Article 451
Serum Omentin-1 Levels in Diabetic and Nondiabetic Patients with Chronic Kidney Disease
Affiliations
Key words ▶ omentin ● ▶ chronic kidney disease ● ▶ diabetes mellitus ● ▶ inflammation ●
received 14.02.2014 first decision 24.03.2014 accepted 29.04.2014 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1375674 Published online: June 11, 2014 Exp Clin Endocrinol Diabetes 2014; 122: 451–456 © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York ISSN 0947-7349 Correspondence H. Tekce, MD Department of Internal Medicine Faculty of Medicine Abant Izzet Baysal University 14280, Bolu Turkey Tel.: + 90/374/253 46 18-3522 Fax: + 90/374/253 46 15 [email protected]
H. Tekce1, B. K. Tekce2, G. Aktas1, A. Alcelik1, E. Sengul3 1
Faculty of Medicine, Department of Internal Medicine, Abant Izzet Baysal University, Bolu, Turkey Faculty of Medicine, Department of Medical Biochemistry, Abant Izzet Baysal University, Bolu, Turkey 3 Department of Nephrology, Derince Education and Research Hospital, Kocaeli, Turkey 2
Abstract
▼
Background: Omentin-1, a novel adipokine identified in visceral adipose tissue, is negatively correlated with different conditions such as diabetes, obesity and inflammation. However, changes in serum Omentin levels associated with the degree of the renal dysfunction and metabolic risk factors in CKD patients has not yet been revealed. In the present study, we aimed to investigate the level of Omentin-1 and related parameters in diabetic and non-diabetic CKD patients. Methods: 64 (30 diabetic, 34 non-diabetic) CKD patients and 27 healthy control subjects enrolled in this cross-sectional study. Anthropometric and laboratory assessment performed and malnutrition and inflammation components evaluated. Serum concentrations of Omentin-1 and insulin were measured by using ELISA.
Introduction
▼
Chronic kidney disease (CKD) is an important health problem which causes high mortality and morbidity [1]. Accelerated atherosclerosis and chronic inflammation are the major underlying pathophysiologic mechanisms of the high mortality in CKD [2]. Many different biomolecules have been shown to predict the atherosclerotic and inflammatory processes in CKD [3–5]. Adipose tissue actively participate neuroendocrine, cardiovascular and immune systems by secreting proteins and other products (called adipokines), as well as responding to neural, hormonal, and nutritional signals [6]. Evaluation of serum levels of adipocytokines in CKD patients is necessary, because of diabetes mellitus (DM) was an increasing cause of CKD and intertwined clinical pathologies impairing the metabolism fundamentally, such as inflammation, malnutrition and accelerated atherogenesis in the disease process.
Results: Serum Omentin-1 levels in CKD patients were significantly lower compared to the healthy controls. Further analyze revealed that decreased omentin in CKD patients was due to the reduced omentin levels in the diabetic subgroup. An increase in inflammation and malnutrition components was correlated with a decrease in the serum level of Omentin. Omentin levels were lower in stage 2 and 3 CKD but not stage 4 CKD patients compared to control. Conclusions: The results of the present study suggest that diabetes mellitus and inflammation should be associated with lower omentin levels in CKD population; however, this reduction resolves due to the failure of degradation and excretion of omentin when creatinine clearance falls below 30 ml/min (stage 4 CKD).
In recent years, one of these useful adipokines called Omentin-1 (also named intelectin-1, endothelial lectin, or galactofuranose-binding lectin) has frequently been studied. Circulating Omentin levels are negatively correlate with body mass index, fat mass, insulin resistance and fasting plasma insulin, and positively correlated with adiponectin, high-density lipoprotein cholesterol (HDL-C), and endothelial functions [7–9]. These findings indicate that Omentin-1 may play a role as a beneficial protective adipokine. Omentin-1 inhibits tumor necrosis factor alphainduced inflammation [10]. Furthermore, recent reports have usually demonstrated an inverse association between Omentin-1 and inflammation [7–9, 11, 12] and atherosclerosis [13–15] in different patient cohorts. However, changes in serum Omentin levels in diabetic and non-diabetic CKD patients have not yet been revealed. In addition, data in the literature about serum Omentin changes according to the stage of renal failure and whether it is affected by conventional
Tekce H et al. Omentin Levels in Chronic Kidney Disease … Exp Clin Endocrinol Diabetes 2014; 122: 451–456
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Authors
risk factors, is quite limited. Therefore, in this study, we aimed to investigate the serum level of Omentin-1 and possibly related parameters in CKD (stage 2–4) patients.
Materials and Methods
▼
The study population consisted of 64 CKD stage 2–4 patients (28 women and 36 men). Age and sex-matched 27 individuals (11 women and 16 men) were selected from apparently healthy subjects who admitted to the Abant Izzet Baysal (AIB) University Hospital for a routine check-up. We did not change the medications (antihypertensive drugs, vitamin D or analogues, and phosphate binders) of the CKD patients. Etiologies of renal failure in the patients were as follows: DM (n = 30), hypertension (n = 18), chronic glomerulonephritis (n = 7), chronic interstitial nephritis (n = 6), and undefined (n = 3). All diabetic patients in study cohort were suffered from type 2 DM. Mean duration of DM was 14.3 ± 6.7 years. 5 of the patients were on metformin and/or other oral anti-diabetic treatment. The remaining 25 patients of 30 diabetic CKD patients were on insulin treatment. The study approved by the local ethics committee of AIB University. It was conducted according to the Declaration of Helsinki. Informed consent obtained from all participants. Patients with conditions that possibly affect serum Omentin levels were excluded. We did not include patients with stage 1 and 5 CKD, malignancy, pregnancy, active infectious disease, polycystic kidney disease, collagen vascular diseases such as; rheumatoid arthritis and systemic lupus erythematosus, conditions required corticosteroid therapy, hepatitis B or C, a history of radio contrast agent or nephrotoxic drug use in last 30 days, a history of ischemic cardiovascular disease (myocardial infarction, stroke, peripheral artery disease, cardiovascular revascularization), heart failure, and chronic obstructive pulmonary disease. 43 of 107 CKD patients who assigned for the study were not included to study (33 patients excluded according to exclusion criteria, 6 patients were not given informed consent and 4 patients could not obey the study protocol). Study was performed with remained 64 CKD patients and 27 healthy controls. Anthropometric measurements (height, weight, body-mass index (BMI), and waist circumference (WC) obtained and recorded. BMI was calculated as body weight divided by the square of the height (kg/m2). We measured abdominal circumference at the umbilical level and expressed in cm. Blood pressure (BP) was measured with a sphygmomanometer in the sitting position bilaterally and higher measurement was recorded if they are different. Blood and urine samples were analyzed at the Biochemistry Laboratory of AIB University Hospital. Venous blood samples were collected in the morning after an overnight fast and obtained for laboratory analysis [blood urea nitrogen (BUN), creatinine (SCr), glucose, insulin, hemoglobin A1c (HbA1c), total cholesterol (Total-C), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDLC), sodium (Na), potassium (K), calcium (Ca), phosphate (P), albumin, uric acid, hemoglobin (Hgb), platelet, C-reactive protein (CRP) and intact parathyroid hormone (iPTH)] with standard methods. Homeostasis model assessment of insulin resistance index (HOMA-IR) calculated by using following formula = [fasting plasma glucose (mg/dL) x fasting plasma insulin (μU/mL)/405] [16]. Diabetes mellitus was defined according to the criteria of
American Diabetes Association – 2012 [17]. Glomerular filtration rate (GFR) was calculated according to the abbreviated Modification of Diet in Renal Disease (MDRD) formula [18]. Serum levels of albumin and CRP were used to determine malnutrition, and inflammation, respectively, just as in studies evaluating high cardiovascular mortality and morbidity in CKD patients [19]. Malnutrition defined as serum albumin < 3.5 g/dL and inflammation was defined as serum CRP level of > 10 mg/L (normal range, 0–5 mg/L). The patients were classified as MI-0 (no component), MI-1 (one component) and MI-2 (2 components). 5 mL of venous blood samples were collected from the peripheral blood vessels of CKD patients and control groups into dry tubes. The samples were centrifuged at 1 000 g for 10 min and stored at − 80 °C until laboratory assays performed. All samples were analyzed simultaneously. Sandwich ELISA kits of Biovendor (Brno, Czech Republic) were used for serum Omentin-1 measurement according to manufacturer’s instructions. The linear range of the assay was 0.50–64.0 ng/mL. The inter- and intraassay coefficients of variation were 4.4 and 3.2 %, respectively.
Statistical analysis SPSS software version 15.0 (SPSS; Chicago, IL, USA) used for statistical analysis. Continuous variables were presented as mean ± standard deviation while categorical variables were presented as percentage. The normal distribution of all variables was tested using the Shapiro-Wilk test. Pearson’s and Spearman correlation tests used to determine the correlation between variables. The Mann-Whitney U test was used to determine differences between nonparametric data. Student’s two-tailed t test was applied to compare continuous variables, and the χ2 test was used for categorical data. Statistical differences among parametric data of 3 groups were analyzed using one-way ANOVA test, and the difference between subgroups was assessed with the post hoc Tukey test. A value of p < 0.05 was considered statistically significant.
Results
▼
Patient characteristics The baseline clinical and demographic data of the CKD patients ▶ Table 1. There were no difand control subjects are shown in ● ferences between groups in terms of age, gender, BMI, WC, platelet and calcium levels. CKD patients had significantly higher levels of systolic and diastolic blood pressures, fasting glucose, HOMA-IR, Total-C, LDL-C, TG, BUN, SCr, P, iPTH, and CRP, and lower levels of eGFR, Hgb, HDL-C and albumin compared to control subjects. Plasma levels of Omentin-1 were found to be markedly lower in CKD (stage 2–4) patients (251.4 ± 102.2 ng/mL) than controls (342.6 ± 125.1 ng/mL). The difference was statistically significant (p < 0.01).
CKD stages and Serum Omentin-1 levels Omentin-1 measurements of the patients according to CKD ▶ Table 2. Serum omentin levels of patients stages are shown in ● with stage 4 CKD were significantly increased compared to the patients with stage 2 (p = 0.014) and stage 3 (p = 0.008) CKD. There was no significant difference in omentin levels of patients with stage 2 and stage 3 CKD (p = 0.138). Similarly, no statistically significant difference in omentin levels revealed between stage 4 CKD and healthy controls (p = 0.224).
Tekce H et al. Omentin Levels in Chronic Kidney Disease … Exp Clin Endocrinol Diabetes 2014; 122: 451–456
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
452 Article
Article 453
CKD group (n = 64)
Control group (n = 27)
55.2 ± 8.9 28 (44 %) 26.1 ± 4.8 97.1 ± 11.0 134.1 ± 17.2 82.1 ± 12.7 57.2 ± 14.8 3.1 ± 1.6 33.7 ± 16.1 8.8 ± 0.7 3.9 ± 0.8 189.9 ± 156.2 10.9 ± 1.5 198.3 ± 41.8 117.8 ± 21.4 4.1 ± 3.2 191.4 ± 30.9 117.8 ± 27.7 35.8 ± 8.2 194.3 ± 36.1 3.4 ± 0.7 11.9 ± 3.3 251.4 ± 102.2
52.8 ± 9.2 11 (41 %) 25.2 ± 4.1 93.8 ± 10.3 116.7 ± 13.3 74.2 ± 9.2 19.1 ± 4.9 0.7 ± 0.2 96.8 ± 9.3 9.1 ± 0.3 3.2 ± 0.5 64.6 ± 15.1 13.6 ± 1.1 206.7 ± 52.8 88.2 ± 7.9 2.7 ± 1.8 178.1 ± 26.3 94.6 ± 19.4 43.1 ± 9.4 167.6 ± 30.8 4.2 ± 0.3 3.1 ± 1.8 342.6 ± 125.1
P 0.431 0.612 0.382 0.102 0.027 0.046 < 0.01 < 0.01 < 0.01 0.203 0.047 < 0.01 < 0.01 > 0.05 0.018 0.033 0.021 0.016 0.042 0.031 0.014 < 0.01 < 0.01
Table 1 Baseline characteristics of CKD patients and control subjects.
Data are mean ± standard deviation. BMI: Body mass index; eGFR, estimated glomerular filtration rate; HOMA-IR: Homeostatic model assessment of insulin resistance; LDL: Low-density lipoprotein; HDL: High-density lipoprotein
Table 2 CKD stages and Serum Omentin-1 levels. Stage of CKD stage 2 stage 3 stage 4
Number of CKD
Omentin-1 levels
patients (n = 64)
(ng/mL)
20 (31 %) 23 (36 %) 21 (33 %)
236.3 ± 82.1 219.2 ± 99.2a 321.9 ± 111.8b
One-way ANOVA test results was demonstrated in table. The ANOVA test p-value was 0.027. CKD: Chronic kidney disease a
Omentin-1 difference between CKD (stage 3) vs. CKD (stage 2), P = 0.138
b
Omentin-1 difference between CKD (stage 4) vs. CKD (stage 2), P = 0.014; Omentin-1 difference between CKD (stage 4) vs. CKD (stage 3), P = 0.008; Omentin-1 difference between CKD (stage 4) vs. healthy controls, P = 0.224
Clinical characteristics and Omentin-1 levels in the diabetic and non-diabetic CKD subgroups Serum Omentin-1 levels and CKD parameters are summarized ▶ Table 3. There was a significant difference in serum Omenin ● tin-1 levels between non-diabetic (324.2 ± 47.7 ng/mL) and diabetic (189.4 ± 31.2 ng/mL) CKD subgroups (p < 0.01). The diabetic CKD subgroup had higher BMI (p = 0.036), WC (p = 0.021), systolic (p = 0.038) and diastolic (p = 0.043) blood pressures, serum glucose (p < 0.01), HOMA-IR (p < 0.01), HbA1c (p < 0.01), total-C (p = 0.037), LDL-C (p = 0.028), TG (p = 0.021), CRP (p < 0.01) and lower HDL-C (p = 0.044), and albumin (p = 0.017) levels compared to non-diabetic CKD subgroup.
Omentin-1 levels in malnutrition-inflammation (MI) subgroups Omentin-1 measurements of the patients according to MI com▶ Table 4. CKD patients were classified ponents were shown in ● according to MI components. 29 patients had none; 24 had one, and 11 had all 2 MI components. Serum Omentin-1 levels were significantly decreased according to the presence of MI components.
Relationship between Omentin-1 and clinical parameters in healthy subjects and CKD (diabetic and nondiabetic) groups a. Healthy subjects: There was a negative correlation between the level of omentin and total-C, and LDL-C (r = –0.402, p = 0.043; r = –0.654, p = 0.024; respectively). b. All CKD (diabetic and nondiabetic) patients: Omentin-1 level was negatively correlated with serum LDL-C, and eGFR (r = –0.447, p = 0.039; r = –0.561, p = 0.021, respectively), and positively correlated with serum fasting glucose, and creatinine (r = –0.669, p = 0.017; r = –0.392, p = 0.04; respectively). There was no correlation between serum Omentin-1 and other clinical parameters in control and CKD (diabetic and nondiabetic) groups.
Discussion
▼
Present study has 4 main findings: (1) Serum Omentin-1 levels in CKD patients were significantly lower compared to the healthy controls (2) Omentin-1 level was significantly lower in the diabetic CKD subgroup compared to the healthy control group and non-diabetic CKD subgroup. However, no significant differences were found between non-diabetic CKD and control groups. (3) An increase in inflammation and malnutrition components was correlated with a decrease in the serum level of Omentin. (4) For stage 2 and 3 CKD, Omentin levels were lower than the control group. However, no significant difference revealed between patients with stage 4 CKD and controls. There are 2 types of obesity, including visceral and peripheral. In terms of obesity related complications, such as insulin resistance and DM, visceral type obesity is at higher risk than peripheral [20]. Omentin-1, mainly secreted by stromal vascular cells in visceral adipose tissue, is a protein of 313 amino acids and
Tekce H et al. Omentin Levels in Chronic Kidney Disease … Exp Clin Endocrinol Diabetes 2014; 122: 451–456
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Parameters age (years) gender (female, %) BMI (kg/m2) waist circumference (cm) systolic blood pressure (mm Hg) diastolic blood pressure (mm Hg) blood urea nitrogen (mg/dL) creatinine (mg/dL) eGFR (ml/min/1.73 m2) calcium (mg/dL) phosphate (mg/dL) parathyroid hormone (pg/mL) haemoglobin (g/dL) platelets (103/μL) fasting glucose (mg/dL) HOMA-IR total-cholesterol (mg/dL) LDL-cholesterol (mg/dL) HDL-cholesterol (mg/dL) triglyceride (mg/dL) albumin (g/dL) C-reactive protein (mg/L) serum omentin-1 (ng/mL)
454 Article
Diabetic CKD subgroup (n = 30)
age (years) gender (female, %) BMI (kg/m2) waist circumference (cm) systolic blood pressure (mm Hg) diastolic blood pressure (mm Hg) blood urea nitrogen (mg/dL) creatinine (mg/dL) eGFR (ml/min/1.73 m2) calcium (mg/dL) phosphate (mg/dL) parathyroid hormone (pg/mL) haemoglobin (g/dL) uric acid (mg/dL) fasting glucose (mg/dL) HOMA-IR hemoglobin A1c ( %) total cholesterol (mg/dL) LDL-cholesterol (mg/dL) HDL-cholesterol (mg/dL) triglyceride (mg/dL) albumin (g/dL) C-reactive protein (mg/L) serum omentin-1 (ng/mL)
Nondiabetic CKD subgroup (n = 34)
56.1 ± 11.2 13 (43 %) 27.1 ± 3.9 103.4 ± 8.3 141.6 ± 18.9 88.3 ± 14.2 55.1 ± 13.2 3.2 ± 1.6 34.8 ± 14.1 8.6 ± 0.7 3.7 ± 0.9 180.2 ± 141.4 10.7 ± 1.2 6.8 ± 0.9 171.9 ± 35.1 5.5 ± 3.5 8.2 ± 2.1 198.4 ± 31.2 131.2 ± 20.7 29.7 ± 8.8 206.2 ± 47.6 3.0 ± 0.9 14.2 ± 4.1 189.4 ± 31.2
53.7 ± 10.4 15 (44 %) 24.3 ± 3.2 92.4 ± 7.1 132.3 ± 14.8 77.9 ± 10.2 58.7 ± 10.7 3.1 ± 1.4 32.0 ± 13.1 9.0 ± 0.7 3.9 ± 0.8 193.7 ± 135.1 11.0 ± 1.4 6.3 ± 0.7 101.4 ± 11.7 3.9 ± 2.0 5.0 ± 0.9 181.2 ± 27.7 112.3 ± 17.2 40.3 ± 9.7 156.3 ± 30.4 3.8 ± 0.7 8.7 ± 3.9 324.2 ± 47.7
P 0.256 0.315 0.036 0.021 0.038 0.043 0.519 0.832 0.471 0.705 0.638 0.561 0.284 0.754 < 0.01 < 0.01 < 0.01 0.037 0.028 0.044 0.021 0.017 < 0.01 < 0.01
Table 3 Characteristics of CKD subgroups.
Data are mean ± standard deviation. BMI: Body mass index; eGFR, estimated glomerular filtration rate; HOMA-IR: Homeostatic model assessment of insulin resistance; LDL: Low-density lipoprotein; HDL: High-density lipoprotein
Table 4 Omentin-1 levels in malnutrition-inflammation (MI) subgroups. Number of MI
Number of CKD
Omentin-1 levels
components
patients (n = 64)
(ng/mL)
none 1 component 2 components
29 (45 %) 24 (38 %) 11 (17 %)
307.4 ± 172.2 191.3 ± 84.7a 145.8 ± 67.3b
One-way ANOVA test results was demonstrated in table. The ANOVA test p-value was 0.019. CKD: Chronic kidney disease; MI: malnutrition, inflammation a
Omentin-1 difference between one MI component vs. no MI components, P = 0.022
b
Omentin-1 difference between 2 MI components vs. no MI components, P = 0.013; Omentin difference between 2 MI components vs. one MI component, P = 0.042
34 kDa [21, 22]. Omentin-1 has 3 main functions that have been identified to date; first, increases the insulin sensitivity in human adipocytes [7, 21], second, reduces inflammation [10] and third, stimulates vasodilatation [23]. There are numerous studies demonstrating reduction in Omentin-1 levels in a variety of clinical conditions. The 2 major factors affecting the level of circulating Omentin-1 are insulin and glucose. Tan et al. reported a significant decrease in the level of Omentin-1 caused by prolonged insulin and glucose infusions [9]. Similarly, fasting plasma glucose was negatively correlated with serum omentin levels in CKD patients reflecting the effects of diabetes mellitus in the present study. These results suggest the previous studies which pointed negative effects of hyperglycemia on omentin levels. Recent studies have reported decreased levels of Omentin-1 in obesity and obesity-related co-morbid clinical conditions [insulin resistance, metabolic syndrome, DM, polycystic over syndrome (PCOS), etc.] [7, 12–14, 24, 25]. Serum omentin levels were lower in Type-1 Diabetes as well as patients with type–2 DM and impaired glucose regulation [8, 26, 27]. The results of
our study revealed Omentin-1 levels were lower in diabetic CKD subgroup compared to both non-diabetic subgroup and controls. There was no significant difference between controls and non-diabetic subgroup, and this suggests that DM might be a significant cause for omentin reduction in CKD population. In another study, serum Omentin-1 levels were negatively correlated with WC, BMI, leptin, fasting insulin, HOMA and positively with adiponectin and HDL-C [7]. However, we could not figure out similar correlation between omentin and other metabolic parameters except total- and LDL-C. An explanation should be that our healthy control group was relatively small which prevent the difference to reach statistically significance level. Still, endothelial dysfunction, atherosclerosis related cardiovascular (CV) diseases were significantly associated with lower levels of omentin [13–15, 28]. Weight loss in obese patients, also the use of metformin in patients with PCOS brings about an increase in the level of omentin [29, 30]. All clinical evidence which has been shown suggests that Omentin, just as adiponectin, is a beneficial adipocytokine. In a study by Alcelik et al. Omentin-1 levels were evaluated in patients with CKD stage 5 [31]. As a result of this study, Omentin levels were found to be significantly higher in hemodialysis patients than the healthy controls. Significant and unexpected increase of Omentin levels in end-stage renal disease patients were linked to the lack of degradation and excretion secondary to renal dysfunction. In our study, absence of significant difference in omentin levels between stage 4 CKD patients and control group can be explained by similar mechanisms. Therefore, decrease in degradation and excretion of omentin, as creatinine, seems to be mainly due to the inability of renal clearance from plasma. This type of defect on excretion and degradation of omentin levels was likely to become more obvious when creatinine clearance falls below 30 ml/min (stage 4 CKD). Other than this special exception, omentin levels were still negatively correlated with eGFR for all CKD patients, in bivariate correlation
Tekce H et al. Omentin Levels in Chronic Kidney Disease … Exp Clin Endocrinol Diabetes 2014; 122: 451–456
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Parameters
analysis in the present study. Accelerated atherosclerosis and insulin resistance are quite common clinical pathologies in the course of CKD [32–35]. Therefore, significant lower levels of Omentin in patients with CKD stage 2 and 3 may be a consequence of arising inflammation in CKD process, malnutrition, insulin resistance as well as reflecting the inhibitory effects of diabetes. Another important factor affect the serum level of Omentin is inflammation. IL-6, which is an important mediator of inflammation in type 2 diabetic patients, has a negative correlation with Omentin-1 [36]. A study conducted by Tan et al. after metformin treatment in women with PCOS, high-sensitivity CRP level, was found to be the only negative variable correlated with Omentin-1 [37]. In a recent study, authors showed that Omentin can inhibit TNF-α induced adhesion molecules expression by blocking the nuclear factor-kappa beta pathway [38]. Likewise, another report concluded that the omentin inhibit TNF-α induced inflammation by stimulating superoxide production in vascular smooth muscle cells [10]. Increased systemic inflammation alone or together with malnutrition-inflammation-atherosclerosis syndrome in CKD patients, is a well-known clinical entity increasing morbidity and mortality [33–35]. Some studies reported that Omentin could be considered as a pro-inflammatory adipokine pointing various chronic inflammatory diseases [39, 40]. Increase in MI components, in our study, was found to be associated with a reduction in the levels of Omentin, and this finding lends support the reduction in omentin in inflammatory conditions. This is especially important in terms of revealing the negative relation between increased inflammation-nutritional disorders and Omentin levels. There are some limitations in our study. First, our study has a cross-sectional design; second, it was a single-center study and third is that, it has a relatively small study cohort, which all prevents our results to be universal. In conclusion, the results of the present study suggest that diabetes mellitus and inflammation should be associated with lower omentin levels in CKD population; however, this reduction resolves due to the failure of degradation and excretion of omentin when creatinine clearance falls below 30 ml/min (stage 4 CKD). However, prospective studies with a larger cohort are needed to confirm our results.
Conflict of interest: My co-authors and I declare no conflicts of interest. References 1 Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. American journal of kidney diseases: the official journal of the National Kidney Foundation 1998; 32: S112–S119 2 Vanholder R, Massy Z, Argiles A et al. Chronic kidney disease as cause of cardiovascular morbidity and mortality. Nephrol Dial Transpl 2005; 20: 1048–1056 3 Akdag I, Yilmaz Y, Kahvecioglu S et al. Clinical value of the malnutrition-inflammation-atherosclerosis syndrome for long-term prediction of cardiovascular mortality in patients with end-stage renal disease: a 5-year prospective study. Nephron Clinical practice 2008; 108: c99–c105 4 Tripepi G, Mattace Raso F, Sijbrands E et al. Inflammation and asymmetric dimethylarginine for predicting death and cardiovascular events in ESRD patients. Clinical journal of the American Society of Nephrology: CJASN 2011; 6: 1714–1721
5 Shoji T, Masakane I, Watanabe Y et al. Committee of Renal Data Registry JSfDT. Elevated non-high-density lipoprotein cholesterol (nonHDL-C) predicts atherosclerotic cardiovascular events in hemodialysis patients. Clinical journal of the American Society of Nephrology: CJASN 2011; 6: 1112–1120 6 Flier JS. Obesity wars: molecular progress confronts an expanding epidemic. Cell 2004; 116: 337–350 7 de Souza Batista CM, Yang RZ, Lee MJ et al. Omentin plasma levels and gene expression are decreased in obesity. Diabetes 2007; 56: 1655–1661 8 Pan HY, Guo L, Li Q. Changes of serum omentin-1 levels in normal subjects and in patients with impaired glucose regulation and with newly diagnosed and untreated type 2 diabetes. Diabetes research and clinical practice 2010; 88: 29–33 9 Tan BK, Adya R, Farhatullah S et al. Omentin-1, a novel adipokine, is decreased in overweight insulin-resistant women with polycystic ovary syndrome – Ex vivo and in vivo regulation of omentin-1 by insulin and glucose. Diabetes 2008; 57: 801–808 10 Kazama K, Usui T, Okada M et al. Omentin plays an anti-inflammatory role through inhibition of TNF-alpha-induced superoxide production in vascular smooth muscle cells. European Journal of Pharmacology 2012; 686: 116–123 11 Shibata R, Ouchi N, Takahashi R et al. Omentin as a novel biomarker of metabolic risk factors. Diabetol Metab Syndr 2012; 4 12 Auguet T, Quintero Y, Riesco D et al. New adipokines vaspin and omentin. Circulating levels and gene expression in adipose tissue from morbidly obese women. BMC medical genetics 2011; 12: 60 13 Zhong X, Zhang HY, Tan H et al. Association of serum omentin-1 levels with coronary artery disease. Acta pharmacologica Sinica 2011; 32: 873–878 14 Liu R, Wang XL, Bu PL. Omentin-1 is associated with carotid atherosclerosis in patients with metabolic syndrome. Diabetes research and clinical practice 2011; 93: 21–25 15 Shibata R, Takahashi R, Kataoka Y et al. Association of a fat-derived plasma protein omentin with carotid artery intima-media thickness in apparently healthy men. Hypertension research: official journal of the Japanese Society of Hypertension 2011; 34: 1309–1312 16 Matthews DR, Hosker JP, Rudenski AS et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412–419 17 Assoc AD. Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2012; 35: S64–S71 18 Levey AS, Bosch JP, Lewis JB et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Annals of internal medicine 1999; 130: 461–470 19 Pecoits-Filho R, Lindholm B, Stenvinkel P. The malnutrition, inflammation, and atherosclerosis (MIA) syndrome – the heart of the matter. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association – European Renal Association 2002; 17 (Suppl 11): 28–31 20 Brunzell JD, Hokanson JE. Dyslipidemia of central obesity and insulin resistance. Diabetes Care 1999; 22: C10–C13 21 Yang RZ, Lee MJ, Hu H et al. Identification of omentin as a novel depotspecific adipokine in human adipose tissue: possible role in modulating insulin action. Am J Physiol-Endoc M 2006; 290: E1253–E1261 22 Schaffler A, Neumeier M, Herfarth H et al. Genomic structure of human omentin, a new adipocytokine expressed in omental adipose tissue. Biochimica et biophysica acta 2005; 1732: 96–102 23 Yamawaki H, Tsubaki N, Mukohda M et al. Omentin, a novel adipokine, induces vasodilation in rat isolated blood vessels. Biochemical and biophysical research communications 2010; 393: 668–672 24 Yoo HJ, Hwang SY, Hong HC et al. Association of circulating omentin-1 level with arterial stiffness and carotid plaque in type 2 diabetes. Cardiovascular diabetology 2011; 10: 103 25 Choi JH, Rhee EJ, Kim KH et al. Plasma omentin-1 levels are reduced in non-obese women with normal glucose tolerance and polycystic ovary syndrome. European journal of endocrinology/European Federation of Endocrine Societies 2011; 165: 789–796 26 Tan BK, Pua S, Syed F et al. Decreased plasma omentin-1 levels in Type 1 diabetes mellitus. Diabetic medicine: a journal of the British Diabetic Association 2008; 25: 1254–1255 27 Tan BK, Adya R, Randeva HS. Omentin: A Novel Link Between Inflammation, Diabesity, and Cardiovascular Disease. Trends Cardiovas Med 2010; 20: 143–148
Tekce H et al. Omentin Levels in Chronic Kidney Disease … Exp Clin Endocrinol Diabetes 2014; 122: 451–456
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Article 455
28 Moreno-Navarrete JM, Ortega F, Castro A et al. Circulating Omentin as a Novel Biomarker of Endothelial Dysfunction. Obesity 2011; 19: 1552–1559 29 Moreno-Navarrete JM, Catalan V, Ortega F et al. Circulating omentin concentration increases after weight loss. Nutrition & metabolism 2010; 7: 27 30 Shaker M, Mashhadani ZI, Mehdi AA. Effect of Treatment with Metformin on Omentin-1, Ghrelin and other Biochemical, Clinical Features in PCOS Patients. Oman medical journal 2010; 25: 289–293 31 Alcelik A, Tosun M, Ozlu MF et al. Serum levels of omentin in end-stage renal disease patients. Kidney Blood Press Res 2012; 35: 511–516 32 Shinohara K, Shoji T, Emoto M et al. Insulin resistance as an independent predictor of cardiovascular mortality in patients with end-stage renal disease. J Am Soc Nephrol 2002; 13: 1894–1900 33 Zanetti M, Barazzoni R, Guarnieri G. Inflammation and insulin resistance in uremia. Journal of renal nutrition: the official journal of the Council on Renal Nutrition of the National Kidney Foundation 2008; 18: 70–75 34 Oberg BP, McMenamin E, Lucas FL et al. Increased prevalence of oxidant stress and inflammation in patients with moderate to severe chronic kidney disease. Kidney international 2004; 65: 1009–1016
35 Mathur S, Devaraj S, Jialal I. Accelerated atherosclerosis, dyslipidemia, and oxidative stress in end-stage renal disease. Current opinion in nephrology and hypertension 2002; 11: 141–147 36 El-Mesallamy H, El-Derany M, Hamdy N. Serum omentin-1 and chemerin levels are interrelated in patients with Type 2 diabetes mellitus with or without ischaemic heart disease. Diabetic Medicine 2011; 28: 1194–1200 37 Tan BK, Adya R, Farhatullah S et al. Metformin Treatment May Increase Omentin-1 Levels in Women With Polycystic Ovary Syndrome. Diabetes 2010; 59: 3023–3031 38 Zhong X, Li X, Liu F et al. Omentin inhibits TNF-alpha-induced expression of adhesion molecules in endothelial cells via ERK/NF-kappaB pathway. Biochemical and biophysical research communications 2012; 425: 401–406 39 Schaffler A, Zeitoun M, Wobser H et al. Frequency and significance of the novel single nucleotide missense polymorphism Val109Asp in the human gene encoding omentin in Caucasian patients with type 2 diabetes mellitus or chronic inflammatory bowel diseases. Cardiovascular diabetology 2007; 6: 3 40 Senolt L, Polanska M, Filkova M et al. Vaspin and omentin: new adipokines differentially regulated at the site of inflammation in rheumatoid arthritis. Ann Rheum Dis 2010; 69: 1410–1411
Tekce H et al. Omentin Levels in Chronic Kidney Disease … Exp Clin Endocrinol Diabetes 2014; 122: 451–456
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
456 Article
Copyright of Experimental & Clinical Endocrinology & Diabetes is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
Serum Omentin-1 Levels in Diabetic and Nondiabetic Patients with Chronic Kidney Disease
Affiliations
Key words ▶ omentin ● ▶ chronic kidney disease ● ▶ diabetes mellitus ● ▶ inflammation ●
received 14.02.2014 first decision 24.03.2014 accepted 29.04.2014 Bibliography DOI http://dx.doi.org/ 10.1055/s-0034-1375674 Published online: June 11, 2014 Exp Clin Endocrinol Diabetes 2014; 122: 451–456 © J. A. Barth Verlag in Georg Thieme Verlag KG Stuttgart · New York ISSN 0947-7349 Correspondence H. Tekce, MD Department of Internal Medicine Faculty of Medicine Abant Izzet Baysal University 14280, Bolu Turkey Tel.: + 90/374/253 46 18-3522 Fax: + 90/374/253 46 15 [email protected]
H. Tekce1, B. K. Tekce2, G. Aktas1, A. Alcelik1, E. Sengul3 1
Faculty of Medicine, Department of Internal Medicine, Abant Izzet Baysal University, Bolu, Turkey Faculty of Medicine, Department of Medical Biochemistry, Abant Izzet Baysal University, Bolu, Turkey 3 Department of Nephrology, Derince Education and Research Hospital, Kocaeli, Turkey 2
Abstract
▼
Background: Omentin-1, a novel adipokine identified in visceral adipose tissue, is negatively correlated with different conditions such as diabetes, obesity and inflammation. However, changes in serum Omentin levels associated with the degree of the renal dysfunction and metabolic risk factors in CKD patients has not yet been revealed. In the present study, we aimed to investigate the level of Omentin-1 and related parameters in diabetic and non-diabetic CKD patients. Methods: 64 (30 diabetic, 34 non-diabetic) CKD patients and 27 healthy control subjects enrolled in this cross-sectional study. Anthropometric and laboratory assessment performed and malnutrition and inflammation components evaluated. Serum concentrations of Omentin-1 and insulin were measured by using ELISA.
Introduction
▼
Chronic kidney disease (CKD) is an important health problem which causes high mortality and morbidity [1]. Accelerated atherosclerosis and chronic inflammation are the major underlying pathophysiologic mechanisms of the high mortality in CKD [2]. Many different biomolecules have been shown to predict the atherosclerotic and inflammatory processes in CKD [3–5]. Adipose tissue actively participate neuroendocrine, cardiovascular and immune systems by secreting proteins and other products (called adipokines), as well as responding to neural, hormonal, and nutritional signals [6]. Evaluation of serum levels of adipocytokines in CKD patients is necessary, because of diabetes mellitus (DM) was an increasing cause of CKD and intertwined clinical pathologies impairing the metabolism fundamentally, such as inflammation, malnutrition and accelerated atherogenesis in the disease process.
Results: Serum Omentin-1 levels in CKD patients were significantly lower compared to the healthy controls. Further analyze revealed that decreased omentin in CKD patients was due to the reduced omentin levels in the diabetic subgroup. An increase in inflammation and malnutrition components was correlated with a decrease in the serum level of Omentin. Omentin levels were lower in stage 2 and 3 CKD but not stage 4 CKD patients compared to control. Conclusions: The results of the present study suggest that diabetes mellitus and inflammation should be associated with lower omentin levels in CKD population; however, this reduction resolves due to the failure of degradation and excretion of omentin when creatinine clearance falls below 30 ml/min (stage 4 CKD).
In recent years, one of these useful adipokines called Omentin-1 (also named intelectin-1, endothelial lectin, or galactofuranose-binding lectin) has frequently been studied. Circulating Omentin levels are negatively correlate with body mass index, fat mass, insulin resistance and fasting plasma insulin, and positively correlated with adiponectin, high-density lipoprotein cholesterol (HDL-C), and endothelial functions [7–9]. These findings indicate that Omentin-1 may play a role as a beneficial protective adipokine. Omentin-1 inhibits tumor necrosis factor alphainduced inflammation [10]. Furthermore, recent reports have usually demonstrated an inverse association between Omentin-1 and inflammation [7–9, 11, 12] and atherosclerosis [13–15] in different patient cohorts. However, changes in serum Omentin levels in diabetic and non-diabetic CKD patients have not yet been revealed. In addition, data in the literature about serum Omentin changes according to the stage of renal failure and whether it is affected by conventional
Tekce H et al. Omentin Levels in Chronic Kidney Disease … Exp Clin Endocrinol Diabetes 2014; 122: 451–456
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Authors
risk factors, is quite limited. Therefore, in this study, we aimed to investigate the serum level of Omentin-1 and possibly related parameters in CKD (stage 2–4) patients.
Materials and Methods
▼
The study population consisted of 64 CKD stage 2–4 patients (28 women and 36 men). Age and sex-matched 27 individuals (11 women and 16 men) were selected from apparently healthy subjects who admitted to the Abant Izzet Baysal (AIB) University Hospital for a routine check-up. We did not change the medications (antihypertensive drugs, vitamin D or analogues, and phosphate binders) of the CKD patients. Etiologies of renal failure in the patients were as follows: DM (n = 30), hypertension (n = 18), chronic glomerulonephritis (n = 7), chronic interstitial nephritis (n = 6), and undefined (n = 3). All diabetic patients in study cohort were suffered from type 2 DM. Mean duration of DM was 14.3 ± 6.7 years. 5 of the patients were on metformin and/or other oral anti-diabetic treatment. The remaining 25 patients of 30 diabetic CKD patients were on insulin treatment. The study approved by the local ethics committee of AIB University. It was conducted according to the Declaration of Helsinki. Informed consent obtained from all participants. Patients with conditions that possibly affect serum Omentin levels were excluded. We did not include patients with stage 1 and 5 CKD, malignancy, pregnancy, active infectious disease, polycystic kidney disease, collagen vascular diseases such as; rheumatoid arthritis and systemic lupus erythematosus, conditions required corticosteroid therapy, hepatitis B or C, a history of radio contrast agent or nephrotoxic drug use in last 30 days, a history of ischemic cardiovascular disease (myocardial infarction, stroke, peripheral artery disease, cardiovascular revascularization), heart failure, and chronic obstructive pulmonary disease. 43 of 107 CKD patients who assigned for the study were not included to study (33 patients excluded according to exclusion criteria, 6 patients were not given informed consent and 4 patients could not obey the study protocol). Study was performed with remained 64 CKD patients and 27 healthy controls. Anthropometric measurements (height, weight, body-mass index (BMI), and waist circumference (WC) obtained and recorded. BMI was calculated as body weight divided by the square of the height (kg/m2). We measured abdominal circumference at the umbilical level and expressed in cm. Blood pressure (BP) was measured with a sphygmomanometer in the sitting position bilaterally and higher measurement was recorded if they are different. Blood and urine samples were analyzed at the Biochemistry Laboratory of AIB University Hospital. Venous blood samples were collected in the morning after an overnight fast and obtained for laboratory analysis [blood urea nitrogen (BUN), creatinine (SCr), glucose, insulin, hemoglobin A1c (HbA1c), total cholesterol (Total-C), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDLC), sodium (Na), potassium (K), calcium (Ca), phosphate (P), albumin, uric acid, hemoglobin (Hgb), platelet, C-reactive protein (CRP) and intact parathyroid hormone (iPTH)] with standard methods. Homeostasis model assessment of insulin resistance index (HOMA-IR) calculated by using following formula = [fasting plasma glucose (mg/dL) x fasting plasma insulin (μU/mL)/405] [16]. Diabetes mellitus was defined according to the criteria of
American Diabetes Association – 2012 [17]. Glomerular filtration rate (GFR) was calculated according to the abbreviated Modification of Diet in Renal Disease (MDRD) formula [18]. Serum levels of albumin and CRP were used to determine malnutrition, and inflammation, respectively, just as in studies evaluating high cardiovascular mortality and morbidity in CKD patients [19]. Malnutrition defined as serum albumin < 3.5 g/dL and inflammation was defined as serum CRP level of > 10 mg/L (normal range, 0–5 mg/L). The patients were classified as MI-0 (no component), MI-1 (one component) and MI-2 (2 components). 5 mL of venous blood samples were collected from the peripheral blood vessels of CKD patients and control groups into dry tubes. The samples were centrifuged at 1 000 g for 10 min and stored at − 80 °C until laboratory assays performed. All samples were analyzed simultaneously. Sandwich ELISA kits of Biovendor (Brno, Czech Republic) were used for serum Omentin-1 measurement according to manufacturer’s instructions. The linear range of the assay was 0.50–64.0 ng/mL. The inter- and intraassay coefficients of variation were 4.4 and 3.2 %, respectively.
Statistical analysis SPSS software version 15.0 (SPSS; Chicago, IL, USA) used for statistical analysis. Continuous variables were presented as mean ± standard deviation while categorical variables were presented as percentage. The normal distribution of all variables was tested using the Shapiro-Wilk test. Pearson’s and Spearman correlation tests used to determine the correlation between variables. The Mann-Whitney U test was used to determine differences between nonparametric data. Student’s two-tailed t test was applied to compare continuous variables, and the χ2 test was used for categorical data. Statistical differences among parametric data of 3 groups were analyzed using one-way ANOVA test, and the difference between subgroups was assessed with the post hoc Tukey test. A value of p < 0.05 was considered statistically significant.
Results
▼
Patient characteristics The baseline clinical and demographic data of the CKD patients ▶ Table 1. There were no difand control subjects are shown in ● ferences between groups in terms of age, gender, BMI, WC, platelet and calcium levels. CKD patients had significantly higher levels of systolic and diastolic blood pressures, fasting glucose, HOMA-IR, Total-C, LDL-C, TG, BUN, SCr, P, iPTH, and CRP, and lower levels of eGFR, Hgb, HDL-C and albumin compared to control subjects. Plasma levels of Omentin-1 were found to be markedly lower in CKD (stage 2–4) patients (251.4 ± 102.2 ng/mL) than controls (342.6 ± 125.1 ng/mL). The difference was statistically significant (p < 0.01).
CKD stages and Serum Omentin-1 levels Omentin-1 measurements of the patients according to CKD ▶ Table 2. Serum omentin levels of patients stages are shown in ● with stage 4 CKD were significantly increased compared to the patients with stage 2 (p = 0.014) and stage 3 (p = 0.008) CKD. There was no significant difference in omentin levels of patients with stage 2 and stage 3 CKD (p = 0.138). Similarly, no statistically significant difference in omentin levels revealed between stage 4 CKD and healthy controls (p = 0.224).
Tekce H et al. Omentin Levels in Chronic Kidney Disease … Exp Clin Endocrinol Diabetes 2014; 122: 451–456
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
452 Article
Article 453
CKD group (n = 64)
Control group (n = 27)
55.2 ± 8.9 28 (44 %) 26.1 ± 4.8 97.1 ± 11.0 134.1 ± 17.2 82.1 ± 12.7 57.2 ± 14.8 3.1 ± 1.6 33.7 ± 16.1 8.8 ± 0.7 3.9 ± 0.8 189.9 ± 156.2 10.9 ± 1.5 198.3 ± 41.8 117.8 ± 21.4 4.1 ± 3.2 191.4 ± 30.9 117.8 ± 27.7 35.8 ± 8.2 194.3 ± 36.1 3.4 ± 0.7 11.9 ± 3.3 251.4 ± 102.2
52.8 ± 9.2 11 (41 %) 25.2 ± 4.1 93.8 ± 10.3 116.7 ± 13.3 74.2 ± 9.2 19.1 ± 4.9 0.7 ± 0.2 96.8 ± 9.3 9.1 ± 0.3 3.2 ± 0.5 64.6 ± 15.1 13.6 ± 1.1 206.7 ± 52.8 88.2 ± 7.9 2.7 ± 1.8 178.1 ± 26.3 94.6 ± 19.4 43.1 ± 9.4 167.6 ± 30.8 4.2 ± 0.3 3.1 ± 1.8 342.6 ± 125.1
P 0.431 0.612 0.382 0.102 0.027 0.046 < 0.01 < 0.01 < 0.01 0.203 0.047 < 0.01 < 0.01 > 0.05 0.018 0.033 0.021 0.016 0.042 0.031 0.014 < 0.01 < 0.01
Table 1 Baseline characteristics of CKD patients and control subjects.
Data are mean ± standard deviation. BMI: Body mass index; eGFR, estimated glomerular filtration rate; HOMA-IR: Homeostatic model assessment of insulin resistance; LDL: Low-density lipoprotein; HDL: High-density lipoprotein
Table 2 CKD stages and Serum Omentin-1 levels. Stage of CKD stage 2 stage 3 stage 4
Number of CKD
Omentin-1 levels
patients (n = 64)
(ng/mL)
20 (31 %) 23 (36 %) 21 (33 %)
236.3 ± 82.1 219.2 ± 99.2a 321.9 ± 111.8b
One-way ANOVA test results was demonstrated in table. The ANOVA test p-value was 0.027. CKD: Chronic kidney disease a
Omentin-1 difference between CKD (stage 3) vs. CKD (stage 2), P = 0.138
b
Omentin-1 difference between CKD (stage 4) vs. CKD (stage 2), P = 0.014; Omentin-1 difference between CKD (stage 4) vs. CKD (stage 3), P = 0.008; Omentin-1 difference between CKD (stage 4) vs. healthy controls, P = 0.224
Clinical characteristics and Omentin-1 levels in the diabetic and non-diabetic CKD subgroups Serum Omentin-1 levels and CKD parameters are summarized ▶ Table 3. There was a significant difference in serum Omenin ● tin-1 levels between non-diabetic (324.2 ± 47.7 ng/mL) and diabetic (189.4 ± 31.2 ng/mL) CKD subgroups (p < 0.01). The diabetic CKD subgroup had higher BMI (p = 0.036), WC (p = 0.021), systolic (p = 0.038) and diastolic (p = 0.043) blood pressures, serum glucose (p < 0.01), HOMA-IR (p < 0.01), HbA1c (p < 0.01), total-C (p = 0.037), LDL-C (p = 0.028), TG (p = 0.021), CRP (p < 0.01) and lower HDL-C (p = 0.044), and albumin (p = 0.017) levels compared to non-diabetic CKD subgroup.
Omentin-1 levels in malnutrition-inflammation (MI) subgroups Omentin-1 measurements of the patients according to MI com▶ Table 4. CKD patients were classified ponents were shown in ● according to MI components. 29 patients had none; 24 had one, and 11 had all 2 MI components. Serum Omentin-1 levels were significantly decreased according to the presence of MI components.
Relationship between Omentin-1 and clinical parameters in healthy subjects and CKD (diabetic and nondiabetic) groups a. Healthy subjects: There was a negative correlation between the level of omentin and total-C, and LDL-C (r = –0.402, p = 0.043; r = –0.654, p = 0.024; respectively). b. All CKD (diabetic and nondiabetic) patients: Omentin-1 level was negatively correlated with serum LDL-C, and eGFR (r = –0.447, p = 0.039; r = –0.561, p = 0.021, respectively), and positively correlated with serum fasting glucose, and creatinine (r = –0.669, p = 0.017; r = –0.392, p = 0.04; respectively). There was no correlation between serum Omentin-1 and other clinical parameters in control and CKD (diabetic and nondiabetic) groups.
Discussion
▼
Present study has 4 main findings: (1) Serum Omentin-1 levels in CKD patients were significantly lower compared to the healthy controls (2) Omentin-1 level was significantly lower in the diabetic CKD subgroup compared to the healthy control group and non-diabetic CKD subgroup. However, no significant differences were found between non-diabetic CKD and control groups. (3) An increase in inflammation and malnutrition components was correlated with a decrease in the serum level of Omentin. (4) For stage 2 and 3 CKD, Omentin levels were lower than the control group. However, no significant difference revealed between patients with stage 4 CKD and controls. There are 2 types of obesity, including visceral and peripheral. In terms of obesity related complications, such as insulin resistance and DM, visceral type obesity is at higher risk than peripheral [20]. Omentin-1, mainly secreted by stromal vascular cells in visceral adipose tissue, is a protein of 313 amino acids and
Tekce H et al. Omentin Levels in Chronic Kidney Disease … Exp Clin Endocrinol Diabetes 2014; 122: 451–456
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Parameters age (years) gender (female, %) BMI (kg/m2) waist circumference (cm) systolic blood pressure (mm Hg) diastolic blood pressure (mm Hg) blood urea nitrogen (mg/dL) creatinine (mg/dL) eGFR (ml/min/1.73 m2) calcium (mg/dL) phosphate (mg/dL) parathyroid hormone (pg/mL) haemoglobin (g/dL) platelets (103/μL) fasting glucose (mg/dL) HOMA-IR total-cholesterol (mg/dL) LDL-cholesterol (mg/dL) HDL-cholesterol (mg/dL) triglyceride (mg/dL) albumin (g/dL) C-reactive protein (mg/L) serum omentin-1 (ng/mL)
454 Article
Diabetic CKD subgroup (n = 30)
age (years) gender (female, %) BMI (kg/m2) waist circumference (cm) systolic blood pressure (mm Hg) diastolic blood pressure (mm Hg) blood urea nitrogen (mg/dL) creatinine (mg/dL) eGFR (ml/min/1.73 m2) calcium (mg/dL) phosphate (mg/dL) parathyroid hormone (pg/mL) haemoglobin (g/dL) uric acid (mg/dL) fasting glucose (mg/dL) HOMA-IR hemoglobin A1c ( %) total cholesterol (mg/dL) LDL-cholesterol (mg/dL) HDL-cholesterol (mg/dL) triglyceride (mg/dL) albumin (g/dL) C-reactive protein (mg/L) serum omentin-1 (ng/mL)
Nondiabetic CKD subgroup (n = 34)
56.1 ± 11.2 13 (43 %) 27.1 ± 3.9 103.4 ± 8.3 141.6 ± 18.9 88.3 ± 14.2 55.1 ± 13.2 3.2 ± 1.6 34.8 ± 14.1 8.6 ± 0.7 3.7 ± 0.9 180.2 ± 141.4 10.7 ± 1.2 6.8 ± 0.9 171.9 ± 35.1 5.5 ± 3.5 8.2 ± 2.1 198.4 ± 31.2 131.2 ± 20.7 29.7 ± 8.8 206.2 ± 47.6 3.0 ± 0.9 14.2 ± 4.1 189.4 ± 31.2
53.7 ± 10.4 15 (44 %) 24.3 ± 3.2 92.4 ± 7.1 132.3 ± 14.8 77.9 ± 10.2 58.7 ± 10.7 3.1 ± 1.4 32.0 ± 13.1 9.0 ± 0.7 3.9 ± 0.8 193.7 ± 135.1 11.0 ± 1.4 6.3 ± 0.7 101.4 ± 11.7 3.9 ± 2.0 5.0 ± 0.9 181.2 ± 27.7 112.3 ± 17.2 40.3 ± 9.7 156.3 ± 30.4 3.8 ± 0.7 8.7 ± 3.9 324.2 ± 47.7
P 0.256 0.315 0.036 0.021 0.038 0.043 0.519 0.832 0.471 0.705 0.638 0.561 0.284 0.754 < 0.01 < 0.01 < 0.01 0.037 0.028 0.044 0.021 0.017 < 0.01 < 0.01
Table 3 Characteristics of CKD subgroups.
Data are mean ± standard deviation. BMI: Body mass index; eGFR, estimated glomerular filtration rate; HOMA-IR: Homeostatic model assessment of insulin resistance; LDL: Low-density lipoprotein; HDL: High-density lipoprotein
Table 4 Omentin-1 levels in malnutrition-inflammation (MI) subgroups. Number of MI
Number of CKD
Omentin-1 levels
components
patients (n = 64)
(ng/mL)
none 1 component 2 components
29 (45 %) 24 (38 %) 11 (17 %)
307.4 ± 172.2 191.3 ± 84.7a 145.8 ± 67.3b
One-way ANOVA test results was demonstrated in table. The ANOVA test p-value was 0.019. CKD: Chronic kidney disease; MI: malnutrition, inflammation a
Omentin-1 difference between one MI component vs. no MI components, P = 0.022
b
Omentin-1 difference between 2 MI components vs. no MI components, P = 0.013; Omentin difference between 2 MI components vs. one MI component, P = 0.042
34 kDa [21, 22]. Omentin-1 has 3 main functions that have been identified to date; first, increases the insulin sensitivity in human adipocytes [7, 21], second, reduces inflammation [10] and third, stimulates vasodilatation [23]. There are numerous studies demonstrating reduction in Omentin-1 levels in a variety of clinical conditions. The 2 major factors affecting the level of circulating Omentin-1 are insulin and glucose. Tan et al. reported a significant decrease in the level of Omentin-1 caused by prolonged insulin and glucose infusions [9]. Similarly, fasting plasma glucose was negatively correlated with serum omentin levels in CKD patients reflecting the effects of diabetes mellitus in the present study. These results suggest the previous studies which pointed negative effects of hyperglycemia on omentin levels. Recent studies have reported decreased levels of Omentin-1 in obesity and obesity-related co-morbid clinical conditions [insulin resistance, metabolic syndrome, DM, polycystic over syndrome (PCOS), etc.] [7, 12–14, 24, 25]. Serum omentin levels were lower in Type-1 Diabetes as well as patients with type–2 DM and impaired glucose regulation [8, 26, 27]. The results of
our study revealed Omentin-1 levels were lower in diabetic CKD subgroup compared to both non-diabetic subgroup and controls. There was no significant difference between controls and non-diabetic subgroup, and this suggests that DM might be a significant cause for omentin reduction in CKD population. In another study, serum Omentin-1 levels were negatively correlated with WC, BMI, leptin, fasting insulin, HOMA and positively with adiponectin and HDL-C [7]. However, we could not figure out similar correlation between omentin and other metabolic parameters except total- and LDL-C. An explanation should be that our healthy control group was relatively small which prevent the difference to reach statistically significance level. Still, endothelial dysfunction, atherosclerosis related cardiovascular (CV) diseases were significantly associated with lower levels of omentin [13–15, 28]. Weight loss in obese patients, also the use of metformin in patients with PCOS brings about an increase in the level of omentin [29, 30]. All clinical evidence which has been shown suggests that Omentin, just as adiponectin, is a beneficial adipocytokine. In a study by Alcelik et al. Omentin-1 levels were evaluated in patients with CKD stage 5 [31]. As a result of this study, Omentin levels were found to be significantly higher in hemodialysis patients than the healthy controls. Significant and unexpected increase of Omentin levels in end-stage renal disease patients were linked to the lack of degradation and excretion secondary to renal dysfunction. In our study, absence of significant difference in omentin levels between stage 4 CKD patients and control group can be explained by similar mechanisms. Therefore, decrease in degradation and excretion of omentin, as creatinine, seems to be mainly due to the inability of renal clearance from plasma. This type of defect on excretion and degradation of omentin levels was likely to become more obvious when creatinine clearance falls below 30 ml/min (stage 4 CKD). Other than this special exception, omentin levels were still negatively correlated with eGFR for all CKD patients, in bivariate correlation
Tekce H et al. Omentin Levels in Chronic Kidney Disease … Exp Clin Endocrinol Diabetes 2014; 122: 451–456
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Parameters
analysis in the present study. Accelerated atherosclerosis and insulin resistance are quite common clinical pathologies in the course of CKD [32–35]. Therefore, significant lower levels of Omentin in patients with CKD stage 2 and 3 may be a consequence of arising inflammation in CKD process, malnutrition, insulin resistance as well as reflecting the inhibitory effects of diabetes. Another important factor affect the serum level of Omentin is inflammation. IL-6, which is an important mediator of inflammation in type 2 diabetic patients, has a negative correlation with Omentin-1 [36]. A study conducted by Tan et al. after metformin treatment in women with PCOS, high-sensitivity CRP level, was found to be the only negative variable correlated with Omentin-1 [37]. In a recent study, authors showed that Omentin can inhibit TNF-α induced adhesion molecules expression by blocking the nuclear factor-kappa beta pathway [38]. Likewise, another report concluded that the omentin inhibit TNF-α induced inflammation by stimulating superoxide production in vascular smooth muscle cells [10]. Increased systemic inflammation alone or together with malnutrition-inflammation-atherosclerosis syndrome in CKD patients, is a well-known clinical entity increasing morbidity and mortality [33–35]. Some studies reported that Omentin could be considered as a pro-inflammatory adipokine pointing various chronic inflammatory diseases [39, 40]. Increase in MI components, in our study, was found to be associated with a reduction in the levels of Omentin, and this finding lends support the reduction in omentin in inflammatory conditions. This is especially important in terms of revealing the negative relation between increased inflammation-nutritional disorders and Omentin levels. There are some limitations in our study. First, our study has a cross-sectional design; second, it was a single-center study and third is that, it has a relatively small study cohort, which all prevents our results to be universal. In conclusion, the results of the present study suggest that diabetes mellitus and inflammation should be associated with lower omentin levels in CKD population; however, this reduction resolves due to the failure of degradation and excretion of omentin when creatinine clearance falls below 30 ml/min (stage 4 CKD). However, prospective studies with a larger cohort are needed to confirm our results.
Conflict of interest: My co-authors and I declare no conflicts of interest. References 1 Foley RN, Parfrey PS, Sarnak MJ. Clinical epidemiology of cardiovascular disease in chronic renal disease. American journal of kidney diseases: the official journal of the National Kidney Foundation 1998; 32: S112–S119 2 Vanholder R, Massy Z, Argiles A et al. Chronic kidney disease as cause of cardiovascular morbidity and mortality. Nephrol Dial Transpl 2005; 20: 1048–1056 3 Akdag I, Yilmaz Y, Kahvecioglu S et al. Clinical value of the malnutrition-inflammation-atherosclerosis syndrome for long-term prediction of cardiovascular mortality in patients with end-stage renal disease: a 5-year prospective study. Nephron Clinical practice 2008; 108: c99–c105 4 Tripepi G, Mattace Raso F, Sijbrands E et al. Inflammation and asymmetric dimethylarginine for predicting death and cardiovascular events in ESRD patients. Clinical journal of the American Society of Nephrology: CJASN 2011; 6: 1714–1721
5 Shoji T, Masakane I, Watanabe Y et al. Committee of Renal Data Registry JSfDT. Elevated non-high-density lipoprotein cholesterol (nonHDL-C) predicts atherosclerotic cardiovascular events in hemodialysis patients. Clinical journal of the American Society of Nephrology: CJASN 2011; 6: 1112–1120 6 Flier JS. Obesity wars: molecular progress confronts an expanding epidemic. Cell 2004; 116: 337–350 7 de Souza Batista CM, Yang RZ, Lee MJ et al. Omentin plasma levels and gene expression are decreased in obesity. Diabetes 2007; 56: 1655–1661 8 Pan HY, Guo L, Li Q. Changes of serum omentin-1 levels in normal subjects and in patients with impaired glucose regulation and with newly diagnosed and untreated type 2 diabetes. Diabetes research and clinical practice 2010; 88: 29–33 9 Tan BK, Adya R, Farhatullah S et al. Omentin-1, a novel adipokine, is decreased in overweight insulin-resistant women with polycystic ovary syndrome – Ex vivo and in vivo regulation of omentin-1 by insulin and glucose. Diabetes 2008; 57: 801–808 10 Kazama K, Usui T, Okada M et al. Omentin plays an anti-inflammatory role through inhibition of TNF-alpha-induced superoxide production in vascular smooth muscle cells. European Journal of Pharmacology 2012; 686: 116–123 11 Shibata R, Ouchi N, Takahashi R et al. Omentin as a novel biomarker of metabolic risk factors. Diabetol Metab Syndr 2012; 4 12 Auguet T, Quintero Y, Riesco D et al. New adipokines vaspin and omentin. Circulating levels and gene expression in adipose tissue from morbidly obese women. BMC medical genetics 2011; 12: 60 13 Zhong X, Zhang HY, Tan H et al. Association of serum omentin-1 levels with coronary artery disease. Acta pharmacologica Sinica 2011; 32: 873–878 14 Liu R, Wang XL, Bu PL. Omentin-1 is associated with carotid atherosclerosis in patients with metabolic syndrome. Diabetes research and clinical practice 2011; 93: 21–25 15 Shibata R, Takahashi R, Kataoka Y et al. Association of a fat-derived plasma protein omentin with carotid artery intima-media thickness in apparently healthy men. Hypertension research: official journal of the Japanese Society of Hypertension 2011; 34: 1309–1312 16 Matthews DR, Hosker JP, Rudenski AS et al. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412–419 17 Assoc AD. Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2012; 35: S64–S71 18 Levey AS, Bosch JP, Lewis JB et al. A more accurate method to estimate glomerular filtration rate from serum creatinine: a new prediction equation. Modification of Diet in Renal Disease Study Group. Annals of internal medicine 1999; 130: 461–470 19 Pecoits-Filho R, Lindholm B, Stenvinkel P. The malnutrition, inflammation, and atherosclerosis (MIA) syndrome – the heart of the matter. Nephrology, dialysis, transplantation: official publication of the European Dialysis and Transplant Association – European Renal Association 2002; 17 (Suppl 11): 28–31 20 Brunzell JD, Hokanson JE. Dyslipidemia of central obesity and insulin resistance. Diabetes Care 1999; 22: C10–C13 21 Yang RZ, Lee MJ, Hu H et al. Identification of omentin as a novel depotspecific adipokine in human adipose tissue: possible role in modulating insulin action. Am J Physiol-Endoc M 2006; 290: E1253–E1261 22 Schaffler A, Neumeier M, Herfarth H et al. Genomic structure of human omentin, a new adipocytokine expressed in omental adipose tissue. Biochimica et biophysica acta 2005; 1732: 96–102 23 Yamawaki H, Tsubaki N, Mukohda M et al. Omentin, a novel adipokine, induces vasodilation in rat isolated blood vessels. Biochemical and biophysical research communications 2010; 393: 668–672 24 Yoo HJ, Hwang SY, Hong HC et al. Association of circulating omentin-1 level with arterial stiffness and carotid plaque in type 2 diabetes. Cardiovascular diabetology 2011; 10: 103 25 Choi JH, Rhee EJ, Kim KH et al. Plasma omentin-1 levels are reduced in non-obese women with normal glucose tolerance and polycystic ovary syndrome. European journal of endocrinology/European Federation of Endocrine Societies 2011; 165: 789–796 26 Tan BK, Pua S, Syed F et al. Decreased plasma omentin-1 levels in Type 1 diabetes mellitus. Diabetic medicine: a journal of the British Diabetic Association 2008; 25: 1254–1255 27 Tan BK, Adya R, Randeva HS. Omentin: A Novel Link Between Inflammation, Diabesity, and Cardiovascular Disease. Trends Cardiovas Med 2010; 20: 143–148
Tekce H et al. Omentin Levels in Chronic Kidney Disease … Exp Clin Endocrinol Diabetes 2014; 122: 451–456
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
Article 455
28 Moreno-Navarrete JM, Ortega F, Castro A et al. Circulating Omentin as a Novel Biomarker of Endothelial Dysfunction. Obesity 2011; 19: 1552–1559 29 Moreno-Navarrete JM, Catalan V, Ortega F et al. Circulating omentin concentration increases after weight loss. Nutrition & metabolism 2010; 7: 27 30 Shaker M, Mashhadani ZI, Mehdi AA. Effect of Treatment with Metformin on Omentin-1, Ghrelin and other Biochemical, Clinical Features in PCOS Patients. Oman medical journal 2010; 25: 289–293 31 Alcelik A, Tosun M, Ozlu MF et al. Serum levels of omentin in end-stage renal disease patients. Kidney Blood Press Res 2012; 35: 511–516 32 Shinohara K, Shoji T, Emoto M et al. Insulin resistance as an independent predictor of cardiovascular mortality in patients with end-stage renal disease. J Am Soc Nephrol 2002; 13: 1894–1900 33 Zanetti M, Barazzoni R, Guarnieri G. Inflammation and insulin resistance in uremia. Journal of renal nutrition: the official journal of the Council on Renal Nutrition of the National Kidney Foundation 2008; 18: 70–75 34 Oberg BP, McMenamin E, Lucas FL et al. Increased prevalence of oxidant stress and inflammation in patients with moderate to severe chronic kidney disease. Kidney international 2004; 65: 1009–1016
35 Mathur S, Devaraj S, Jialal I. Accelerated atherosclerosis, dyslipidemia, and oxidative stress in end-stage renal disease. Current opinion in nephrology and hypertension 2002; 11: 141–147 36 El-Mesallamy H, El-Derany M, Hamdy N. Serum omentin-1 and chemerin levels are interrelated in patients with Type 2 diabetes mellitus with or without ischaemic heart disease. Diabetic Medicine 2011; 28: 1194–1200 37 Tan BK, Adya R, Farhatullah S et al. Metformin Treatment May Increase Omentin-1 Levels in Women With Polycystic Ovary Syndrome. Diabetes 2010; 59: 3023–3031 38 Zhong X, Li X, Liu F et al. Omentin inhibits TNF-alpha-induced expression of adhesion molecules in endothelial cells via ERK/NF-kappaB pathway. Biochemical and biophysical research communications 2012; 425: 401–406 39 Schaffler A, Zeitoun M, Wobser H et al. Frequency and significance of the novel single nucleotide missense polymorphism Val109Asp in the human gene encoding omentin in Caucasian patients with type 2 diabetes mellitus or chronic inflammatory bowel diseases. Cardiovascular diabetology 2007; 6: 3 40 Senolt L, Polanska M, Filkova M et al. Vaspin and omentin: new adipokines differentially regulated at the site of inflammation in rheumatoid arthritis. Ann Rheum Dis 2010; 69: 1410–1411
Tekce H et al. Omentin Levels in Chronic Kidney Disease … Exp Clin Endocrinol Diabetes 2014; 122: 451–456
This document was downloaded for personal use only. Unauthorized distribution is strictly prohibited.
456 Article
Copyright of Experimental & Clinical Endocrinology & Diabetes is the property of Georg Thieme Verlag Stuttgart and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use.
