpatient DMT2 patients, it showed that high plasma HDL levels were strongly associated with a reduction in the incidence of CKD (GFR ≤ 60 mL / min / 1.73 m2). Similar results in a study by Ravid showed low plasma HDL levels predicted the development of microalbuminuria in 574 people with DMT2 during a 7-8 year follow-up. 18 The biological mechanisms underlying HDL in protecting the development and progression of CKD in people with DMT2 are poorly understood. Actually, HDL is involved in reverse transportation (reversal) of cholesterol, but HDL can also use several other effects, including antioxidants, anti-inflammatory, anti-thrombotic effects and protective effects of blood vessels. All of these beneficial vascular effects can also play a role at the level of kidney microcirculation, so it might explain the lower risk of CKD in the presence of higher HDL levels. 18 Finally, pharmacological interventions that are known to be effective in preventing or delaying the development of cardiovascular disease in people with DMT2, including close monitoring of blood pressure, LDL levels and glucose, can reduce the development and progression of kidney disease. The potential clinical implications of this finding for patient care is that in people with DMT2 with low plasma HDL levels, physicians must be more aware of the greater possible risk for developing CKD, and that pharmacological treatment aimed specifically at increasing plasma HDL levels may be a promising approach to reducing risk of development and progression of kidney disease.

Conclusion
There is a significant association between systolic blood pressure and fasting blood glucose level with albuminuria. Whereas in diastolic blood pressure, waist circumference, low HDL, and hypertriglycerida, there was no significant association. In the future, it is necessary to control the components of the metabolic syndrome, so that the risk for cardiovascular disease complications marked by albuminuria can be reduced. The high proportion of microalbuminuria in DMT2 patients has led to the need for increased attention from health care providers to conduct microalbuminuria screening tests for each DMT2 patients.