Resistin and adiponectin levels in subjects with coronary artery disease and type 2 diabetes

www.elsevier.com/locate/issn/10434666 Cytokine 34 (2006) 219–223

Resistin and adiponectin levels in subjects with coronary artery disease and type 2 diabetes Subhashini Yaturu

a,b,*

, Robert P. Daberry a, Justin Rains b, Sushil Jain a

b

Overton Brooks VA Medical Center, USA b LSUHSC, USA

Received 19 December 2005; received in revised form 1 May 2006; accepted 19 May 2006

Abstract Background: Resistin and adiponectin are implicated in insulin resistance and atherosclerosis. The objective of this study was to evaluate the association between plasma resistin levels and the presence of coronary artery disease (CAD) or diabetes compared to the controls. In a cross-sectional study, we measured glucose, fasting lipid panel, resistin, adiponectin, insulin, C-reactive protein (CRP) and TNF-a in 57 subjects with CAD, 58 subjects with diabetes compared to 45 normal control subjects. Results: Subjects with CAD compared to the control subjects had increased insulin resistance index (39 ± 32 vs. 13.45 ± 12.73 with p < 0.0001), CRP levels (3.8 ± 4.03 vs. 2.0 ± 2.0 with p < 0.05) and decreased levels of adiponectin (12.5 ± 4.8 vs. 17.26 ± 10.4 with p < 0.0003). Subjects with diabetes compared to the controls had had increased insulin resistance index (69 ± 19 vs. 13.45 ± 12.73 with p < 0.001), CRP levels (4.1 ± 4.8 vs. 2.0 ± 2.0 with p < 0.01) and decreased levels of adiponectin (11.58 ± 4.8 vs. 17.26 ± 10.4 with p < 0.001). Compared to the controls, there was no significant difference in the levels of resistin in subjects with CAD (4.92 ± 3.2 vs. 4.1 ± 2.4) as well as diabetes (4.92 ± 3.2 vs. 4.6 ± 2.6). Both CRP and resistin levels correlate with TNF-a (r = 0.557, p < 0.000001; r = 0.84, p < 0.000001). Conclusions: The present study shows decreased plasma adiponectin levels in subjects with diabetes as well as in subjects with CAD is similar to the literature. Plasma levels of resistin in subjects with CAD or diabetes are similar to the controls. However, there was a strong correlation of resistin levels with inflammatory markers. This suggests resistin as an inflammatory marker associated with CAD.  2006 Elsevier Ltd. All rights reserved. Keywords: Resistin; Adiponectin; Insulin resistance; TNF-a; CRP; Type 2 diabetes; Coronary artery disease

1. Introduction 1.1. DM and atherosclerosis The risk of cardiovascular disease (CVD) in subjects with diabetes and no known CVD is similar to that of those who have already had a cardiovascular event [1]. Obesity is strongly associated with insulin resistance and dyslipidemia and increased risk of cardiovascular disease [2]. Adipose tissue synthesises and secretes adiponectin, resistin, TNFa, IL-6 and other cytokines. Increased synthesis of these cytokines in obese subjects leads to insulin resistance in

*

Corresponding author. E-mail address: [email protected] (S. Yaturu).

1043-4666/$ - see front matter  2006 Elsevier Ltd. All rights reserved. doi:10.1016/j.cyto.2006.05.005

muscle [3], increased synthesis of acute-phase reactants in the liver (CRP and fibrinogen), and/or activation of macrophages in atheromatous plaques [4], which leads to an increased incidence of vascular diseases. Circulating levels of resistin are proportional to the degree of adiposity [5], more so in abdominal adiposity [6], with a 15-fold greater expression in visceral compared with subcutaneous adipose tissue [7]. Elevated levels of resistin are reported in subjects with elevated BMI and type 2 diabetes [6,8,9], and correlate with hepatic insulin resistance [10–12] and glucocorticoid induced insulin resistance [13]. Resistin has been shown to promote endothelial cell activation and had been linked to cardiovascular disease in the metabolic syndrome [14]. Resistin is reported to have a direct effect on vascular endothelial cells; however, this effect is reduced by adiponectin [15]. Both resistin gene

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expression and protein levels are regulated in parallel with insulin and glucose during fasting and refeeding [16]. Adiponectin is exclusively secreted by adipocytes. In cross-sectional studies, plasma adiponectin levels correlated negatively with obesity [17,18], dyslipidemia [19], coronary artery disease [20], insulin resistance [21,22], waistto-hip ratio [22] and increased levels of CRP and IL-6 [23], two inflammatory mediators and markers of increased cardiovascular risk. Low levels of adiponectin in obese subjects are associated with higher levels of resistin and are considered to contribute to insulin resistance and the accelerated atherogenesis associated with obesity [24]. Decreased levels of adiponectin have been noted in subjects with diabetes without coronary artery disease, and even lower levels were noted among diabetics with CAD [20]. TNF-a and IL-6 are also expressed in adipose tissues [25], with visceral fat responsible for more TNF-a production than subcutaneous fat [26]. These cytokines inhibit insulin signaling [27] and TNF-a may play a crucial role in the systemic insulin resistance of type 2 diabetes [28]. There are conflicting reports on the role of serum resistin in obesity-mediated type 2 diabetes. Few studies in the literature have addressed the relationship of resistin with CRP and TNF-a in CAD. This study investigated the levels of resistin, adiponectin and the inflammatory markers CRP and TNF-a in subjects with CAD or diabetes compared with those of control subjects. We hypothesize that the plasma level of resistin is a marker of vascular inflammation similar to those of CRP and TNF-a. 2. Materials and methods 2.1. Subjects The study includes 58 subjects with well-controlled type 2 diabetes on oral hypoglycemic agents (HbA1C levels <7.0), 57 subjects with known CAD, 45 controls. It is a cross-sectional study. The study was conducted in accordance with the Declaration of Helsinki and was approved by the Regional Scientific Ethics Committee Institutional Review Board. Diagnosis of CAD was based on history of acute myocardial infarction, cardiac catheterization, or gated nuclear medicine imaging studies. Some of the clinical and demographic data of subjects, obtained on clinical evaluation, along with lipid parameters are given in Table 1. The clinical details include blood pressure, height, weight, BMI, measurement of waist circumference, smoking, alcohol use and family history of diabetes. Exclusion criteria included subjects with known diseases associated with disordered glucose metabolism, such as Cushing’s disease, acromegaly, pheochromocytoma, chronic pancreatitis, pancreatectomy, dumping syndrome, sub-optimally treated thyroid disease, or those currently pregnant; subjects on medications that alter glucose metabolism, including glucocorticoids, pentamidine, nicotinic acid, diazoxide, b-adrenergic agonists, thiazides, dilantin,

interferon-a, retroviral agents and anti-neoplasic agents; and subjects with chronic kidney disease. 2.2. Collection of samples Blood samples are obtained in the morning after an overnight fast (10 h). For each subject, a basal metabolic panel, HbA1C and lipid panel were analyzed in the central chemistry laboratory. Plasma from the venous blood samples drawn for insulin, CRP, TNF-a, resistin and adiponectin was stored at 70 C until further analysis. 2.3. Assay methods Levels of total adiponectin, resistin, TNF-a, CRP and insulin were measured in duplicate by the enzyme-linkedimmunosorbent assay (ELISA) using commercially available kits (ALPCO diagnostics, Salem, NH, USA). The sensitivity of the adiponectin assay is 0.234 ng/ml with a range of 0.375–12 ng/ml. Inter- and intra-assay coefficients of variation were 2.8–5.5% and 2.97–3.84%, respectively. The sensitivity of the resistin assay is 0.2 ng/ml. Interand intra-assay coefficients of variation were 4.2–7.2% and 2.8–5.1%, respectively. The sensitivity of the CRP assay is 0.124 ng/ml. Inter- and intra-assay coefficients of variation were 5.5–6% and 11–13%, respectively. The sensitivity of the TNF-a assay is 4.8 pg/ml. Inter- and intra-assay coefficients of variation were ± 0.8% and 4–8.3%, respectively. The sensitivity of the insulin assay is 1 IU/ ml. Inter- and intra-assay coefficients of variation were 2.6–3.6% and 2.8–4%, respectively. The insulin resistance index was calculated from fasting glucose and insulin using the formula of homeostatic model assessment insulin resistance (HOMA-R). HOMA-R = (plasma glucose level · plasma insulin level/22.5). 2.4. Statistical analysis The results are expressed as the means ± SD unless otherwise stated. Comparisons of the mean differences in the biochemical parameters between the controls and CAD and controls and diabetes were performed using Student’s t-test. The relationships between resistin and adiponectin with other parameters were explored using the Pearson’s correlation technique. Statistical significance is defined as a p value <0.05 on two-tailed testing. 3. Results The study population includes 57 subjects with CAD, 58 subjects with type 2 diabetes and 45 controls. Demographic characteristics of the study population are presented in Table 1. Healthy individuals with BMI in a non-obese range and with neither diabetes nor CAD served as controls. Compared with the subjects with diabetes or CAD,

S. Yaturu et al. / Cytokine 34 (2006) 219–223

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Table 1 Clinical characteristics and lipid parameters of subjects in the study Controls (45) Age BMI (kg/m2) Total Cho Triglycerides HDL-C LDL-C HTN % Smoking

CAD (57)

54 ± 13 26 ± 5.8 189 ± 43 113 ± 46 53 ± 18 88 ± 25 68 33 (15)

DM (58)

64 ± 7 31 ± 6 155 ± 27 125 ± 46 42 ± 9.5 87 ± 25 89 54 (31)

64 ± 7 33 ± 9 159 ± 28 134 ± 53 44 ± 10 88 ± 25 98 32 (19)

Controls vs. DM *

5.34E 06 3.31E 05* 6.01E 05* 0.04* 0.001* 0.0001* 3.99E 05* <0.01*

Controls vs. CAD 2.77E 06* 6.22E 05* 4.89E 06* 0.2– 0.0003* 7.84E 05* 0.01* NS

Data are means ± SE; *p 6 0.05 is considered significant; NS, not significant; CAD, coronary artery disease; BMI, basal metabolic index; Total Cho, total cholesterol; HDL-C, HDL-cholesterol; LDL-C, LDL-cholesterol; HTN, hypertension.

Table 2 Biochemical data in subjects with CAD compared to those without CAD

No of subjects IRI Adiponectin (lg/ml) Resistin CRP (mg/l) TNF-a

Controls

CAD

p value

45 13.45 ± 12.73 17.26 ± 10.4 4.9 ± 3.2 2 ± 2.0 3.5 ± 2.4

57 39 ± 32 12.5 ± 4.8 4.1 ± 2.4 3.8 ± 4.03 3.9 ± 2.8

0.0001* 0.0003* 0.13– 0.02* 0.37–

Data are means ± SE; *p 6 0.05 is considered significant; –Not significant; IRI, insulin resistance index; DM, diabetes; CRP, C-reactive protein; TNF-a, tumor necrosis factor alpha.

Table 3 Biochemical data of subjects with diabetes compared to the control subjects

No of Subjects IRI Adiponectin (lg/ml) Resistin CRP (mg/l) TNF-a

Controls

DM

45 13.45 ± 12.73 17.26 ± 10.4 4.9 ± 3.2 2 ± 2.0 3.5 ± 2.4

58 69 ± 19 11.58 ± 4.8 4.6 ± 2.6 4.1 ± 4.8 4.3 ± 2.9

p value 0.000615* 0.00024* 0.627769 0.01* 0.11

Data are means ± SE; *p 6 0.05 is considered significant; IRI, insulin resistance index; DM, diabetes; CRP, C-reactive protein; TNF-a, tumor necrosis factor alpha.

control subjects were 10 years younger, with BMI in a nonobese range, and had higher HDL cholesterol and lower triglyceride levels. The duration of diabetes in the study subjects was 6 ± 4.5 years from the time of diagnosis with HbA1C levels of 6.2 ± 1.5. Decreased adiponectin levels and increased CRP and insulin resistance index (IRI) were noted in subjects with CAD, compared with those of controls, as shown in Table 2. Similarly, we noted decreased adiponectin levels and increased CRP and IRI in subjects with diabetes, compared with those of controls, as shown in Table 3. Fig. 1 illustrates a strong correlation between levels of resistin and those of TNF-a (r = 0.84; p < 0.000001). However, resistin levels did not correlate with the insulin resistance index (r = 0.05; p = 0.60) or BMI (r = 0.13 p = 0.17). The insulin resistance index correlates with BMI (r = 0.26; p < 0.05), CRP (r = 0.32; p = 0.0006), TNF-a (r = 0.29; p = 0.0019), triglycerides (r = 0.20; p = 0.0345) and HDL cholesterol levels (r = 0.28; p = 0.0028). Adiponectin levels correlate positively with HDL cholesterol levels (r = 0.39; p < 0.00001). Levels of CRP correlate negatively with those HDL cholesterol levels (r = 0.20; p = 0.0345) and strongly positively with those of TNF-a (r = 0.847; p < 0.000001) and BMI (r = 0.24; p = 0.01).

Fig. 1. Strong correlation of resistin with the levels of TNF-a.

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4. Discussion There are several interesting findings in our study. Our data are similar to those of other studies showed that adiponectin levels correlate positively with HDL cholesterol levels [29,30] and decreased levels seen in subjects with CAD [31] and DM [20,32–34]. In addition, we found that CRP and TNF-a levels correlate with insulin levels (r = 0.33, p = 0.0005; r = 0.30, p < 0.001) and insulin resistance index. It is currently established that central obesity is a contributing factor to the pathogenesis of insulin resistance and consequently to type 2 diabetes. Our data are consist with these observations with IRI in that BMI correlates with IRI and CRP [35] levels. In our study, insulin resistance is associated with obesity (BMI) and dyslipidemia, components of metabolic syndrome—as well as the inflammatory markers (CRP and TNF-a) that are associated with diabetes and CAD. In our study, adiponectin levels do not correlate with glucose or insulin levels, in contrast to other studies [20]. Resistin levels in subjects with diabetes or CAD were similar to the control subjects. There are varied observations of resistin levels in relation to obesity. Similarly, the literature indicates inconsistent results in studying levels of resistin in diabetes [36,37]. As discussed in detail in a review [37], human studies indicate that suppression of resistin expression may contribute to the insulin-sensitizing and glucose-lowering actions of the thiazolidinediones. Resistin levels in our study correlate strongly with TNF-a and CRP, even with BMI as a covariate (p = 0.005). Our data support the hypothesis and data of Lehrke et al. that inflammation is a hyperresistinemic state and that cytokine induction of resistin may contribute to insulin resistance in obesity and other inflammatory states [38]. The potential anti-inflammatory effects of TZDs on adipocytokine mediation may result in the insulin-sensitizing and glucose-lowering actions of the TZDs. Our data are in contrast to the findings of Burnett, which showed increased levels of resistin in subjects with premature CAD [39], and to those of Kougias and co-workers, whose porcine vascular studies showed that resistin can cause endothelial dysfunction in porcine coronary arteries through oxidative stress and down-regulation of eNOS, thus possibly directly contributing to vascular disease [40]. Resistin has been shown to promote endothelial cell activation and had been linked to cardiovascular disease in the metabolic syndrome [14]. Plasma levels of resistin in association with CRP and TNF-a suggest a role for resistin as a possible surrogate marker of inflammation. Subjects with either CAD or diabetes have decreased levels of adiponectin as well as increased levels of CRP and TNF-a levels indicating both being subclinical inflammatory states. Subjects with CAD as well as subjects with diabetes have significantly decreased levels of adiponectin compared with the controls, as shown in Tables 2 and 3. The limitation in this study is that the study population is small.

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