|Year : 2013 | Volume
| Issue : 3 | Page : 143-148
Visfatin and adiponectin as early markers of atherosclerosis in type 2 diabetes mellitus
Ibtissam Zakaria1, Mary N. Rizk1, Maha Rakha1, Amal Shehaby2
1 Department of Internal Medicine, Cairo University, Cairo, Egypt
2 Department of Biochemistry, Cairo University, Cairo, Egypt
|Date of Submission||24-Feb-2013|
|Date of Acceptance||25-Mar-2013|
|Date of Web Publication||2-Jul-2014|
Mary N. Rizk
Department of Internal Medicine, Cairo University, 26 st.18 Mokattam, Cairo
Source of Support: None, Conflict of Interest: None
As cardiovascular disease is the leading cause of mortality in type 2 diabetes mellitus, new markers for early detection and risk stratification of diabetic macroangiopathy and microangiopathy are highly desired. Adipocytokines were considered to lead to an increased risk of vascular complications in patients with type 2 diabetes by modulating vascular function and affecting the inflammatory process, thus enhancing atherosclerosis. Two of these were of particular interest, namely, visfatin and adiponectin.
The aim of this study was to evaluate serum visfatin, serum, and urinary adiponectin as early, sensitive surrogate markers of vascular atherosclerosis. We also correlated the levels of these markers to the degree of carotid intimal medial thickness (reflecting the atherosclerotic burden) in type 2 diabetic patients.
Sixty diabetic patients were subdivided into two groups: group I (30 patients with carotid atherosclerosis as assessed by carotid Doppler) and group II (30 patients without carotid atherosclerosis). Twenty healthy volunteers participated as controls. Serum visfatin as well as serum and urinary adiponectin were assessed in all the study groups. We found significantly higher levels of serum visfatin among diabetics compared with the control group. Visfatin was also significantly higher in group I diabetics with atherosclerosis than those without (P<0.05). Similarly, urinary adiponectin was significantly higher in group I than in group II and in diabetics than in the control group. Serum adiponectin was higher in the control group than both the study groups. Using a regression model, visfatin proved to be the only significant predictor in the model (β=0.03, P<0.001). In fact, visfatin alone proved significant, explaining 63% of the variability in carotid intima-media thickness (P<0.001).
Serum visfatin is highly correlated with macrovascular complications in diabetic patients. Serum visfatin may emerge as a valuable and cheaper surrogate marker for the prediction of prevalent macrovascular complications in a type 2 diabetic population. It is a novel and easy-to-obtain method for the clinical assessment of vascular stress and cardiovascular disease risk in type 2 diabetes. Future prospective studies are needed to confirm our results.
Keywords: atherosclerosis, type 2 diabetes mellitus, visfatin
|How to cite this article:|
Zakaria I, Rizk MN, Rakha M, Shehaby A. Visfatin and adiponectin as early markers of atherosclerosis in type 2 diabetes mellitus. Egypt J Intern Med 2013;25:143-8
|How to cite this URL:|
Zakaria I, Rizk MN, Rakha M, Shehaby A. Visfatin and adiponectin as early markers of atherosclerosis in type 2 diabetes mellitus. Egypt J Intern Med [serial online] 2013 [cited 2020 Feb 22];25:143-8. Available from: http://www.esim.eg.net/text.asp?2013/25/3/143/135856
| Introduction|| |
Cardiovascular disease (CVD) is one of the leading causes of morbidity and mortality in type 2 diabetic patients and early detection of macrovascular alterations is of paramount importance for the primary and secondary prevention of CVD and monitoring of optimal medical treatment 1. There is an interest in identifying markers of subclinical atherosclerosis in order to facilitate earlier diagnosis. Several measures have been used to allow risk stratification of diabetic macroangiopathy and progression of atherosclerosis. Noninvasive measurements of surrogate markers of atherosclerosis, such as carotid intima-media thickness (CIMT) 2, can be helpful in the detection of subclinical diseases, especially among individuals at the highest cardiovascular risk, and for determination of the intensity of pharmaceutical treatment. However, over the past few years, there has been a trend toward the measurement of a number of inflammatory and metabolic markers, which may provide an indirect indicator of vascular damage, hence replacing radiological procedures as more readily available and cheaper modalities. Although many studies 3,4 have addressed this point, the most accurate and more importantly cost-effective marker(s) are yet to be determined.
Recently, diabetes-related adiposity was correlated with multiple cardiometabolic risk factors through altered secretion of adipocytokines and exacerbation of insulin resistance 5,6. Adipocytokines were considered to lead to an increased risk of vascular complications in patients with type 2 diabetes by modulating vascular function and affecting the inflammatory process, thus enhancing atherosclerosis 7,8. Two adipocytokines were major players, namely, visfatin and adiponectin 9,10. Visfatin is a pre-B cell colony-enhancing factor that is highly expressed in human visceral fat 11. Patients with type 2 diabetes mellitus expressed higher plasma visfatin concentrations than normoglycemic individuals 12. Although there are indications of visfatin being related to increased cardiovascular risk in the diabetic population, the data available are extremely limited 13. However, adiponectin is a vasoactive peptide with anti-inflammatory and antiatherosclerotic properties on endothelial cells, limiting the initiation and progression of vascular lesions 14. Recently, adiponectin was associated with glomerular capillary stress in type 2 diabetes, hence promoting shedding of adiponectin and its subsequent appearance in urine. Recent studies have linked adiponectinuria to diabetic microangiopathy 7, especially nephropathy; yet, only a few studies have explored the possible link with atherosclerotic disease.
Aim of work
The aim of this study was to evaluate serum visfatin, serum, and urinary adiponectin as early, sensitive surrogate markers of vascular atherosclerosis. We also correlated the levels of these markers to the degree of CIMT (reflecting the atherosclerotic burden) in type 2 diabetic patients.
| Patients and methods|| |
This is a cross-sectional observational comparative study carried out in the Diabetes, Endocrinology and Metabolism center in the Faculty of Medicine, Cairo University, in the period from January 2009 to March 2011. Sixty type 2 diabetic patients were divided into two equal groups according to the presence or absence of carotid atherosclerosis as follows: group I included 30 patients with carotid atherosclerosis and group II included 30 patients without carotid atherosclerosis. Quantification of atherosclerotic burden was assessed by common carotid artery intima-media thickness (IMT) through Doppler study. Carotid atherosclerosis was defined as increased IMT and the presence of at least one discrete plaque defined as a focal thickening at least 50% more than that of the surrounding vessel wall or a locally thickened IMT greater than 1.3 mm. There were 20 healthy volunteers matched for age and sex as the control group. We excluded those aged more than 65 years, those with a history of autoimmune disease, liver impairment, renal insufficiency (creatinine>2 mg/dl), and those with a history of present or previous malignancy.
The degree of glycemic control and multiple cardiovascular risk factors were assessed in all groups in addition to serum visfatin and urinary adiponectin. Serum adiponectin and albumin/creatinine ratio measurements were also included in the study to broaden the comparative analysis.
Analysis of data was carried out by an IBM (USA) computer using statistical program for social science (version 12). P value was considered significant when less than 0.05.
| Results|| |
[Table 1] and [Table 2] show the demographic and laboratory data of the studied groups. [Table 2] shows the statistically significant difference between the studied groups in laboratory results using the one-way analysis of variance test.
|Table 1: Comparison between the demographic data among the studied groups|
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[Table 3] shows that group I had a higher level of serum visfatin compared with group II. Both diabetic groups had higher levels of visfatin than the controls. Furthermore, urinary adiponectin and serum adiponectin were significantly higher among the controls. However, group I had higher albumin/creatinine ratio (ACR) and visfatin compared with group II.
We found a statistically significant positive correlation between urinary adiponectin and diabetes duration, HBA1c, and serum creatinine. Serum visfatin correlated positively to the duration of illness, systolic blood pressure, diastolic blood pressure, and CIMT in group I patients using a correlation coefficient test.
Group I had higher levels of CIMT (1.66±0.2) compared with group II (0.79±0.2). The latter group had higher levels than the control group (0.57±0.04). The difference was highly significant among the different groups (P<0.001).
In [Table 4], we used standard multiple regression to assess the predictive ability of visfatin, urinary adiponectin, serum adiponectin, and ACR to CIMT in diabetic patients. It also shows the correlation between the different variables. The model is significant (F=28.1, P<0.001).
|Table 4: Correlation between variables and carotid intimal thickness carotid intima-media thickness among diabetic patients|
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We constructed four regression models as shown in [Table 5] to assess the predictive ability of visfatin to CIMT after adjusting for urinary adiponectin, serum adiponectin, and ACR. Model 1, with all of the four factors, had R2 equal to 0.647, thus explaining 65% of the variability in CIMT, with visfatin being the only significant predictor in the model (β=0.03, P<0.001).
|Table 5: Regression model to assess the predictive capacity of the different variables to carotid intima-media thickness|
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Model 4 with visfatin alone still proved significant [Table 5] (F=101.7, P<0.001), explaining 63% of the variability in CIMT (β=0.03, P<0.001). Further adjustments made for age, sex, SMI, systolic and diastolic blood pressures, lipid profile, and blood glucose levels did not alter the results.
| Discussion|| |
Diabetes mellitus is known to lead to a higher predisposition to atherosclerotic disease 2. We found significantly higher serum visfatin in both diabetic groups in comparison with the control participants [Table 3]. Visfatin was also significantly higher in diabetics with carotid atherosclerosis than in those without carotid atherosclerosis. Moreover, in diabetics with carotid atherosclerosis, we found a highly significant positive correlation between serum visfatin on the one hand, and the degree of CIMT, systolic, and diastolic blood pressure, as well as duration and degree of glycemic control on the other.
Visfatin, an adipocytokine produced by macrophages in visceral fat, is identical to pre-B cell colony-enhancing factor secreted by the lymphocytes. Evidence exists that visfatin exerts autocrine and endocrine effects in the liver, muscle, and heart cells, where it is also produced 11. Studies have shown a strong correlation between visfatin and increased visceral obesity (as shown by CT scan) and a weaker one with subcutaneous fat 15.
In fact, some recent studies 16,17 found a positive correlation of visfatin with BMI and WHR, implicating its association with obesity and showing a potential link between diabetes-related insulin resistance and obesity. However, other studies presented contradictory results 9,18. This may be partly because of the considerable differences found in visfatin immunoassays 9.
In agreement with our results, Lopez Bermejo et al. 19 found that visfatin levels were partly associated with higher glycated hemoglobin levels (A1C), suggesting a possible link between higher visfatin levels and progressive β-cell dysfunction. Nevertheless, Takebayashi et al. 20 found no correlation between diabetes and visfatin, whereas another study reported decreased visfatin in patients with type 1 diabetes mellitus and an inverse relationship between A1C and visfatin levels 21.
Visfatin has also been reported to correlate with ultrasound-evident carotid atherosclerosis in patients with metabolic syndrome 22. Lu et al. 23 found higher visfatin levels in Chinese individuals with stroke, suggesting a possible role of visfatin in the development and progression of cerebrovascular disease. Diabetes mellitus, being itself a state of chronic low-grade inflammation, together with the inflammatory state in carotid atherosclerotic plaques, increases the macrophage population, which in turn could increase the production of visfatin. This may result in a vicious positive cycle of inflammation. However, the exact association between visfatin and carotid atherosclerosis warrants further larger scale prospective studies. Nevertheless, this can partly explain the link between obesity, insulin resistance, β-cell dysfunction, endothelial dysfunction, and atherosclerosis 15.
Our study proved a significant positive correlation between serum visfatin and ACR in diabetic patients. Yilmaz et al. 7 also showed that visfatin levels were associated positively not only with insulin resistance but also with the degree of albuminuria in type 2 diabetic patients. Thus, endothelial dysfunction in early diabetic nephropathy is associated with altered circulating levels of visfatin.
Visfatin is synthesized in cultured mesangial cells 4. Visfatin also stimulates glucose uptake in glomerular mesangial cells 4,7. Thus, it was hypothesized that visfatin may contribute toward acceleration of diabetic nephropathy through aggravation of metabolic alterations 4,12. Whether visfatin could be considered as a surrogate marker of diabetic nephropathy and whether its modulation could play a role in possible therapeutic strategies warrants further studies.
Our study found higher urinary adiponectin levels in diabetics compared with the control group and higher levels in diabetics with carotid atherosclerosis versus those without carotid atherosclerosis. In addition, we found a moderately significant positive correlation between urinary adiponectin level and the degree of CIMT as well as ACR. Von Eynatten et al. 24 reported findings that were in agreement with ours. They found that urinary adiponectin was significantly increased in type 2 diabetes and that adiponectinuria was associated with increased IMT. Moreover, we found that urinary adiponectin was correlated positively with the duration of diabetes and degree of glycemic control evidenced by the level of HbA1c among diabetics with carotid atherosclerosis, which was not established in the previous studies.
Previous studies addressing microalbuminuria alone and the association with CIMT showed conflicting results 2, 25, 26. Microalbuminuria has been used as a marker of endothelial dysfunction and predicts CVD in patients with type 2 diabetes 1,2. However, risk prediction by assessment of urinary albumin levels shows some important limitations. A diabetes duration of more than 6 years may precede the first appearance of urinary albumin 2, 27, and vascular changes start long before the first appearance of albumin in urine and even before the diagnosis of diabetes 27. Hence, it appears that the applicability of microalbuminuria for CVD risk evaluation in type 2 diabetes per se is limited. Moreover, in large prospective cohort studies, the increased risk for CVD started from urinary albumin levels well below the cutoff for microalbuminuria 24. Thus, a considerable percentage of high-risk patients will be missed by screening for albuminuria utilizing current cut-off values. This has been supported recently by data in the Finnish Diabetic Nephropathy (FinnDiane) Study, in which a significant number of type 1 diabetic patients at high risk of premature death had normoalbuminuria 28. Hence, newer, more sensitive detectors of early diabetic atherosclerosis are warranted.
In agreement with our study, von Eynatten et al. 24 showed that serum adiponectin was significantly lower in diabetics in comparison with the control group and lower in diabetics with carotid atherosclerosis than in those without carotid atherosclerosis. However, in contrast to von Eynatten et al. 24, we failed to establish a significant positive correlation of serum adiponectin levels with the degree of CIMT. It was shown in type 2 diabetic patients that adiponectin is the lowest in the presence of impaired glucose regulation and early diabetes, whereas long diabetes duration is associated with a significant increase in circulating adiponectin levels 4. Hence, hypoadiponectinemia may have clinical value at the early stages of atherogenesis, but at more advanced disease stages, its role as a meaningful biomarker is questionable 14.
Although previous studies have evaluated markers such as serum visfatin 28, 29, urinary adiponectin 4, ACR, and serum adiponectin 14 as novel markers of vascular damage in diabetes, this is the first comparative study including all four variables to assess their predictive value, sensitivity, and specificity in the degree of increase in IMT (reflecting macrovascular disease in type 2 diabetes and CVD risk evaluation) both collectively and separately.
Our study established that serum visfatin exceeded urinary and serum adiponectin as well as ACR as a highly valid marker of increased CIMT with 100% sensitivity and 92% specificity. Furthermore, serum visfatin was the only significant predictor in our stepwise regression model (including all four variables), explaining 65% of the variability in CIMT. This was still significant after controlling for urinary adiponectin, serum adiponectin, and ACR. In fact, visfatin alone accounted for 63% of the variability in CIMT. Urinary adiponectin exceeded ACR in sensitivity (83 and 80%, respectively) whereas ACR had a higher specificity (65 and 60%, respectively) for increased CIMT.
Ultrasonic measurement of CIMT has been used for several years as a surrogate for predicting rates of cardiovascular events. However, this is limited by the fact that age-related thickening IMT of the CCA also occurs in the absence of overt atherosclerosis. This has been shown in some human and animal models 2, 27, which is not synonymous with atherosclerosis. In addition, regression of IMT has been found to be poorly predictive of reduction in cardiovascular events in a meta-analysis of published studies 2.
The relatively small sample size and cross-sectional design of our study did not allow us to infer a causal relationship of visfatin and urinary adiponectin with subclinical atherosclerosis and subsequent CVD events.
Nevertheless, the significant correlation between serum visfatin with the degree of IMT indicates that visfatin levels may play a role as an earlier and cheaper detector of atherosclerotic changes in the subclinical phase. Hence, early detection of atherosclerotic changes through elevated visfatin levels may possibly over-ride the need for atherosclerotic burden assessment by radiological methods. This provides for early prediction and management of transient ischemic attacks and vertebrobasilar insufficiency.
| Conclusion|| |
Serum visfatin may emerge as a valuable and cheaper surrogate marker for prevalent macrovascular complications in a type 2 diabetic population. It is a novel and easy-to-use method for the clinical assessment of vascular stress and CVD risk in type 2 diabetes. Future prospective studies are needed to confirm our results.
| References|| |
|1.||Sukhija R, Aronow WS, Kakar P, Garza L, Sachdeva R, Sinha A, et al..Relation of microalbuminuria and coronary artery disease in patients with and without diabetes mellitus.Am J Cardiol2006;98:279–281. |
|2.||Yokoyama H, Aoki T, Imahori M, Kuramitsu M.Subclinical atherosclerosis is increased in type 2 diabetic patients with microalbuminuria evaluated by intima-media thickness and pulse wave velocity.Kidney Int2004;66:448–454. |
|3.||Wang P, Vanhoutte PM, Miao CY.Visfatin and cardio-cerebro-vascular disease.J Cardiovasc Pharmacol2012;59:1–9. |
|4.||Hye KS, Mi HL, Bo KK, Yun GP, Gang JK, Young SK, et al..Visfatin: a new player in mesangial cell physiology and diabetic nephropathy.Am J Physiol Renal Physiol2008;295:F1485–F1494. |
|5.||Clodi M, Resl M, Stelzeneder D, Pacini G, Tura A, Mörtl D, et al..Interactions of glucose metabolism and chronic heart failure.Exp Clin Endocrinol Diabetes2009;117:99–106. |
|6.||Després JP.Abdominal obesity: the most prevalent cause of the metabolic syndrome and related cardiometabolic risk.Eur Heart J Suppl2006;8BB4–B12. |
|7.||Yilmaz MI, Saglam M, Qureshi AR, Carrero JJ, Caglar K, Eyileten T, et al..Endothelial dysfunction in type-2 diabetics with early diabetic nephropathy is associated with low circulating adiponectin.Nephrol Dial Transplant2008;23:1621–1627. |
|8.||Mohammadzadeh G, Zarghami N.Hypoadiponectinemia in obese subjects with type II diabetes: a close association with central obesity indices.J Res Med Sci2011;16:713–723. |
|9.||Laudes M, Oberhauser F, Schulte DM, Freude S, Bilkovski R, Mauer J, et al..Visfatin/PBEF/Nampt and resistin expressions in circulating blood monocytes are differentially related to obesity and type 2 diabetes in humans.Horm Metab Res2010;42:268–273. |
|10.||Shargorodsky M, Boaz M, Goldberg Y, Matas Z, Gavish D, Fux A, et al..Adiponectin and vascular properties in obese patients: is it a novel biomarker of early atherosclerosis.Int J Obes2009;33:553–558. |
|11.||Fukuhara A, Matsuda M, Nishizawa M, Segawa K, Tanaka M, Kishimoto K, et al..Visfatin: a protein secreted by visceral fat that mimics the effects of insulin.Science2005;307:426–430. |
|12.||Chen MP, Chung FM, Chang DM, Tsai JCR, Huang HF, Shin SJ, et al..Elevated plasma level of visfatin/pre-B cell colony-enhancing factor in patients with type 2 diabetes mellitus.J Clin Endocrinol Metab2006;91:295–299. |
|13.||Dahl TB, Yndestad A, Skjelland M, Øie E, Dahl A, Michelsen A, et al..Increased expression of visfatin in macrophages of human unstable carotid and coronary atherosclerosis: Possible role in inflammation and plaque destabilization.Circulation2007;115:972–980. |
|14.||Patel DA, Srinivasan SR, Xu JH, Chen W, Berenson GS.Adiponectin and its correlates of cardiovascular risk in young adults: the Bogalusa Heart Study.Metabolism2006;55:1551–1557. |
|15.||Saddi Rosa P, Oliveira CS, Giuffrida FM, Reis AF.Visfatin, glucose metabolism and vascular disease: a review of evidence.Diabetol Metab Syndr2010;2:21. |
|16.||Dogru T, Sonmez A, Tasci I, Bozoglu E, Yilmaz MI, Genc H, et al..Plasma visfatin levels in patients with newly diagnosed and untreated type 2 diabetes mellitus and impaired glucose tolerance.Diabetes Res Clin Pract2007;76:24–29. |
|17.||Berndt J, Klöting N, Kralisch S, Kovacs P, Fasshauer M, Schön MR, et al..Plasma visfatin concentrations and fat depot-specific mRNA expression in humans.Diabetes2005;54:2911–2916. |
|18.||Hunt KJ, Williams K, Rivera D, O'Leary DH, Haffner SM, Stern MP, et al..Elevated carotid artery intima-media thickness levels in individuals who subsequently develop type 2 diabetes.Arterioscler Thromb Vasc Biol2003;23:1845–1850. |
|19.||López Bermejo A, Chico Julià B, Fernàndez Balsells M, Recasens M, Esteve E, Casamitjana R, et al..Serum visfatin increases with progressive β-cell deterioration.Diabetes2006;55:2871–2875. |
|20.||Takebayashi K, Suetsugu M, Wakabayashi S, Aso Y, Inukai T.Association between plasma visfatin and vascular endothelial function in patients with type 2 diabetes mellitus.Metabolism2007;56:451–458. |
|21.||Toruner F, Altinova AE, Bukan N, Arslan E, Akbay E, Ersoy R, et al..Plasma visfatin concentrations in subjects with type 1 diabetes mellitus.Horm Res2009;72:33–37. |
|22.||Zhong M, Tan HW, Gong HP, Wang SF, Zhang Y, Zhang W.Increased serum visfatin in patients with metabolic syndrome and carotid atherosclerosis.Clin Endocrinol2008;69:878–884. |
|23.||Lu LF, Yang SS, Wang CP, Hung WC, Yu TH, Chiu CA, et al..Elevated visfatin/pre-B-cell colony-enhancing factor plasma concentration in ischemic stroke.J Stroke Cerebrovasc Dis2009;18:354–359. |
|24.||Von Eynatten M, Liu D, Hock C, Oikonomou D, Baumann M, Allolio B, et al..Urinary adiponectin excretion: a novel marker for vascular damage in type 2 diabetes.Diabetes2009;58:2093–2099. |
|25.||Keech AC, Grieve SM, Patel A, Griffiths K, Skiltont M, Watts GF, et al..Urinary albumin levels in the normal range determine arterial wall thickness in adults with type 2 diabetes: a FIELD substudy.Diabet Med2005;22:1558–1565. |
|26.||Freedman BI, Langefeld CD, Lohman KK, Bowden DW, Carr JJ, Rich SS, et al..Relationship between albuminuria and cardiovascular disease in type 2 diabetes.J Am Soc Nephrol2005;16:2156–2161. |
|27.||Agewall S, Björn F.Microalbuminuria and intima-media thickness of the carotid artery in clinically healthy men.Atherosclerosis2002;164:161–166. |
|28.||Mäkinen VP, Forsblom C, Thorn LM, Wadén J, Gordin D, Heikkilä O, et al..Metabolic phenotypes, vascular complications and premature deaths in a population of 4,197 patients with type 1 diabetes.Diabetes2008;57:2480–2487. |
|29.||Kadoglou NPE, Sailer N, Moumtzouoglou A, Kapelouzou A, Tsanikidis H, Vitta I, et al..Visfatin (Nampt) and ghrelin as novel markers of carotid atherosclerosis in patients with type 2 diabetes.Exp Clin Endocrinol Diabetes2010;118:75–80. |
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5]