Serum resistin in acute myocardial infarction patients with and without diabetes mellitus

The Egyptian Heart Journal (2012) 64, 27–33

Egyptian Society of Cardiology

The Egyptian Heart Journal www.elsevier.com/locate/ehj www.sciencedirect.com

ORIGINAL ARTICLE

Serum resistin in acute myocardial infarction patients with and without diabetes mellitus Hesham H. Ibrahim a b c

a,*

, Tarek E. Korah b, Eman A.E. Badr c, Maathir K. Elshafie

c

Department of Cardiology, Faculty of Medicine, Menoufiya University, Egypt Department of Internal Medicine, Faculty of Medicine, Menoufiya University, Egypt Department of Medical Biochemistry, Faculty of Medicine, Menoufiya University, Egypt

Received 2 February 2011; accepted 16 March 2011 Available online 14 October 2011

KEYWORDS Resistin; Acute myocardial infarction; Diabetes mellitus

Abstract Aim: Human resistin is an adipokine, which has been suggested to be an inflammatory marker, with possible links to atherosclerosis and coronary heart disease. Meanwhile, the relationship between serum resistin, insulin resistance, and type 2 diabetes mellitus (T2DM) is still controversial. Therefore, this study aimed to assess serum resistin in patients with acute ST-segment elevation myocardial infarction (STEMI), with and without T2DM. Patients and methods: A total of 55 subjects included in this study, were categorized into three groups: 20 non-diabetic patients with acute STEMI (group I), 20 diabetic patients with acute STEMI (group II), and 15 healthy age and gender-matched controls (group III). Levels of serum lipids, fasting blood glucose (FBG), insulin, troponin I, creatine kinase (CK), lactate dehydrogenase (LDH), and resistin, were estimated. Results: Serum total cholesterol, low density lipoprotein cholesterol (LDLc), FBG, troponin I, CK (total and MB), LDH, and resistin, were significantly higher in group II, than in group I and group III (p < 0.05). In group II, serum resistin was positively correlated with serum troponin I and TG (r = 0.59, p < 0.05 and r = 0.47, p < 0.05, respectively), but was negatively correlated with high density lipoprotein cholesterol (HDLc) (r = 0.46, p > 0.05). However, in this patients’ group, serum resistin was not correlated with age, gender, body mass index (BMI), total cholesterol, FBG, insulin, CK, LDH, and the calculated homeostasis model for insulin resistance (HOMA-

* Corresponding author. E-mail address: [email protected] (H.H. Ibrahim). 1110-2608 ª 2011 Egyptian Society of Cardiology. Production and hosting by Elsevier B.V. All rights reserved. Peer review under responsibility of Egyptian Society of Cardiology. doi:10.1016/j.ehj.2011.08.036

Production and hosting by Elsevier

28

H.H. Ibrahim et al. IR) (p > 0.05). As regards group I, serum resistin was not correlated to any of these studied parameters (p > 0.05). Conclusion: Serum resistin levels are elevated in patients with acute STEMI. This increase is more evident in patients with T2DM than those without T2DM, denoting higher degrees of inflammation. However, serum resistin is not correlated with age, gender, BMI, and insulin resistance. These data denote that serum resistin concentration might be used as a diagnostic biomarker for acute STEMI. In addition, optimization of the treatment of T2DM could improve cardioprotection. ª 2011 Egyptian Society of Cardiology. Production and hosting by Elsevier B.V. All rights reserved.

1. Introduction In humans, studies suggest that monocytes and macrophages produce large quantities of resistin, but rather very little resistin is expressed in adipocytes.1,2 Human resistin (12.5 kDa) is an adipokine which belongs to a family of small cysteine-rich secretory proteins, named FIZZ (found in inflammatory zone) or resistin-like molecules.3 Resistin has been suggested to be an inflammatory marker in humans, because macrophages are known inflammatory modulators. This suggests a possible link between resistin and cardiovascular (CV) disease via pro-inflammatory pathways.4,5 A number of studies show that the resistin may be involved in promoting atherosclerosis.6,7 The risk of developing atherosclerotic CV disease is known to be 2–4-fold higher in patients with type 2 diabetes mellitus (T2DM) than in non-diabetic subjects.8 Chronic sub-clinical inflammation has been identified as an important mechanism in the pathogenesis of T2DM and associated CV complications.9 However, several human studies have not shown differences in the resistin expression between normal, insulin-resistant, or patients with T2DM.10–12 Thus, the role of resistin in human diabetes remains controversial. Therefore, the aim of our study was to evaluate serum resistin in patients with acute myocardial infarction (MI), with and without T2DM. Moreover, our aim was to correlate serum resistin with clinical and biochemical markers. 2. Patients and methods This study was carried out among the departments of Cardiology, Internal Medicine, and Medical Biochemistry, Faculty of Medicine, Menofiya University, on 55 subjects categorized into three groups: Group I: included 20 patients with acute ST segment elevation myocardial infarction (STEMI) without diabetes mellitus (14 males and 6 females) with a mean age of 61.4 ± 7.08 years. Group II: included 20 patients with acute STEMI with diabetes mellitus (13 males and 7 females) with a mean age of 62.1 ± 6.49 years. Group III: included 15 healthy subjects (10 males and 5 females), matched for age and gender, with a mean age of 58.67 ± 5.58 years, as control group. All controls had no history of CV disease (including all categories of CHD and stroke). Exclusion criteria include all patients who had acute nonST segment elevation myocardial infarction (NSTEMI); valvu-

lar heart disease; heart failure; hepatic or renal dysfunction; evidence of active infective, or neoplastic conditions; chronic inflammatory diseases (including rheumatoid arthritis, osteoarthritis, inflammatory bowel disease); major surgery or trauma,; type 1 DM; or those who were taking thiazolidinediones (TZD) or insulin. Insulin was considered to be the main inhibitor of resistin, and TZD effect on resistin via PPAr-c (peroxisome proliferator activated receptor-c).13 Criteria for the diagnosis of acute STEMI were based on the European Society of Cardiology/American College of Cardiology’s redefinition of MI guidelines.14 Participants were classified as having T2DM if they were taking oral antidiabetic medication (mainly metformin, glimepiride, and/or glibenclamide, in this study), or if they met 2009 American Diabetes Association criteria for the diagnosis of DM.15 All individuals were subjected to full history taking, clinical examination, anthropometric measurement of weight and height with the estimation of body mass index (BMI), and laboratory investigations including: serum lipid profile, troponin I, total creatine kinase (CK), CK-MB, lactate dehydrogenase enzyme (LDH), serum resistin, fasting blood glucose (FBG), fasting insulin level, and calculation of homeostasis model assessment for insulin resistance (HOMA-IR) according to: HOMA-IR = fasting glucose (mg/dl) · fasting insulin (lIU/ ml)/405.16 2.1. Sample collection and assay After taking consent of all studied subjects, 10 ml of fasting venous blood were withdrawn from all subjects (patients with an attack of acute MI within 6 h of the appearance of symptoms, and controls). One milliliter of venous blood was transferred slowly into a tube with fluoride, and centrifuged for 10 min. The clear supernatant was separated in aliquots, kept frozen at 20 C, till the colorimetric measurement of FBG.17 The rest of venous blood was transferred slowly into a plain tube, allowed to clot, and then centrifuged for 10 min. The clear supernatant was separated in several aliquots, kept frozen at 20 C, till the analysis of the following: Quantitative determination of total creatine kinase (CK) and CKMB levels in the serum using commercial kit was supplied by Biosystem Spain.18 Determination of LDH activity was done by measuring the rate of NADH consumption spectrophotometrically which is proportional to the LDH activity.19 Determination of total cholesterol and triacylglycerides (TG) was done using colorimetric enzymatic method.20 HDLc was measured by the precipitation of chylomicrons, VLDL, and LDL by adding phosphotungstic acid and magnesium ions to the samples. Centrifugation leaves only the HDL in the

Serum resistin in acute myocardial infarction patients with and without diabetes mellitus supernatant, their cholesterol content is determined enzymatically. LDLc was calculated if TG <400 mg/dl by the formula of Friedewald et al.21 Enzyme linked immunosorbant assay (ELISA) was used for the quantitative determination of serum troponin I22 and insulin.23 Resistin assay, using ELISA for the quantitative determination of resistin hormone was supplied by Ray Biotech. Inc.24 This method of assay employs an antibody specific for the human resistin coated on a well plate. 2.2. Statistical analysis Data were statistically analyzed by SPSS version 11. All data were presented as a mean ± SD. Statistical differences between data of the two main patients’ groups, and the control group, were determined according to F-test. Qualitative data were expressed as numbers and percentage and analyzed by v2-test. Correlation between the variables was performed by spearman correlation coefficient. p values were significant if <0.05. 3. Results There was no significant difference in age, gender, and BMI, among the studied groups (p > 0.05) (Table 1). Significantly higher levels of serum total cholesterol, TG, LDLc, FBG, insulin, troponin I, total CK (total and MB), LDH, resistin, as well as calculated HOMA-IR, and significantly lower levels of HDLc, in group II than in group I and group III (p < 0.001).were observed. However, there was no significant difference between serum TG, FBG, insulin, and calculated HOMA-IR, between group I and group II (p > 0.05) (Table 2). There was a significantly positive correlation between the serum resistin level in group II, and each of serum TG, troponin I, whereas, there was a significantly negative correlation with HDLc (r = 0.59, p < 0.05; r = 0.47, p < 0.05; and r = 0.46, p > 0.05, respectively). In this group, serum resistin levels had no significant correlation with all other parameters, i.e. age, gender, BMI, total cholesterol, FBG, insulin, CK, LDH, and calculated HOMA-IR. On the other hand, as regards group I, there was no significant correlation between serum resistin and any of these studied parameters (Table 3). 4. Discussion Resistin appears to be derived from different sources in humans and animals. Reports point to monocytes and macro-

Table 1

29

phages as the main sources of resistin in humans, whereas, adipocytes are the main source in animals.25,26 In humans, the relationship between resistin and coronary artery disease (CAD) has been controversial.27 In our study, we found that the serum resistin levels were significantly increased in the patients presented with acute STEMI, when compared with controls. These results were in agreement with similar studies done in patients with acute MI.28,29 In line with our results, other reports have similarly reported increased serum resistin levels in patients with CAD. Reilly et al.30 discovered that the circulating resistin level was independently associated with coronary artery calcification (CAC), a quantitative index of atherosclerosis. Also, Burnett et al.,6 reported that the serum resistin levels of premature coronary artery diseased (PCAD) patients were higher than normal controls. However, serum resistin levels in our study were different from the levels found in the last two studies. These differences could be due to a number of potential explanations. These two studies examined an earlier stage of disease, i.e. CAC,30 or angiographically proven PCAD,6 whereas we have measured resistin in the survivors of myocardial infarction, so, it is possible that differences in resistin are found only early in the course of disease or that those with the highest resistin levels are dying from their disease and are not represented in our study. It is also possible that differences in the resistin levels exist between different ethnic groups. Reilly et al.,30 reported that median resistin levels in a predominantly Caucasian population to be 5 ng/ml. Median resistin levels in patients with PCAD in Caucasians and African-Americans (using the assay used in this study) were 9 ng/ml, whereas the median value obtained in this study (2.8 in controls) is much lower and similar to a previous study in American Indians.31 These observed differences in serum resistin levels may reflect the impact of genetic or environmental factors on resistin expression. It is known that inflammation and endothelial dysfunction play a critical role in plaque destabilization and vulnerability. It has been suggested that resistin may mediate partly its proatherosclerotic properties by influencing the systemic inflammation. Resistin contributes to atherosclerosis partly by modulating the endothelial function and inciting endothelial activation.27 Compared with patients who had chronic stable angina, patients with ACS had coronary plaques with more extensive macrophage-rich areas, which was the major source of resistin. Inflammatory responses stimulated resistin secretion,32,33 and resistin could also promote production of pro-inflammatory mediators such as interleukin-6 (IL-6), tumor necrosis factor-

Demographic data for all studied groups.

Studied groups

Age (year)

BMI

Gender Male

Female

Mean ± SD

Mean ± SD

No

%

No

%

Group I (n = 20) Group II (n = 20) Group III (n = 15)

61.4 ± 7.08 62.1 ± 6.49 62.67 ± 3.87

22.7 ± 0.84 23.43 ± 5.15 21.93 ± 0.96

14 13 10

70 65 66.6

6 7 5

30 35 33.3

Test of significance p value

F-test (0.19) >0.05

F-test (1.38) >0.05

v2 >0.05

30 Table 2

H.H. Ibrahim et al. Comparison of biochemical parameters among the studied groups.

Parameters

Group I (n = 20)

Group II (n = 20)

Group III (n = 15)

Test of significance

Mean ± SD Total cholesterol (mg/dl)

203.5 ± 10.69

Mean ± SD

Mean ± SD

F-test

210.3 ± 9.91

171.53 ± 9.17

Triglycerides (mg/dl)

110 ± 5.44

166 ± 16.01

92 ± 5.3

242.89

HDLc (mg/dl)

37.9 ± 1.33

31.8 ± 1.36

48.6 ± 1.5

629.22

LDLc (mg/dl)

143.6 ± 9.89

145.7 ± 10.97

104.6 ± 8.1

90.02

Fasting blood glucose (mg/dl)

101.15 ± 3.51

194.45 ± 9.71

82.07 ± 5.38

1434.29

Fasting insulin (lIU/ml)

3.87 ± 0.18

20.97 ± 2.97

4.21 ± 0.58

550.88

HOMA-IR

0.89 ± 0.04

10.05 ± 1.51

0.82 ± 0.11

641.65

Troponin I (lg/l)

12.85 ± 1.06

18.08 ± 1.84

0.09 ± 0.01

865.87

CK (Total) (IU/ml)

2000.8 ± 14.63

2226.45 ± 659.31

90.73 ± 5.84

142.06

CK (MB) (IU/ml)

131.05 ± 30.14

136.2 ± 8.21±

21.27±2.25

181.96

LDH (IU/l)

536.1 ± 28.06

551.95 ± 26.38

180.07 ± 10.02

1271.36

Resistin (ng/ml)

10.07 ± 0.26

17.11 ± 0.67

5.47 ± 0.81

1658.65

70.34

p value

P1 < 0.05* P2 < 0.001* P3 < 0.001* P1 < 0.001* P2 > 0.05NS P3 < 0.001* P1 < 0.001* P2 < 0.001* P3 < 0.001* P1 > 0.05NS P2 < 0.001* P3 < 0.001* P1 < 0.001* P2 > 0.05NS P3 < 0.001* P1 < 0.001* P2 > 0.05NS P3 < 0.001* P1 < 0.001* P2 > 0.05NS P3 < 0.001* P1 < 0.001* P2 < 0.001* P3 < 0.001* P1 < 0.05* P2 < 0.001* P3 < 0.001* P1 < 0.001* P2 < 0.001* P3 < 0.001* P1 < 0.05* P2 < 0.001 * P3 < 0.001* P1 < 0.001* P2 < 0.001* P3 < 0.001*

HDLc, high density lipoprotein cholesterol; LDLc, low density lipoprotein cholesterol; HOMA-IR, homeostasis model assessment for insulin resistance; CK, creatine kinase; LDH, lactic acid dehydrogenase; P1, the difference between group I and group II; P2, the difference between group I and group III; P3, the difference between group II and group III; NS, non-significant. * Significant.

a (TNF-a), IL-12, hence aggravate the pro-inflammatory response. On the other hand resistin could also affect the functions of vascular cells, activate endothelial cells, up-regulate the expression ET-1, adhesion molecules and chemokines, induce matrix metalloproteinases expression,34 increase CD40 ligand signaling by down-regulating the TNF receptorassociated factor-3. These pro-inflammatory mediators have already been implicated in plaque instability. In addition, resistin could also promote lipid accumulation in macrophages.35 Collectively, the above observations suggest that resistin may have a role in accelerating atherosclerosis, and acts as a destabilizing agent contributing to the occurrence of ACS. Regarding serum troponin, we found that, serum troponin I levels were significantly higher (like serum resistin) in patients with STEMI with DM than those without DM. This is compatible with the results of Macı´ n et al. study.36 Troponins are known cardio specific contractile proteins that have high sensitivity and specificity for the detection of myocardial dam-

age.37,38 The increase of cardiac troponins is associated with more frequent thrombosis, and impairment of myocardial tissue perfusion.39 Patients with hyperglycemia more often suffer greater impairment of the cardiac muscle, increased release of markers of myocardial necrosis, and more severe coronary diseases.40,41 Actually, the presence of DM is associated with similar risk to that of previous MI.42 Moreover, elevated serum glucose concentrations have been independently associated with negative outcome in those patients.43,44 In human studies, the relationships of circulating resistin to BMI, insulin sensitivity, and T2DM had been inconsistent.45,46 In our work, we found that plasma concentrations of resistin were not associated with BMI, insulin resistance, parameters of glucose, and lipid metabolism, which indicates that the effect of resistin is independent of BMI and glycemic and lipid metabolism. This is in accordance with other previous studies. 47,48 In contrast to our work, Mikako et al.,49 found a weak correlation between serum resistin and BMI. Also, Silha

Serum resistin in acute myocardial infarction patients with and without diabetes mellitus Table 3

31

Correlation between serum resistin and various parameters in group I and group II. Serum resistin (ng/ml) Group I

Group II

Correlation coefficient (r) p value Correlation coefficient (r) p value Age (years) Gender BMI Total cholesterol (mg/dl) Triglycerides (mg/dl) HDLc (mg/dl) LDLc (mg/dl) Fasting blood glucose (mg/dl) Fasting insulin (lIU/ml) HOMA-IR Troponin I (lg/l) CK (total) (IU/ml) CK (MB) (IU/ml) LDH (IU/l) *

0.0 0.12 0.24 0.12 0.19 0.34 0.05 0.33 0.06 0.39 0.09 0.1 0.05 0.34

>0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05 >0.05

0.37 0.09 0.33 0.22 0.59 0.46 0.0 0.03 0.22 0.15 0.47 0.02 0.31 0.17

>0.05 >0.05 >0.05 >0.05 <0.05* <0.05* >0.05 >0.05 >0.05 >0.05 <0.05* >0.05 >0.05 >0.05

Significant.

et al.,50 reported that resistin concentrations were not correlated with BMI, although the concentrations were correlated significantly with HOMA-IR. On the other hand, in vivo human analysis of the relationship between serum resistin and glucose has produced conflicting results.51,52 No correlations were identified in serum resistin and glucose among non-obese, obese, and obese T2DM subjects by examining the glucose disposal rate during a hyperinsulinemic glucose clamp across groups.51 Moreover, Azuma et al. reported no significant correlation in serum resistin and glucose with cross-sectional analysis; but longitudinal analysis in the same cohort revealed changes in serum resistin to be positively correlated with glucose as well as other factors such as BMI, and insulin.52 Hence, these studies may suggest that cross-sectional analysis of serum resistin may also be inadequate to determine correlations. Further, the specificity of the resistin ELISA assay emerges as an important factor in these and other studies; to date, however, only one commercial ELISA appears to have been validated for cross reactivity with different members of the resistin-like molecules (RELM) family and this may affect the findings in other studies.48 Acute hyperglycemia is a phenomenon commonly seen in patients presented with acute myocardial infarction even when they have never been previously diagnosed with diabetes.44 Close interrelation between glucose metabolism and inflammation has been shown in several studies. Chronic inflammation is involved in an early process in the pathogenesis of diabetes,53 and, conversely, high levels of blood glucose, even in levels within the normal range, promote inflammation in the vascular cells.54 5. Conclusion Patients with acute STEMI, have significantly higher serum resistin levels (similar to the increased serum troponin I), compared with controls. The levels of resistin (and troponin I) are much higher in patients with, than those without T2DM, denoting higher degrees of inflammation. Moreover, serum resistin is correlated with serum troponin I and TG, in patients

with, but not in those without, T2DM. However, it is not correlated with age, gender, BMI, and insulin resistance. Clinical implications of our study include: first, serum resistin might play a role as a diagnostic biomarker for acute STEMI in patients with or without T2DM. Second, early diagnosis and treatment of DM are important, since optimization of the treatment for DM could improve cardioprotection,55 and may further improve future morbidity and mortality in these patients. References 1. Yang RZ, Huang Q, Xu A, McLenithan JC, Eisen JA, Shuldiner AR, et al Comparative studies of resistin expression and phylogenomics in human and mouse. Biochem Biophys Res Commun 2003;310(3):927–35. 2. Savage DB, Sewter CP, Klenk ES, Segal DG, Vidal-Puig A, Considine RV, et al Resistin/Fizz3 expression in obesity and peroxisome proliferator-activated receptor c in humans. Diabetes 2001;50:2199–202. 3. Muse ED, Lam TK, Scherer PE, Rossetti L. Hypothalamic resistin induces hepatic insulin resistance. J Clin Invest 2007;117(6):1670–8. 4. Bokarewa M, Nagaev I, Dahlberg L, Smith U, Tarkowski A. Resistin, an adipokine with potent proinflammatory properties. J Immunol 2005;174(9):5789–95. 5. Verma S, Li SH, Wang CH, Fedak PWM, Li RK, Weisel RD, et al Resistin promotes endothelial cell activation: further evidence of adipokine–endothelial interactions. Circulation 2003;108:736–40. 6. Burnett MS, Lee CW, Kinnaird TD, Stabile E, Durrani S, Dullum MK, et al The potential role of resistin in atherogenesis. Atherosclerosis 2005;182:241–8. 7. Jung HS, Park KH, Cho YM, Chung SS, Cho HJ, Cho SY, et al Resistin is secreted from macrophages in atheromas and promotes atherosclerosis. Cardiovasc Res 2006;69:76–85. 8. On YK, Park HK, Hyon MS, Jeon ES. Serum resistin as a biological marker for coronary artery disease and restenosis in type 2 diabetic patients. Circ J 2007;71:868–73. 9. Pickup JC. Inflammation and activated innate immunity in the pathogenesis of type 2 diabetes. Diabetes Care 2004;27:813–23.

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