Role of Adiponectin Level and Cystatin-C Level in Type II Diabetic Patients with Albuminurea

Noor Thair Tahir^1*, Mithal R Alkubaisi², Raghd AY ALKhader³, Abdilya R ALAbdaly⁴ and Luay Asaad Mahmood²

^*Correspondence: Noor Thair Tahir, National Diabetes Center, Mustansiriyah University, Iraq, Email:

Author info »

Introduction

In most adult populations, type 2 diabetes (T2D) accounts for nearly 90% of all cases of diabetes [1]. Subjects with T2D are at increased risk of developing vascular complications, e.g., peripheral vascular disease, stroke, myocardial infarction, neuropathy, retinopathy and nephropathy [2] .The increasing number of subjects having diabetes mellitus has had a strong impact in regards to the diabetic nephropathy (DN) prevalence [3]. Diabetic nephropathy, is one of the most frequent longterm complications of diabetes, that affects over 40% of patients suffering from diabetes mellitus and still being the leading cause of end-stage kidney disease (ESKD) in most countries [4]. The overall burden for subjects having DN is very high due to the strong relation of DN and cardiovascular disease with ESKD [3].

Diabetic nephropathy was classically defined as a progressive rise in urinary albumin excretion, combined with increasing blood pressure, resulting in declining glomerular filtration and ultimately ESKD [5]. Injury to the podocytes, that are a vital constituent of the glomerular filtration barrier, appears to play an important role in DN development. Several reports have implied “that dysregulation of AMP activated kinase protein, which is an essential cellular energy sensor, may play a fundamental role in this process” [4].

Given that albuminuria is a significant component of diabetic nephropathy, it is essential to establish definition of different degrees of urine albumin excretion (UAE). Normo-albuminurea refers to UAE less than30 mg/day (or less than 20 μg/min), and micro-albuminurea refers to UAE between 30 and 300 mg/day (or between 20 and 200 μg/min), whilst macro-albuminurea refers to UAE over 300 mg/day (or over 200 μg/min) [6].

Adiponectin (ADPN), an adipocyte-derived plasma protein, is composed of 244 amino acid and is chiefly secreted by the white adipocytes. ADPN is generally encoded by the gene ADIOPOQ which is located on the chromosomal locus3q27 [7]. It is additionally secreted by the placenta and kidney [8]. Circulating ADPN exists in 3 different forms: low-molecular-weight, mediummolecular- weight and high-molecular-weight. Indeed, high-molecular-weight ADPN is the most biologically active form that is principally cleared by the liver [9]. The physiological functions of ADPN occur secondary to the binding of ADPN to specific receptors on the surface of target cell membranes [10]. At the present time, the following ADPN receptors were identified: receptor 1 (AdipoR1), receptor 2 (AdipoR2), and T-cadherin [11].

ADPN uniquely possesses 2 major properties: 1) its circulating level is around 3 to 6 orders of magnitude higher than ordinary cytokines and hormones; 2) its level inversely associates with body fat mass in spite of its adipocyte-specific production. The low levels of serum ADPN associate with cardio metabolic diseases. Based on extensive experimental evidence, ADPN possesses multiple properties, such as anti-inflammatory, antiatherosclerotic, and anti-diabetic activities. It was demonstrated to play a fundamental role against the development of metabolic syndrome along with its complications [12].

Cystatin-C has emerged as a promising plasma biomarker of renal function which is less influenced by changes in muscle mass in comparison with Creatinine. Cystatin-C ) Cys-C(, is a 13 kilo Daltons basic nonglycated protein, that is produced by all the nucleated cells of the human body at a constant rate , in addition, it functions as a cysteine proteases inhibitor. Cys-C is freely filtered through the glomerulus and reabsorbed chiefly by the proximal tubular cells while there is no tubular secretion. Hence, it was proposed “to be closer to the ideal endogenous marker” [13]. Its level is almost totally dependent upon glomerular filtration rate (GFR) [14]. Previous studies have reported that serum Cys-C) sCys-C (is an early renal marker in subjects with diabetes [15], however not all studies have done so [16].

Cystatin-Chas emerged as the most prominent nontraditional GFR biomarker, and Cystatin-C has also emerged as the most prominent non-traditional GFR renal biomarker, as well as it is included in the chronic kidney disease (CKD) diagnostic criteria for the KDIGO guidelines [17]. Cystatin-C was additionally found to be more strongly correlated with adverse nonretail outcomes, for example death, in comparison with serum Creatinine-based evaluations, even after accounting for mGFR in several cases [18].

The aim of the present research was to study the role of ADPN and Cys-C levels in T2D patients with nephropathy complications, and their relation with the other clinical parameters.

Materials and Methods

The study was done in National Diabetes Center, Mustansiriyah University, Baghdad, Iraq in January 2020 to October 2020. A total of 90 subjects, with age range between (40-60) years. Sixty-nine T2D nephropathy subjects, subdivided into 3 groups based on urinary albumin/creatinine ratio: group one (G1)=22 normoalbuminurea; group two (G2)=22 micro-albuminurea and group three (G3)=25 macro-albuminurea, when compared with 21 healthy controls (G4). The blood samples were taken for the laboratory investigation that included: total cholesterol (T-Cho), low-density lipoprotein-cholesterol (LDL-Cho), high-density lipoprotein-cholesterol (HDL-Cho), triglyceride (TG), fasting glucose (FG), serum creatinine and urea levels were estimated by the use of automated analyzer (BIOLABO Kenza240TX). The glycated hemoglobin (HbA1c) levels were estimated by the use of automated analyzer Bio-Rad VARIANT [19]. Furthermore, estimated the Micral tests; supplied by Bayer Healthy Care, V.S. A. [20]. Determination of serum ADPN and sCys-C levels were done by ELISA (Demeditec Diagnostic, Germany, Catalog DEE009 kit) and (Ray Biotech, Parkway land, Catalog ELH-Cystatin C Kit) respectively. Analysis of data was carried out using statistical package for social sciences (SPSS).

Results

Results in Table 1 demonstrated that there was no statistically significant difference among the 4 studied groups regarding age, weight, height, BMI and HDL-Cho, whereas a significant statistical difference was found regarding systolic blood pressure (SBP), diastolic blood pressure (DBP), FG, HbA1c, fasting insulin (FI), HOMA-IR, T-Cho, LDL-Cho, TG, serum urea and serum creatinine.

Table 1: Comparison of anthropometrics measurement and biochemical parameters among the study groups.

Results showed statistically highly significant differences in the mean levels of ADPN on the overall ANOVA comparison of the studied groups (P<0.001) (Table 2), with macroalbuminuric T2D subjects, having a significantly higher ADPN concentrations compared with control subjects. Serum ADPN concentrations were significantly increased in macro-albuminurea group compare to all 3 studied groups; micro-albuminurea (p<0.05), normo-albuminurea, and healthy controls (p<0.01). Moreover, serum ADPN levels were significantly increased in micro-albuminurea group (p<0.05) compared with normo-albuminurea and healthy controls (p˂0.01). Interestingly, serum ADPN levels were statistically significantly increased in normoalbuminurea group when compared with healthy controls group (p<0.05). These findings are given in Table 2 and shown graphically in Figure 1.

Table 2: The Comparison of Cystatin-C (ng/dl) and Adiponectin (ng/dl) among the study groups

Figure 1. Graphical representation of mean values of serum ADPN level (ng/dl) among controls and cases.

Results showed statistically highly significant differences in the mean levels of sCys-C on the overall ANOVA comparison of the studied groups (P<0.001). Also, concentrations of sCys-C were significantly increased in macro-albuminurea group compare to all 3 studied groups; micro-albuminurea (p<0.05), normoalbuminurea, and healthy controls (p<0.01). Moreover, concentrations of sCys-C were significantly increased in micro-albuminurea group compare to normoalbuminurea and healthy controls (p˂0.01). Though, in contrary with ADPN, levels of sCys-C were not statistically significantly increased in normo-albuminurea group when compared with healthy controls (p˃0.05). These findings are given in Table 2 and shown graphically in Figure 2.

Figure 2. Graphical representation of mean values of sCys-C level (ng/dl) among controls and cases.

Data in Table 3 showed that ADPN level had a highly significant positive correlation with HDL-Cho in T2D subjects who were having normo-albuminurea (r=0.561, p=0.007). Also, ADPN level was positively correlated with serum urea in subjects with T2D who were having microalbuminurea

Table 3: Correlations coefficient between Adiponectin level in sera of three groups (normo-albuminurea, Micro-albuminurea, macro-albuminurea).

(r=0.502, p=0.017). Moreover, ADPN level was positively correlated with DBP in subjects with T2D who were having macro-albuminurea (r=0.396, p˂0.050). There was no correlation found between serum ADPN and Cys-C.

Figure 3 shows the Receiver Operating Characteristic curve (ROC) of serum ADPN and Cys-C levels for prediction of micro-albuminurea in T2D patients. For ADPN, the area-under-the-curve (AUC) was 0.722 and for Cys-C, the AUC was 0.683.

Figure 3. The ROC-curve analysis of serum ADPN and Cys-C in micro-albuminuric patients.

Figure 4 shows the ROC-curve analysis of the 2 studied biomarkers for prediction of macro-albuminurea. For ADPN, the AUC was 0.904and for Cys-C, the AUC was 0.836.

Figure 4. ROC-curve analysis of serum ADPN and Cys- C in macro-albuminuric patients.

Figure 5 shows the ROC curve analysis of ADPN levels and Cys-C level in serum of three groups normoalbuminurea, micro-albuminurea and macroalbuminurea in diabetic patients. For ADPN, the AUC 0.912 and for Cys-C, the AUC was 0.795.

Figure 5. ROC-curve analysis of serum ADPN and Cys- C in normo-albuminuric, micro-albuminuric and macro-albuminuric patients.

Discussion

In this study, serum ADPN levels and sCys-C have been measured in T2D patients, classified into 3 groups according to the amount of protein excretion and the levels have been compared with control group (Table 2). Statistically significant differences in serum ADPN concentrations across the 4 studied groups (p<0.001) were found in the present study, with the macroalbuminuric T2D subjects, having significantly higher ADPN concentrations compared with control subjects. Savadi et al. [21] reported similar findings in their study. Also, serum ADPN concentrations were significantly increased in macro-albuminurea group compare to both diabetic groups; micro- and normoalbuminurea. Moreover, serum ADPN concentrations were significantly increased in micro-albuminurea group compare to normo-albuminurea.

Furthermore, in this study, serum ADPN levels in normoalbuminurea group showed highly significant positive correlation with HDL-Cho. Serum ADPN levels in microalbuminurea were positively correlated with serum urea. ADPN levels in the macro-albuminurea group showed significant positive correlation with DBP.

Other previous studies of Koshimura et al. [22] and Galovicova et al. [23] reported similar results of elevated ADPN concentrations in DN with macro-albuminurea. Increased ADPN concentrations can be because of either an increased ADPN biosynthesis in adipocytes along with its secretion into the circulation in an attempt to overcome the micro-vascular damage in advanced stage of DN, or a reduced clearance of ADPN in the setting of impaired kidney function, or both [22,23]. Fujita et al. [24] predicted that the elevation in ADPN concentrations result from the increased biosynthesis in adipocyte as well as secretion of this biomarker rather than decreased clearance as a result of impaired kidney function, even though, Pradeepa et al., [25] could not detect any statistically significant differences in ADPN concentrations in T2D subjects with and without nephropathy. On the contrary, Jung et al. [26] found reduced ADPN concentrations in T2D subjects with nephropathy in comparison with those without nephropathy.

Recently, Alnaggar et al [27] showed that plasma ADPN level was significantly increased in subjects with T2D and micro-albuminurea compare to subjects with normoalbuminurea. This finding agreed with the result of present study.

ADPN is cleared from blood circulation in urine; thus, its serum concentration is affected by the renal clearance. In fact, serum ADPN concentrations as well as expression of AdipoR1/R2 in the tissue are significantly elevated in subjects suffering from kidney diseases [28]. In particular, the former is inversely related to GFR [29]. Nonetheless, decreased clearance of ADPN does not account for its elevated concentration in subjects suffering from kidney diseases. Instead, the “adiponectin resistance” caused by kidney diseases results in increased ADPN concentrations [30]. Actually, mRNA levels of ADPN along with AdipoR1 are increased in the adipocyte of individuals having ESKD [28]. Moreover, interruption at post-receptor level by uremia results in failure of downstream signaling of the AdipoR1/R2, leading to “adiponectin resistance” [31]. Consequently, high serum ADPN concentration in subjects having CKD, involving diabetic nephropathy, indicates adiponectin resistance as a result of renal dysfunction plus it is a predictive of poor long-term outcomes [32,33]. Notably, the beneficial effects of ADPN in kidney are mediated by its antifibrotic, anti-apoptotic, antioxidant, and antiinflammatory activities [32]. Particularly, the antioxidant capacity of ADPN plays a key role in decreasing metabolic injury in subjects having diabetic nephropathy. In particular, ADPN decreases oxidative stress by suppressing Nox4 expression that is a “nicotinamide adenine dinucleotide phosphate (NADPH) oxidase which is abundant in human kidney, primarily through AMPK pathway [34]. ADPN is increased in renal disease involving nephrotic syndrome, and especially in ESKD, with levels up to 3 times higher in comparison with the normal population in type 1 diabetes [35].

A number of previous studies have established that ADPN was significantly elevated in the presence of advanced DN [29,36,37]. Kato et al., [29] demonstrated that serum levels of ADPN were significantly increased in people having macro-albuminurea or chronic renal failure compared with normo- and micro-albuminurea. Another study by Saito et al., [38] showed that serum ADPN concentrations were significantly higher in subjects with stage IV and stage V of nephropathy (increased serum creatinine and under dialysis treatment respectively), but were lower in T2D subjects who have normal serum creatinine compare to controls. Even though the reason why serum ADPN concentration is increased in patients having CKD compare to those without CKD still being unclear, Cys-C might be one of the suggested causes. A study by Hosokawa et al. [39] demonstrated that serum ADPN level was associated with sCys-C level in T2D patients. They also suggested that the increased in serum ADPN level in advanced CKD could not only be due to the decrease of the eGFR, but also partially attributed to binding of Cys-C with ADPN, that would delay clearance of ADPN from the bloodstream. However, there was no correlation found between serum ADPN and Cys-C in the present study.

Cha et al [33] demonstrated that the plasma circulating concentrations of ADPN were significantly higher in T2D subjects with renal insufficiency and were significantly inversely correlated with the eGFR. They additionally found that ADPN was positively associated with HDLCho. Similarly, Ran et al. [37] also found significantly positive correlation between ADPN and HDL-Cho. These findings are in line with the current study especially in the normo-albuminurea group (Table 3).

This study found that sCys-C levels were significantly increased in T2D subjects with micro-albuminurea and macro-albuminurea when compared with healthy controls. This finding is in accord with previous studies [40]. Nevertheless, in this study, there was no statistically significant difference between sCys-C levels in normoalbuminuric patients and healthy controls. These findings are in agreement with the results recently reported by Mahfouz et al., [41] and Al-Hazmi et al. [42] that included subjects with T2D classified based on their albumin to creatinine ratio (ACR), in which sCys-C was not significantly different in normoalbuminuric patients having diabetes compared with healthy controls. In contrast to our study, Takir et al., [43] demonstrated that Cys-C could play a substantial role in development of early diabetic nephropathy and that the concentration of Cys-C was statistically significantly increased in normoalbuminuric subjects with diabetes who have GFR<60 ml/m/1.73 m². Nonetheless, this discrepancy with the findings of the present study can be attributed to the different groups classification because their subjects have been classified based on their GFR instead of ACR.

Conclusion

The findings of present study indicated that among T2D nephropathy subjects, serum ADPN and Cys-C levels were gradually and significantly elevated with the progression of renal disease in addition to the levels of albuminuria. Interestingly, serum ADPN levels were statistically significantly increased in normoalbuminurea group when compared with healthy controls group. Indicating that serum ADPN could be utilized as an early sensitive biomarker of diabetic nephropathy in T2D. The findings as well suggest that sCys-C could play an important role in the diagnosis and follow-up of T2D subjects with the onset of microalbuminurea. Hence, ADPN and Cys-C together are useful bio-markers of diabetic nephropathy, as well as in monitoring disease progression.

Abbreviations

ADPN, adiponectin; AUC, area under the curve; BMI, body mass index; CKD, chronic kidney disease; Cys-C, Cystatin- C; DBP, diastolic blood pressure; DN, diabetic nephropathy; ESKD, end stage kidney disease; FG, fasting glucose; FI, fasting insulin; GFR, glomerular filtration rate; HbA1c, glycated haemoglobin; ROC, receiver operating characteristic; sCys-C, serum Cystatin-C; SBP, systolic blood pressure; T-Cho, total cholesterol; T2D, type 2 diabetes.

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