| Abstract|| |
Adiponectin is a novel collagen-like protein synthesized by white adipose tissue. Its levels are decreased in obesity, type-2 diabetes and insulin-resistant states, and are increased in chronic renal failure. It has anti-inflammatory and anti-atherogenic properties. This study was planned to evaluate the levels of adiponectin in uremic patients with and without diabetes and to find any relationship between adiponectin levels and some cardiovascular risk factors, and to determine the possible predictive value of adiponectin for cardiovascular complications (CVC). The study included 100 subjects, 20 of them were healthy subjects and served as the control group (group I), 40 were uremic non-diabetic patients (group II) (half of them were without CVC, group IIA, and the other half were patients with CVC, group IIB) and, lastly, 40 uremic diabetic patients (group III) (half of them were without CVC, group IIIA, and the other half were patients with CVC, group IIIB). All subjects were subjected to complete clinical examination, including determination of mean arterial blood pressure (MABP), body mass index (BMI), waist to hip ratio, routine laboratory investigations, fasting plasma glucose, fasting plasma insulin, lipid profile (cholesterol, TG, LDL, HDL), determination of insulin resistance by homeostasis model assessment index (HOMA-IR) and estimation of serum levels of adiponectin. There was a significant increase in serum adiponectin levels in all the uremic patients (group II and group III) when compared with the control (group I) group, P <0.01; also, serum adiponectin levels were significantly decreased in uremic diabetic patients (group III) when compared with uremic non-diabetic patients (group II), P <0.01; but this was still higher than in the controls. The patients with CVC, whether uremic non-diabetic (group IIB) or uremic diabetic (group IIIB), had a significant decrease in serum adiponectin levels when compared with patients without CVC (group IIA and group IIIA), P <0.01. Serum adiponectin has a significant positive correlation with HDL and a significant negative correlation with MABP, BMI, plasma insulin, HOMA-IR, LDL, TG and cholesterol in all the patients. Therefore, it can be concluded that adiponectin levels in uremic patients, whether diabetic or non-diabetic, may be a good indicator of cardiovascular disease risk.
|How to cite this article:|
Elokely A, Shoukry A, Ghonemy TA, Atia M, Amr G. Association of adiponectin with cardiovascular events in diabetic and non-diabetic hemodialysis patients. Saudi J Kidney Dis Transpl 2012;23:736-42
|How to cite this URL:|
Elokely A, Shoukry A, Ghonemy TA, Atia M, Amr G. Association of adiponectin with cardiovascular events in diabetic and non-diabetic hemodialysis patients. Saudi J Kidney Dis Transpl [serial online] 2012 [cited 2020 Jun 3];23:736-42. Available from: http://www.sjkdt.org/text.asp?2012/23/4/736/98151
| Introduction|| |
Atherosclerotic complications are the leading cause of high cardiovascular mortality rates among patients with end-stage renal disease (ESRD);  classic risk factors partly explain the high cardiovascular risk in these patients. 
Adiponectin, which is a novel collagen-like protein synthesized by white adipose tissue that circulates at relatively high (2-20 μg/mL) serum concentrations,  has gained attention for its role in glucose and lipid metabolism. There is a strong positive relationship between adiponectin and insulin sensitivity. 
Adiponectin is reported to be abundant in human blood, with its plasma levels accounting for 0.01% of the total plasma.  Plasma adiponectin is decreased in obesity, suggesting that the dysregulation of adiponectin may be relevant to obesity-linked disorders.  It is also reduced in type-2 diabetes, insulin-resistant states, coronary artery disease and dyslipidemia. , Apart from the anti-diabetic effect, adiponectin has anti-atherogenic properties.  In fact, adiponectin has been shown to suppress all processes involved in atherosclerotic vascular changes, including the expression of adhesion molecules in vascular endothelial cells and proliferation of vascular smooth muscle cells.  Adiponectin plays an important role in inhibition of the inflammatory response, perhaps because it suppresses the attachment of monocytes to endothelial cells. 
Plasma adiponectin levels are dependent on glomerular filtration rate, being markedly increased among patients with renal impairment,  and also in patients on maintenance hemodialysis, peritoneal dialysis and ESRD.  Most of the interest in adiponectin depends on its potential protective role for the cardiovascular system.  Hyperinsulinemia, which is a well known metabolic complication of chronic renal failure, might downregulate plasma adiponectin levels among dialysis patients. 
Low levels of adiponectin are associated with adverse metabolic states such as diabetes,  metabolic syndrome,  dyslipidemia,  lipodystrophy and atherosclerotic cardiovascular disease. 
We aimed, in this study, to evaluate the levels of adiponectin in uremic patients with and without diabetes and to find any relationship between adiponectin levels and some cardiovascular risk factors, and to determine the possible predictive value of adiponectin for cardiovascular complications (CVC).
| Subjects and Methods|| |
This study was carried out in the Internal Medicine and Clinical Pathology Departments, Faculty of Medicine, Zagazig University.
The study was conducted on 100 subjects classified into three groups:
- Group 1 (control group): This group comprised 20 apparently healthy volunteers.
- Group II: comprised 40 patients with ESRD on regular hemodialysis without diabetes. This group was further divided into two subgroups:
- Group IIA: Comprised 20 patients without CVC.
- Group IIB: Comprised 20 patients with CVC (seven with myocardial infarction [MI], ten with angina and three with stroke).
- Group III: Comprised 40 patients with ESRD on regular hemodialysis with dia betes. This group was further divided into two subgroups:
- Group IIIA: Comprised 20 patients without CVC.
Group IIIB: Comprised 20 patients with CVC (six with MI, ten with angina and four with stroke).
All the patients including the control subjects were submitted to full clinical assessment including medical history and detailed clinical examination including blood pressure measurement, assessment of mean arterial blood pressure (MABP) (1/3 systolic arterial pressure) + 2/3 diastolic arterial pressure) and assessment of body mass index (BMI) and waist to hip ratio (WHR).
The laboratory investigations included fasting and 2 hours post-prandial blood glucose, complete blood count (by sysmex SF 3000), blood urea and serum creatinine, liver function tests and lipid profile, including total cholesterol, serum triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C) and low-density lipoprotein-cholesterol (LDL-C). Lipid profile, serum urea, creatinine, glucose and liver function tests were performed by Advia® chemistry and using the Advia® 1650 chemistry system (Siemens, Los Angeles, CA, USA).
Fasting plasma insulin was estimated by Immulite kits (Siemens, USA), which is a solid phase chemiluminescent immunoassay, using Immulite 1000 autoanalyzer (Siemens,, USA).
We determined the insulin resistance by homeostasis model assessment (HOMA) index, which was calculated by the following formula:
HOMA-IR index = fasting insulin (μU/mL) × fasting plasma glucose (mmol/L) / 22.5
Subjects were categorized as insulin resistant if their HOMA was greater than 1.64.
Estimation of serum levels of adiponectin was performed using the Human Adiponectin Elisa Kit (Linco Research, St. Charles, MO, USA). The assay was a Sandwich ELISA technique based, sequentially, on concurrent capture of human adiponectin molecules from samples to the wells of a microtiter plate, which was coated with monoclonal anti-human adiponectin antibodies, and binding of a second biotinylated monoclonal anti-human antibody to the captured molecules. The unbound materials from samples were washed, followed by binding of streptavidin-horseradish peroxidase conjugate to the immobilized biotinylated antibodies. Excess free enzyme conjugates were washed and quantification of immobilized antibody enzyme conjugates was estimated by monitoring horse-radish peroxidase activities in the presence of the substrate 3,3', 5, 5'-tetra-methylbenzidine.
ELISA assay was performed using a Behring Elisa processor Π instrument. The lowest level of adiponectin that can be detected by this assay is 0.78 ng/mL-urinalysis.
Other investigations included resting ECG, pelvi-abdominal ultrasound (US) and echocardiography to detect left ventricle hypertorphy (LVH).
Anthropometric measures include body mass index (BMI) = weight (kg) / height (m 2 ) and waist to hip circumference ratio (WHR) = waist circumference (cm) / hip circumference (cm).
| Statistical Analysis|| |
Data are presented as means ± SD. Comparisons between groups were performed by analysis of variance (ANOVA). When comparing two groups, the independent "t" test was performed. All data were coded, checked, entered and analyzed using Epi-Info version I for the year 2000, software computer package. 
| Results|| |
There was a statistically highly significant difference between the mean values ± SD of BMI, WHR, MABP, cholesterol, triglycerids HDL, LDL, glucose, insulin, HOMA-IR and creatinine among the different groups of the study (P <0.01) [Table 1].
|Table 1: Comparisons between mean values ± SD of some studied parameters in different groups of the study.|
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Both patients with ESRD on regular hemodialysis without diabetes (group II) and patients with ESRD on regular hemodialysis with diabetes (group III) had a statistically highly significant increase in the mean values ± SD of adiponectin, BMI, WHR, cholesterol, triglycerides and LDL, as well as a statistically significant decrease in the mean value ± SD of HDL as compared with the control group (group I) (P < 0.01) [Table 1].
There was a statistically significant increase in the mean values ± SD of cholesterol, TG and LDL and a decrease in the mean values ± SD of adiponectin and HDL in group III when compared with group II (P <0.01). However, there was no significant difference between group II and group III with regard to BMI and WHR. Moreover, there was a statistically significant increase in the mean values ± SD of glucose, insulin and HOMA-IR in group III when compared with group I and also when compared with group II, while no significant difference was found between group I and group II of the previous parameters [Table 1].
In group II (non-diabetic), serum adiponectin levels had a highly significant positive correlation with HDL (P <0.01) and a significantly negative correlation with each of MABP, triglyceride and LDL (P <0.05), while it was not significantly correlated with BMI, WHR, cholesterol, glucose, insulin, HOMA-IR and creatinine (P >0.05) [Table 2].
|Table 2: Correlation between adiponectin and some studied parameters in different subgroups of the study.|
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In group III (diabetic), serum adiponectin had a statistically significant positive correlation with each of WHR (P <0.01) and HDL (P <0.05), while it had a statistically significant negative correlation with MABP and triglycerides (P <0.05) [Table 2].
In group I (control group), serum adiponectin levels had a significant negative correlation with insulin (P <0.05), while it did not significantly correlate with other parameters [Table 2]. Furthermore, there was a significant positive correlation between serum adiponectin levels and HDL and glucose levels (in each of group IIA, IIB and IIIA), while they correlated with HDL levels only in group IIIB. In addition, there was a significant negative correlation between serum adiponectin levels and age, BMI, MABP, cholesterol, triglyceride, insulin and HOMA-IR (in group IIA, IIB, IIIA and IIIB), LDL (in group IIA, IIB and IIIB only) and WHR in group IIIA only [Table 2].
Adiponectin levels in the non-diabetic patients were highly significantly increased in those without CVC as compared with those with CVC (14.9 ± 4.5 and 11.3 ± 2.9, respectively, P <0.01).
The adiponectin levels were also highly significantly increased in diabetic patients without CVC as compared with those with CVC (12.9 ± 4.0 and 9.0 ± 2.5, respectively, P <0.01).
Adiponectin levels were highly significantly increased in non-diabetic patients without CVC when compared with diabetics without CVC (14.9 ± 4.5 and 12.9 ± 4.0, respectively, P <0.01). In addition, the adiponectin levels were highly significantly increased in non-diabetics with CVC in comparison with diabetics with CVC (11.3 ± 2.9, 9.0 ± 2.5, respectively, P <0.01).
| Discussion|| |
Our study revealed a significant increase in adiponectin levels in both uremic non-diabetic and diabetic patients as compared with control subjects. These results were consistent with those found by Zoccali et al,  who revealed that adiponectin levels were markedly increased among patients with ESRD. The increase in adiponectin levels in our uremic patients may be due to reduced adiponectin clearance by the kidney. 
The second important revealed result in our study was a significant decrease in serum adiponectin levels in uremic diabetic patients as compared with uremic non-diabetic patients, but still higher than controls even when stratified to those with and without CVC. This means that the presence of diabetes is associated with decreased levels of adiponectin irrespective of the absence or presence of uremia or CVC. These results were supported by those obtained by both Yang et al,  and Steffes et al,  who found decreased adiponectin levels in insulin-resistant and diabetic non-uremic patients. The explanation of reduced levels of adiponectin in diabetic patients may be due to an inhibitory effect of adiponectin on tumor-necrosis factor (TNF-α B) pathway, which contributes to insulin resistance. 
Our study revealed a significant negative correlation between adiponectin and each of HOMA-IR and insulin in all patients (groups IIA, IIB, IIIA and IIIB). These results were in agreement with those obtained by both Zoccali et al,  and Matsubara et al,  who reported that hyperinsulinemia downregulates plasma adiponectin levels among dialysis patients (non-diabetic uremic and diabetic uremic). This inverse relation between insulin and adiponectin may be due to decreased tyrosin phosphorylation of muscle insulin receptors when adiponectin concentrations decrease, and the low levels are predictive of the subsequent development of diabetes.  The present study demonstrated a significant negative correlation between serum adiponectin levels and BMI. Our results are compatible with those obtained by Zoccali et al,  who reported significantly more reduced adiponectin levels in obese subjects than those in lean, healthy, control subjects. The link between BMI and adiponectin seems to be a causal one, because weight loss induces a marked increase in plasma adiponectin levels among both normal individuals and type-2 diabetic patients.  The inverse correlation between adiponectin levels and BMI suggests presence of a feedback inhibition process as the total body fat mass increases, perhaps by increased secretion of other adipokines, such as TNF-α, which has been shown to decrease the expression of adiponectin from cultured adipocytes; another possibility is the decrease in metabolic function of aged adipocytes, which became not only more insulin resistant and have decreased gene expression of adiponectin compared with young adipocytes. 
The current study revealed a significant negative correlation between serum adiponectin level and each of serum cholesterol, serum TG and serum LDL in all patients (groups IIA, IIB, IIIA and IIIB) and a significant positive correlation of adiponectin serum levels and serum HDL in the same groups. These results are in agreement with those obtained by both Deborah et al,  and Zoccali et al. 
Our study revealed a significant negative correlation between adiponectin serum levels and MABP in all uremic patients, and this is consistent with those obtained by both Emilio et al.  and Iwashima et al,  which may be related to an increase in the sympathetic nervous activity, which may inhibit adiponectin gene expression via adrenergic stimulation and induced activation of the renin angiotensin system in the adipose tissue by hypoadiponectinemia. 
The relation between adiponectin serum levels and insulin resistant status in our study is consistent collectively with those obtained by Salvado et al,  who found significantly decreased plasma adiponectin levels, which increased after weight loss, in obese subjects and insulin-resistant and diabetic patients. 
The present study revealed significantly lower adiponectin serum levels in diabetic and non-diabetic patients with CVC than in those without CVC. Our results are supported by the results of Ouchi et al,  who demonstrated that adiponectin levels were reduced among non-diabetic and non-uremic patients with CVC. Moreover, our results are consistent with those of Hotta et al,  who found that subjects with higher adiponectin levels had a significantly decreased risk of myocardial infarction even after adjustment for LDL, HDL levels, BMI, history of diabetes and hypertension at baseline. This relation between reduced adiponectin levels and cardiovascular risk may be explained by binding of adiponectin to matrix proteins such as collagen I, III and V but not collagen II and IV or laminin or fibronectin,  and this may explain why it accumulates in injured vascular tissue, where it may intervene with the repair process. Adiponectin interferes with TNF-α-induced endothelial cell NF-α B signaling  and inhibits the phagocytic activity of macrophages. The initial steps in atherogenesis comprise increased expression of adhesion molecules on endothelial cells, permitting monocyte adhesion and invasion, and adiponectin is thought to inhibit the endothelial expression of the adhesion molecules VCAM-1, ICAM-1 and E-selectin, which are triggered by inflammatory cytokines such as TNF-α. Adiponectin also suppresses the production of cytokines such as TNF-α in macrophages. Similar results were obtained by Zoccali et al, who found that reduced adiponectin levels seem to be a strong and independent predictor of cardiovascular outcomes.
Accordingly, adiponectin may have a protective role for the cardiovascular system among the ESRD patients, as the inflammatory response detected in atherosclerotic lesions is effectively counteracted by adiponectin.
In conclusion, serum adiponectin levels increase in uremic patients with and without diabetes, and are significantly associated with dyslipidemia, insulin resistance and CVC.
| References|| |
|1.||Levey AS. Controlling the epidemic of cardiovascular disease in chronic renal disease: where do we start? Am J Kidney Dis 1998;32: S5-13. |
|2.||Zoccali C. Cardiovascular risk in uraemic patients: is it fully explained by classical risk factors? Nephrol Dial Transplant 2000;15:454-7. |
|3.||Chandran M, Phillips SA, Ciaraldi T, Henry RR. Adiponectin: more than just another fat cell hormone? Diabetes Care 2003;26:2442-50. |
|4.||Steffes MW, Gross MD, Schreiner PJ, et al. Serum adiponectin in young adults interactions with central adiposity, circulating levels of glucose, and insulin resistance: The CARDIA study. Ann Epidemiol 2004;14:492-8. |
|5.||Hotta K, Funahashi T, Arita Y, Takahashi M. Plasma concentrations of a novel, adipose-specific protein, adiponectin, in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 2000; 20:1595-9. |
|6.||Arita Y, Kihara S, Ouchi N, Maeda K. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999;257:79-83. |
|7.||Weyer C, Funahashi T, Tanaka S, et al. Hypo-adiponectinemia in obesity and type 2 diabetes: Close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 2001;86:1930-5. |
|8.||Gehan S. Adiponectin in patients with type 2 diabetes mellitus with possible relation to pathogenesis metabolic control and complications. MD Thesis, Internal Medicine, under supervision of Rashwan, Fawzy, and Saad. Faculty of Medicine, Zagazig University. 2006. |
|9.||Ouchi N, Kihara S, Arita Y. Novel modulator of enothelial adhesion molecules adipocyte-derived plasma protein adiponectin. Circulation 1999;100:2473-6. |
|10.||Arita S, Kihara S, Ouchi N, et al. Adipocyte-derived plasma protein adiponectin acts as a platelet-derived growth factor-BB-binding protein and regulates growth factor-induced common postreceptor signal in vascular smooth muscle cell. circulation 2002;105:2893-8. |
|11.||Huang JW, Yen CJ, Chiang HW, Hung KY, Tsai TJ, Wu KD. Adiponectin in peritoneal dialysis patients: A Comparison with hemodialysis patients and subjects with normal renal function. Am J Kidney Dis 2004;43:1047-55. |
|12.||Zoccali C. Traditional and emerging cardiovascular and renal risk factors. Kidney Int 2005;70:26-33. |
|13.||Matsubara M, Katayose S, Maruoka S. Decreased plasma adiponectin concentrations in nondiabetic women with elevated homeostasis model assessment ratios. Eur J Endocrinol 2003;148:343-50. |
|14.||Phillips SA, Ciaraldi TP, Kong AP. Modulation of circulating and adipose tissue adiponectin levels by antidiabetic therapy. Diabetes 2003; 52:667-74. |
|15.||Bays L, Mandarino L, DeFronzo RA. Role of adipocyte, free fatty acids, and ectopic fat in the pathogenesis of type 2 diabetes mellitus: peroxisomal proliferator-activated receptor agonists provide a rational therapeutic approach, J Clin Endocrinol Metab 2004;89:463-78. |
|16.||Kadowaki T, Yamauchi T. Adiponectin and adiponectin receptros. Endocr Rev 2005;26: 439-51. |
|17.||Shetty GK, Economides PA, Horton ES, Veves A. Circulating adiponectin and resistin levels in relation to metabolic factors, inflammatory markers, and vascular reactivity in diabetic patients and subjects at risk for diabetes. Diabetes Care 2004;27:2450-7. |
|18.||Zoccali C, Benedetto FA, Mallamaci F, et al. Inflammation is associated with carotid atherosclerosis in dialysis patients. J Hypertens 2001;18:1207-13. |
|19.||Yang WS, Lee WJ, Funahashi T, et al. Weight reduction increases plasma levels of an adipose-derived anti-inflammatory protein, adiponectin. J Clin Endocrinol Metab 2001;86: 3815-9. |
|20.||Stefan N, Vozarova B, Funahashi T, Matsuzawa Y. Plasma adiponectin concentration is associated with skeletal muscle insulin receptor tyrosine phosphorylation, and low plasma concentration precedes a decrease in whole-body insulin sensitivity in humans. Diabetes 2002;51:1884-8. |
|21.||Cnop M, Havel PJ, Utzschneider KM, Carr DB. Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Daibetologia 2003;46:459-9. |
|22.||Wang B, Jenkins JR, Trayhurn P. Expression and secretion of inflammation-related adipokines by human adipocytes differentiated in culture: Integrated response to TNF-alpha. Am J Physiol Endocrinol Metab 2005;288:E731-40. |
|23.||Kosmiski L, Kuritzkes D, Lichtenstein K, Eckel R. Adipocyte-derived hormone levels in HIV lipodystrophy. Antivir There 2003;8:9-15. |
|24.||Oh DK, Ciaraldi T, Henry RR. Adiponectin in health and disease. Diabetes Obes Metab 2007;9:282-9. |
|25.||Francischetti EA, Celoria BM, Duarte SF, et al. Hypoadiponectinemia is associated with blood pressure increase in obese insulin-resistant individuals. Metabolism 2007;56:1464-9. |
|26.||Iwashima Y, Katsuya T, Ishikawa K, et al. Hypoadiponectinemia is an independent risk factor for hypertension. Hypertension 2004;43: 1318-23. |
|27.||Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R. Adiponectin gene expression is inhibited by beta-adrenergic stimulation via protein kinase A in 3T3-L1 adipocytes. FEBS Lett 2001;507:142-6. |
|28.||Salvado JS, Granda M, Bullo M, Corominas A, Casas P, Foz M. Plasma adiponectin distribution in meditranian population and its association with cardiovascular risk factors and metabolic syndrome. Metabolism 2007;56: 1486-92. |
|29.||Okamoto Y, Arita Y, Nishida M, et al. An adipocyte-derived plasma protein, adiponectin, adheres to injured vascular walls. Horm Metab Res 2000;32:47-50. |
|30.||Ouchi N, Kihara S, Arita Y. Adiponectin and adipocyte-derived plasma protein, inhibits endothelial NF-, B signaling through a cAMP-dependent pathway. Circulation 2000;102: 1296-301. |
|31.||Dean MN, Stein FN, Viboud ST (2000): EPIINFO (version 6.1) software computer package. |
Tarek A Ghonemy
Internal Medicine and Nephrology Unit, Faculty of Medicine, Zagazig University, P. O. Box 44519, Zagazig
[Table 1], [Table 2]