Insulin resistance in nondiabetic patients with acute myocardial infarction

Cardiovascular Revascularization Medicine 7 (2006) 54 – 60

Insulin resistance in nondiabetic patients with acute myocardial infarction Kazuaki Nishioa,4, Meiei Shigemitsua, Taro Kusuyamaa, Tomoyasu Fukuib, Kitaro Kawamuraa, Seiji Itoha, Noburu Konnoa, Takashi Katagiria a

The Third Department of Internal Medicine, School of Medicine, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan The First Department of Internal Medicine, School of Medicine, Showa University, 1-5-8 Hatanodai, Shinagawa-ku, Tokyo 142-8666, Japan

b

Received 8 November 2005; received in revised form 5 December 2005; accepted 5 December 2005

Abstract

Background: Recent studies have shown that insulin resistance (IR) is an independent predictor of early restenosis after coronary stenting. The aim of this study was to examine the effects of IR and its linkage to late loss with bare metal stenting in nondiabetic patients with acute myocardial infarction (AMI). Materials and Methods: We enrolled 61 nondiabetic patients with AMI who have undergone coronary stenting. Quantitative analyses of coronary angiographic data before and after the procedure and at 4 months were performed. Fasting plasma glucose (FPG) and insulin were measured every week until the subjects’ hospital discharge. Stress hormones, endothelial nitric oxide synthase, tumor necrosis factor a, interleukin-6, leptin, and adiponectin were measured on admission and at 4 months after coronary stenting. Results: Simple linear regression analyses showed a relationship between FPG and insulin [IR group: r=0.297, P=.0428; no insulin resistance (NIR) group: r=0.539, P=.0466] and that late loss was associated with the homeostasis model assessment of IR (HOMA-IR) at 4 months (r=0.435, P=.03). At multiple regression analyses, HOMA-IR on admission in the IR group significantly correlated with thyroid-stimulating hormone, glucagon, and cortisol. The HOMA-IR at 4 months correlated with leptin. Conclusions: Nondiabetic patients with AMI can be classified into two groups: the IR group and the NIR group. The IR consisted of the transient IR, which correlated with stress hormones, and the continuous IR, which correlated with leptin and contributed to restenosis after coronary stenting. D 2006 Elsevier Inc. All rights reserved.

Keywords:

Acute myocardial infarction; eNOS; Insulin resistance; Leptin; Stress hormones

1. Introduction The evidence that high blood glucose on admission predicts in-hospital mortality after acute myocardial infarction (AMI) are strong [1–4]. Concentrations of cortisol, adrenaline, and noradrenaline are the main determinants of plasma glucose concentration measured in nondiabetic patients when admitted to a hospital after experiencing AMI [1]. The plasma insulin concentration is positively 4 Corresponding author. Heights Matsugaoka 202, 4105 Katsuyama, Fijikawaguchiko-machi, Minamitsuru-gun, Yamanashi 401-0310, Japan. Tel.: +81 555 72 2764; fax: +81 555 72 2764. E-mail address: [email protected] (K. Nishio). 1553-8389/06/$ – see front matter D 2006 Elsevier Inc. All rights reserved. doi:10.1016/j.carrev.2005.12.004

correlated with the admission glucose concentration in patients with AMI [5]. It has been reported that hyperinsulinemia is an independent risk factor for ischemic heart disease [6]. Insulin resistance with hyperinsulinemia is associated with hypertension, glucose intolerance, obesity, and dyslipoproteinemias of low high-density lipoprotein cholesterol (HDL-C) levels or hypertriglyceridemias, which are wellknown risk factors for coronary artery disease [7,8]. Recent studies have shown that IR is an independent predictor of early restenosis after coronary stenting [9] and is associated with an increased incidence of myocardial infarction and death [10]. However, IR in patients with AMI is unclear.

K. Nishio et al. / Cardiovascular Revascularization Medicine 7 (2006) 54 – 60

The aim of this study was to examine the effects of IR and its linkage to late loss with bare metal stenting in nondiabetic patients with AMI.

2. Methodology

55

immediately after the intervention and at follow-up. Quantitative analyses of all angiographic data before and after the procedure were performed. The luminal diameter of the coronary artery and the degree of stenosis were measured before dilation, at the end of the procedure, and at 4 months. Restenosis was defined as stenosis of 50% or more of the luminal diameter.

2.1. Protocol We enrolled 61 nondiabetic patients admitted to our institution for AMI. The study population consisted of patients in whom intracoronary stents were successfully placed after primary percutaneous transluminal coronary angioplasty (PTCA) at our institution. The indications for stenting were extensive coronary artery dissection after PTCA, complete vessel closure, and residual stenosis of 25% or more of the vessel diameter. Patients were not eligible for enrollment if they had chronic heart failure [11]; cardiac shock [12]; impaired glucose tolerance; diabetes mellitus (DM); hepatic dysfunction; or endocrine disorders of the growth hormone, thyroid, adrenal gland, and glucagon. All patients gave their written informed consent to participate in the study. The study was carried out according to the principles of the Declaration of Helsinki and was approved by our institutional ethics committee. All patients were Japanese living in the same area [13]. Patients were evaluated at 4 months after stent implantation by an angiographic study and laboratory studies. 2.1.1. Quantitative coronary angiographic evaluation Coronary angiograms were obtained in multiple views after the intracoronary injection of nitrates. Matched views were selected for angiograms recorded before and

2.1.2. Laboratory studies We measured the subjects’ concentrations of overnight fasting plasma glucose (FPG), total cholesterol, HDL-C, triglycerides, insulin, glycosylated hemoglobin (HbA1c), and plasma hormones [growth hormone, thyroid-stimulating hormone (TSH), free triiodothyronine (FT3), free thyroxine (FT4), catecholamines, cortisol, and glucagon] on admission. We measured concentrations of FPG and insulin every week until the subjects’ hospital discharge. A standardized oral glucose tolerance test with 75 g of glucose was taken, and concentrations of FPG, insulin, HbA1c, and plasma hormones were measured at 4 months after PTCA [14]. An estimate of IR was calculated using the homeostasis model assessment of IR (HOMA-IR) as follows: IR=FPG (mg/dl)  fasting plasma insulin (AU/ml)/405 [15]. Low-density lipoprotein cholesterol concentrations were estimated with the equation of Friedewald et al. [16]. Catecholamines (adrenaline, noradrenaline, and dopamine) were determined using high-performance liquid chromatography with electrochemical detection. Cortisol was estimated by radioimmunoassay using a commercial kit (Amerlex, Amersham International, Buckinghamshire, UK). The TSH, FT3, and FT4 were estimated by radioimmunoassay using a commercial kit (Electrochemiluminescence immunoassay Roche Diagnostics, Mannheim, Germany).

Fig. 1. The relationship between FPG and insulin.

56

K. Nishio et al. / Cardiovascular Revascularization Medicine 7 (2006) 54 – 60

Fig. 2. The change of HOMA-IR with the passage of time.

Growth hormone and glucagon were estimated by radioimmunoassay using a commercial kit (Radioimmunoassay, Daiichi Radioisotope Labs, Tokyo, Japan). Endothelial nitric oxide synthase (eNOS) and leptin were measured with ELISA kits (R&D Systems, Minneapolis, MN, USA). In addition, because studies have also implicated several adipocyte-derived hormones [tumor necrosis factor a (TNFa) [17], interleukin-6 (IL-6) [18], and adiponectin [19]] in causing IR, we also measured the plasma concentrations of these factors. We have demonstrated that the cutoff value of HOMA-IR for restenosis after coronary stenting is 2.0 (In Press, Intern J Cardiol). Insulin resistance was defined as HOMA-IR of not less than 2.0 whereas no insulin resistance (NIR) was as that of less than 2.0 on admission. We defined normal glucose tolerance according to the World Health Organization definition from 1998 [20]. Normal glucose tolerance was defined as FPG less than 6.1 mmol/l and 2-h blood glucose was as less than 7.8 mmol/l. We defined AMI according to criteria jointly recommended by the European Society of Cardiology and the American College of Cardiology [21,22]. Patients were diagnosed as having an AMI if they had two values of serum troponin T greater than 0.0027 nmol/l (0.1 ng/ml) or CK-MB greater than 0.0875 nmol/l (7 ng/ml), together with typical symptoms (chest pain of N15 min; pulmonary edema in the absence of valvular heart disease; cardiogenic shock; arrhythmias such as ventricular fibrillation and ventricular tachycardia), new Q waves in at least 2 of the 12 standard electrocardiographic leads, or electrocardiogram changes indicating acute ischemia (ST elevation, ST depression, or T-wave inversion).

2.1.3. Statistical analysis Results are expressed as mean valueFS.D. or as n (%). Student’s t test was used for parametric data when normal distribution and equal dispersion were recognized. The Mann–Whitney U test and the Wilcoxon signed rank test Table 1 Clinical and laboratory characteristics of patients on admission Age (years) Women BMI (kg/m2) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Smoking Hypertension Hyperlipidemia h-blockers ACE inhibitors ARB Statin Glucose (mmol/l) Insulin (pmol/l) HbA1c Insulinogenic index T-CHO (mmol/l) HDL-C (mmol/l) TG (mmol/l) LDL-C (mmol/l) Uric acid (Amol/l)

IR group (n=47)

NIR group (n=14)

P

62.9F11.8 11 (23.4) 23.8F2.9 127.3F21.0

68.8F13.6 3 (21.4) 22.3F2.3 124.8F14.2

.21 N.99 .32 .65

75.3F11.4

73.9F9.6

.7

9 (19) 10 (21.3) 38 (80.9) 9 (19.1) 21 (44.7) 8 (17) 14 (29.8) 7.7F1.5 101F20 5.2F0.4 1.18F0.61 5.18F1.11 1.07F0.25 1.30F0.69 3.50F0.99 345F107

3 (27) 5 (35.7) 11 (78.6) 3 (21.4) 5 (35.7) 2 (14.3) 5 (35.7) 6.7F0.9 25F8 5.3F0.2 1.07F0.56 4.94F1.17 1.03F0.14 1.09F0.37 3.41F1.04 327F83

N.99 .3 N.99 N.99 .55 N.99 .75 .05 b.001 .11 .34 .62 .78 .15 .94 .51

Data are presented as mean valueFS.D. or n (%) of patients. BMI indicates body mass index; ACE, angiotensin converting enzyme; ARB, angiotensin receptor blocker; T-CHO, total cholesterol; TG, triglyceride; LDL-C, low-density lipoprotein cholesterol.

K. Nishio et al. / Cardiovascular Revascularization Medicine 7 (2006) 54 – 60

57

Table 2 Hormone and adipocytokine concentrations of patients On admission

CRP (mg/l) TSH (mU/l) FT3 (pmol/l) FT4 (pmol/l) Glucagon (ng/l) Growth hormone (Ag/l) Adrenaline (pmol/l) Noradrenaline (pmol/l) Dopamine (pmol/l) Cortisol (mmol/l) eNOS (pg/ml) IL-6 (pg/ml) TNFa (pg/ml) Leptin (ng/ml) Adiponectin (Ag/ml)

IR group (n=47)

NIR group (n=14)

P

Total (N=61)

At 4 months (N=61)

P

29F37 1.72F1.40 4.13F1.06 17.9F3.5 106.6F53.3 3.6F4.7 992F730 6035F4551 358F361 828F337 23.3F11.6 34.5F35.1 10.1F20.2 18.3F11.4 7.4F4.0

20F32 1.87F0.76 4.16F0.39 16.4F1.8 131.7F31.7 4.4F6.6 1121F528 7140F3913 416F251 786F295 21.9F11.6 30.9F12.3 4.0F2.1 13.9F4.1 7.6F2.2

.65 .69 .89 .58 .64 .83 .1 .43 .76 .34 .34 .87 .8 .03 .39

27F35 1.76F1.26 4.13F0.92 17.7F3.2 112.5F49.7 3.8F5.1 1020F685 6366F4327 378F322 817F320 22.7F11.5 34.1F33.0 9.4F19.0 17.7F10.8 7.4F3.8

2F4 2.26F2.07 4.00F0.46 16.3F1.4 76.6F25.1 1.3F2.0 123F91 2725F1590 86F44 469F149 23.7F11.0 19.6F14.8 6.3F3.5 13.3F9.2 8.3F4.3

.02 .3 .67 .06 .01 .07 .0003 .01 .009 .0003 .69 .01 .32 .004 .28

Data are presented as mean valueFS.D.

were used when the variance was unequal. Simple linear regression analysis was conducted to take account of the relationship between FPG and HOMA-IR and that between late loss and HOMA-IR. Two-way repeated-measures analysis of variance (ANOVA) and Fisher’s protected least significant difference were used to compare changes with the passage of time in HOMA-IR. Plasma hormones, adipocyte-derived hormones, and C-reactive protein (CRP) were entered into multiple regression analyses to test for their relationship to HOMA-IR on admission and at 4 months after PTCA. Differences in the categorical data (sex, existence of hypertension, DM, hyperlipidemia, etc.) were analyzed by m2 analysis. Differences were considered to be statistically significant when the P values were lower than .05.

3. Results 3.1. Insulin resistance Simple linear regression analyses are shown to take account of the relationship between FPG and insulin in Fig. 1. Two-way repeated-measures ANOVA revealed that there are two significantly different groups among nondiabetic patients with AMI from the point of view of IR. One is an IR group; the other, an NIR group. Fasting plasma glucose was correlated positively with insulin on the first morning after admission in the IR group (r=0.297, P=.0428) and in the NIR group (r=0.539, P=.0466). The HOMA-IR was of the highest value on admission and decreased to a steady state until the second week in the IR group (on admission: 6.0F2.7 vs. 1.1F0.3, P=.006; 1 week: 3.0F1.4 vs. 1.2F0.4, P=.008; 2 weeks: 2.1F0.8 vs. 1.1F0.4, P=.009; 4 months: 2.2F0.9 vs. 1.2F0.4, P=.02) but had no change in the NIR group. The HOMA-IR of the IR group was higher than that of the NIR group until 4 months after PTCA (Fig. 2).

3.2. Clinical and laboratory characteristics The major clinical and laboratory characteristics of the patients on admission are shown in Table 1. There was no significant difference between the two groups for clinical characteristics. The FPG and insulin concentrations of the IR group were higher than those of the NIR group on admission and not significantly different between the two groups at 4 months after PTCA. Concentrations of adrenaline, noradrenaline, dopamine, glucagon, cortisol, and CRP on admission were higher than those at 4 months after PTCA and were not significantly different between the two groups on admission (Table 2). Concentrations of leptin and IL-6 on admission were higher than those at 4 months after PTCA. Concentrations of leptin of the IR group were higher than those of the NIR group on admission (18.3F11.4 ng/ml vs. 13.9F4.1 ng/ml, P=.03) and at 4 months (15.8F10.0 ng/ ml vs. 8.5F4.4 ng/ml, P=.03). Concentrations of leptin on admission were higher than those at 4 months in the IR Table 3 Multiple regression analyses for HOMA-IR on admission in the IR group Regression coefficient CRP TSH FT3 FT4 Glucagon Growth hormone Adrenaline Noradrenaline Dopamine Cortisol IL-6 TNFa Leptin Adiponectin

Coefficient S.E.

t

P

0.517 4.677 7.108 5.288 0.089 0.461

0.369 1.342 3.481 8.536 0.039 0.943

1.4 3.484 2.042 0.62 2.316 0.489

.18 .002 .054 .54 .03 .63

0.017 0.0004 0.0001 0.413 0.011 0.132 0.009 0.118

0.018 0.003 0.0004 0.12 0.025 0.222 0.102 0.241

0.984 0.146 0.353 3.444 0.439 0.594 0.092 0.489

.34 .89 .73 .002 .66 .56 .93 .63

58

K. Nishio et al. / Cardiovascular Revascularization Medicine 7 (2006) 54 – 60

group (18.3F11.4 ng/ml vs. 15.8F10.0 ng/ml, P=.03) and in the NIR group (13.9F4.1 ng/ml vs. 8.5F4.4 ng/ml, P=.03). IL-6 on admission was higher than that at 4 months in the IR group (34.5F35.1 pg/ml vs. 20.0F15.6 pg/ml, P=.02) and in the NIR group (30.9F12.3 pg/ml vs. 18.8F13.6 pg/ml, P=.02). There was no significant difference in TNFa and adiponectin between the IR group and the NIR group. Endothelial nitric oxide synthase on admission was lower than that at 4 months in the IR group (23.3F11.6 pg/ml vs. 27.4F9.2 pg/ml, P=.03). The eNOS of the IR group was higher than that of the NIR group at 4 months (27.4F9.2 pg/ml vs. 15.7F10.4 pg/ml, P=.007). At multiple regression analyses, FPG on admission significantly correlated with FT3 (r= 116, P=.0001), FT4 (r=272, P=.0002), adrenaline (r=0.785, Pb.0001), noradrenaline (r= 0.78, P=.005), dopamine (r=0.007, P=.03), and cortisol (r=2.147, P=.02). Insulin on admission significantly correlated with TSH (r= 9.979, P=.002), glucagon (r=0.188, P=.03), and cortisol (r= 0.733, P=.008). The HOMA-IR on admission in the IR group (Table 3) significantly correlated with TSH (r= 4.677, P=.002), glucagon (r=0.089, P=.03), and cortisol (r= 0.413, P=.002); that at 4 months in the IR group (Table 4) significantly correlated with leptin (r=0.107, P=.04). 3.3. Quantitative coronary angiographic evaluation The quantitative coronary angiographic analysis data are shown in Table 5. Late loss was significantly higher in the IR group than in the NIR group. Simple linear regression analyses showed that late loss was not associated with HOMA-IR on admission (r=0.115, P=.6189) but was with HOMA-IR at 4 months after PTCA (r=0.435, P=.03). All stents were of bare metal, including the PENTA and the ZETA stents (Guidant, Santa Clara, CA, USA), the Express stent (Boston Scientific, ON, Canada), the Duraflex stent (Avantec Vascular, Sunnyvale, CA, USA), and the S670 stent (Medtronic, Minneapolis, MN, USA). Table 4 Multiple regression analyses for HOMA-IR at the 4-month follow-up in the IR group Regression coefficient CRP TSH FT3 FT4 Glucagon Growth hormone Adrenaline Noradrenaline Dopamine Cortisol IL-6 TNFa Leptin Adiponectin

Coefficient S.E.

t

P

0.404 0.279 11.585 4.23 0.002 0.376

6.458 1.066 9.844 24.184 0.014 1.63

0.063 0.262 1.177 0.175 0.138 0.231

.95 .8 .28 .87 .89 .83

0.151 0.006 0.882 0.252 0.121 0.031 0.107 0.664

0.155 0.01 0.458 0.42 0.069 0.051 0.044 0.333

0.971 0.624 1.924 0.6 1.738 0.6 2.453 1.995

.37 .56 .1 .57 .13 .56 .04 .08

Table 5 Angiographic and procedural characteristics of the patients

No. of narrowed coronary arteries One Two Three Lesion-related variables LAD LCX RCA Lesion type A B1 B2 C Procedural variables Stent length (mm) Stent diameter (mm) Final balloon pressure (atm) Quantitative coronary analysis Reference vessel diameter (mm) Minimal luminal diameter (mm) Acute gain (mm) Late loss (mm) Loss index Lesion length (mm)

IR group (n=47)

NIR group (n=14)

P

19 (40.4) 22 (46.8) 6 (12.8)

10 (58.8) 4 (23.5) 3 (17.6)

.19 .09 .62

26 (55.3) 15 (31.9) 6 (12.8)

8 (47.1) 4 (23.5) 5 (29.4)

.56 .52 .12

9 10 20 8

3 5 7 2

(17.6) (29.4) (41.2) (11.8)

.89 .5 .62 .61

17.7F2.6 3.2F0.4 12.1F2.0

16.8F3.6 3.3F0.4 12.8F1.7

.24 .19 .21

3.05F0.50 0.08F0.11 2.98F0.53 1.46F0.89 0.51F0.34 11.5F6.3

3.26F0.42 0.06F0.1 3.20F0.46 0.51F0.79 0.17F0.27 10.9F4.5

.2 .95 .24 .01 .02 .23

(19.1) (21.3) (42.6) (17.0)

Data are presented as n (%) mean valueFS.D. LAD indicates left anterior descending coronary artery; LCX, left circumflex coronary artery; RCA, right coronary artery.

3.4. Major adverse cardiac events Death, Q-wave myocardial infarction, or non-Q-wave myocardial infarction did not occur in either group during a follow-up period. Percutaneous revascularization of the target lesion was performed in 1 patient in the NIR group and in 21 patients in the IR group. Coronary artery bypass grafting was not performed in either group.

4. Discussion This is the first study to elucidate the mechanism of IR in nondiabetic patients with AMI. Our data show that there are two significantly different groups among nondiabetic patients with AMI from the point of view of IR. One is the IR group; the other, the NIR group. In the IR group, HOMA-IR gradually decreased to the steady state until the second week. This transient IR (Area 1: HOMA-IR of N2.0) is dependent on hyperglycemia and hyperinsulinemia and correlated with TSH, glucagon, and cortisol. The HOMA-IR of the IR group is higher than that of the NIR group at 4 months. The continuous IR (Area 2: HOMA-IR of b2.0 and of N1.0) correlated with leptin. The IR in nondiabetic patients with AMI consists of the transient IR and the continuous IR. Hyperglycemia is common in nondiabetic patients presenting with AMI [1,23]. The relationship between

K. Nishio et al. / Cardiovascular Revascularization Medicine 7 (2006) 54 – 60

hyperglycemia and catecholamine concentrations is controversial. Previous studies investigated the interrelations of hyperglycemia on admission to the hospital and hormonal response to stress in patients with AMI but without DM [1,24]. The notion that stress related to myocardial infarction, including the acute stress response involving cortisol and catecholamines, is a major determinant of plasma glucose during AMI [1,14]. Stubbs et al. [25] recently demonstrated that circulating catecholamines were not the main determinants of hyperglycemia and that cortisol is a likely partial cause of the elevation in blood glucose. The present study shows that there is a strong correlation between FPG and catecholamines in the IR group. The difference in the previous studies may be caused by the existence of the NIR group in this study. It is reported that euthyroid sick syndrome exists in AMI [26]. High catecholamine levels are known to cause euthyroid sick syndrome [27]. Euthyroid sick syndrome was not observed in this study. The difference may be that patients in the previous study did not receive PTCA. In the present study, TSH, FT3, and FT4 were not significantly decreased on admission but hyperinsulinemia and HOMAIR correlated with TSH and hyperglycemia correlated with FT3 and FT4. The thyroid hormone metabolism affects IR in nondiabetic patients with AMI. Willerson et al. [28] suggested that glucagon may also contribute to hyperglycemia. The present study shows that glucagon on admission is higher than that at 4 months and that glucagon on admission correlated with insulin and HOMA-IR on admission, but not FPG. Leptin, a hormone related to fat metabolism and IR, has been recognized as an independent risk factor for coronary heart disease in a large cohort of the West of Scotland (West of Scotland Coronary Prevention Study) [29] and promotes vascular remodeling and neointimal tissue proliferation [30]. Several studies suggested that insulin regulates leptin production and that there are strong positive correlations between leptin and insulin concentrations [31,32]. Moreover, recent studies have suggested that leptin enhances the nitric oxide system, which contributes to the glucose uptake in skeletal muscles [33,34]. Endothelial production of nitric oxide plays an important role in preventing vascular disease through regulation of thrombosis, inflammation, vascular tone, and remodeling [35]. The increase in fasting nitric oxide levels, suggesting impairment of endothelial function and cardiovascular disease, has been reported in IR patients [36–39]. Our data suggest that there was endothelial dysfunction in the IR group and that the glucose uptake in skeletal muscles of the IR group may be higher than that of the NIR group and may decrease on admission. The relationship between FPG and HOMA-IR suggests that the difference of HOMA-IR between the IR group and the NIR group is dependent on insulin secretion, as HOMAIR is calculated with FPG and insulin. To assess insulin secretion, we used the insulinogenic index, calculated as the ratio of the increment in the plasma insulin level to that in the

59

plasma glucose level during the first 30 min after the ingestion of glucose. In the present study, plasma hormones and the insulinogenic index did not significantly differ between the IR group and the NIR group. It suggests that there is a glucose-dependent stimulation of insulin secretion. The insulin concentrations are caused by the effect of hyperglycemia in stimulating release. Insulin resistance in the offspring of patients with Type 2 diabetes is caused by dysregulation of intramyocellular fatty acid metabolism, which may be caused by an inherited defect in mitochondrial oxidative phosphorylation [40]. The difference of IR between the IR group and the NIR group may be caused by this impaired mitochondrial activity in skeletal muscles. Recent studies have shown that IR is an independent predictor of early restenosis after coronary stenting [9] and is associated with an increased incidence of myocardial infarction and death [10]. The present study shows that the continuous IR is associated with the increase of the late loss and that the minimal luminal diameter significantly decreased in the IR group. It suggests that endothelial dysfunction owing to the continuous IR affects restenosis after coronary stenting. It is important to treat the continuous IR in nondiabetic patients with AMI. Nondiabetic patients with AMI can be classified into two groups: the IR group and the NIR group. The IR consists of the transient IR, which correlated with TSH, glucagon, and cortisol, and the continuous IR, which correlated with leptin. Hyperleptinemia caused endothelial dysfunction and neointimal tissue proliferation. The continuous IR affects restenosis after coronary stenting. It is important to treat the continuous IR in nondiabetic patients with AMI.

Acknowledgment We are indebted to the 61 study participants whose cooperation made this study possible.

References [1] Oswald G, Smith C, Betteridge J, Yudkin J. Determinants and importance of stress hyperglycemia in non-diabetic patients with myocardial infarction. BMJ 1986;293:917 – 22. [2] O’Sullivan J, Conroy R, Robinson K, Hickey N, Mulcahy R. Inhospital prognosis of patients with fasting hyperglycemia after first myocardial infarction. Diabetes care 1991;14:758 – 60. [3] Bellodi G, Manicardi V, Malvasi V, Veneri L, Bernini G, Bossini P, Distefano S, Magnani L, Rossi G. Hyperglycemia and prognosis of acute myocardial infarction in patients without diabetes mellitus. Am J Cardiol 1989;64:885 – 8. [4] Fava S, Aquilina O, Azzopardi J, Muscat H, Fenech F. The prognostic value of blood glucose in diabetic patients with acute myocardial infarction. Diabetic Med 1996;13:80 – 3. [5] Stubbs PJ, Laycock J, Alaghband-Zadeh J, Carter G, Noble MI. Circulating stress hormone and insulin concentrations in acute coronary syndrome: identification of insulin resistance on admission. Clin Sci 1999;96:589 – 95.

60

K. Nishio et al. / Cardiovascular Revascularization Medicine 7 (2006) 54 – 60

[6] Despres JP, Lamarche B, Mauriege P, Cantin B, Dagenais GR, Moorjani S, Lupien PJ. Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 1996;334:952 – 7. [7] Reaven GM. Banting Lecture 188: Role of insulin resistance in human disease. Diabetes 1988;37:1595 – 607. [8] DeFronzo RA, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care 1991; 14:173 – 94. [9] Piatti PM, Mario CD, Monti LD, Fragasso G, Sgura F, Caumo A, Setola E, Lucotti P, Galluccio E, Ronchi C, Origgi A, Zavaroni I, Margonato A, Colombo A. Association of insulin resistance, hyperleptinemia, and impaired nitric oxide release with in-stent restenosis in patients undergoing coronary stenting. Circulation 2003;108:2074 – 81. [10] Hedblad B, Nilsson P, Engstrfm G, Berglund G, Janzon L. Insulin resistance in non-diabetic subjects is associated with increased incidence of myocardial infarction and death. Diabet Med 2002; 19:470 – 5. [11] Cohn JN, Levine TB, Olivari MT, Garberg V, Luna D, Francis GS, Simon AB, Rector T. Plasma norepinephrine as a guide to prognosis in patients with chronic heart failure. N Engl J Med 1984;311:819 – 23. [12] Jewitt DE, Mercer CL, Reid D, Valori C, Thomas M, Shillingford JP. Free noradrenaline and adrenaline excretion in relation to the development of cardiac arrhythmia and heart-failure in patients with acute myocardial infarction. Lancet 1969;i:635 – 41. [13] Klein DJ, Anderson Friedman L, Harlan WR, Barton BA, Schreiber GB, Cohen RM, Harlan LC, Morrison JA. Obesity and the development of insulin resistance and impaired fasting glucose in Black and White adolescent girls. Diabetes Care 2004;27:378 – 83. [14] Tenerz A, Norhammar A, Silveira A, Hamsten A, Nilsson G, Ryde´n L, Malmberg K. Diabetes, insulin resistance, and metabolic syndrome in patients with acute myocardial infarction without previously known diabetes. Diabetes Care 2003;26:2770 – 6. [15] Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and hcell function from fasting plasma glucose and insulin concentration in man. Diabetologia 1985;28:412 – 9. [16] Friedewald WT, Levy RI, Fredrickson DS. Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 1978;18: 499 – 502. [17] Hotamisligil GS, Shargill NS, Spiegelman BM. Adipose expression of tumor necrosis factor-alpha: direct role in obesity-linked insulin resistance. Science 1993;259:87 – 91. [18] Kern PA, Ranganathan S, Li C, Wood L, Ranganathan G. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab 2001;280:E745 – 51. [19] Yamauchi T, Kamon J, Waki H, Terauchi Y, Kubota N, Hara K, Mori Y, Ide T, Murakami K, Tsuboyama-Kasaoka N, Ezaki O, Akanuma Y, Gavrilova O, Vinson C, Reitman ML, Kagechika H, Shudo K, Yoda M, Nakano Y, Tobe K, Nagai R, Kimura S, Tomita M, Froguel P, Kadowaki T. The fat-derived hormone adiponectin reverses insulin resistance associated with both lipoatrophy and obesity. Nat Med 2001;7:941 – 6. [20] Alberti KGMM, Zimmet P, for the WHO consultation. Definition, diagnosis and classification of diabetes mellitus and its complications: Part 1 Diagnosis and classification of diabetes mellitus—provisional report of a WHO consultation. Diabetic Med 1998;15:539 – 53. [21] Anon. Myocardial infarction redefined: a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction. Eur Heart J 2000;21:1502 – 13. [22] Anon. Myocardial infarction redefined: a consensus document of the Joint European Society of Cardiology/American College of Cardiology

[23] [24]

[25]

[26]

[27] [28]

[29]

[30]

[31]

[32]

[33]

[34]

[35] [36]

[37]

[38]

[39]

[40]

Committee for the Redefinition of Myocardial Infarction. J Am Coll Cardiol 2000;36:959 – 69. Opie LH. Glucose and the metabolism of ischemic myocardial infarction. Lancet 1995;345:1520 – 1. Christenson NJ, Videbak J. Plasma catecholamines and carbohydrate metabolism in patients with acute myocardial infarction. J Clin Invest 1974;54:278 – 86. Stubbs PJ, Laycock J, Alaghband-Zadeh J, Carter G, Noble MI. Circulating stress hormone and insulin concentrations in acute coronary syndromes: identification of insulin resistance on admission. Clin Sci 1999;96:589 – 95. Pavlou HN, Kliridis PA, Panagiotopoulos AA, Goritsas CP, Vassilakos PJ. Euthyroid sick syndrome in acute ischemic syndromes. Angiology 2002;53:699 – 707. Klein I. Thyroid hormone and the cardiovascular system. Am J Med 1990;88:631 – 7. Willerson JT, Hutcheson DR, Leshin SJ, Faloona GR, Unger RH. Serum glucagon and insulin levels and their relationship to blood glucose values in patients with acute myocardial infarction and acute coronary insufficiency. Am J Med 1974;57:747 – 53. Wallace AM, McMahon AD, Packard CJ, Kelly A, Shepherd J, Gaw A, Sattar N. Plasma leptin and the risk of cardiovascular disease in the West of Scotland Coronary Prevention Study (WOSCOPS). Circulation 2001;104:3052 – 6. Sch7fer K, Halle M, Goeschen C, Dellas C, Pynn M, Loskutoff DJ, Konstantinides S. Leptin promotes vascular remodeling and neointimal growth in mice. Arterioscler Thromb Vasc Biol 2004;24:112 – 7. Kolaczynski JW, Nyce MR, Considine RV, Boden G, Nolan JJ, Henry R, Mudaliar SR, Olefsky J, Caro JF. Acute and chronic effects of insulin on leptin production in humans: studies in vivo and in vitro. Diabetes 1996;45:699 – 701. Wabitsch M, Jensen PB, Blum WF, Christoffersen CT, Englaro P, Heinze E, Rascher W, Teller W, Tornqvist H, Hauner H. Insulin and cortisol promote leptin production in cultured human fat cells. Diabetes 1996;45:1435 – 8. Bradley SJ, Kingwell BA, McConell GK. Nitric oxide synthase inhibition reduced leg glucose uptake but not blood flow during dynamic exercise in humans. Diabetes 1999;48:1815 – 21. Shiuchi T, Nakagami H, Iwai M, Takeda Y, Cui T, Chen R, Minokoshi Y, Horiuchi M. Involvement of bradykinin and nitric oxide in leptinmediated glucose uptake in skeletal muscle. Endocrinology 2001; 142:608 – 12. Lusis AJ. Atherosclerosis. Nature 2000;407:233 – 41. Piatti PM, Monti LD, Zavaroni I, Valsecchi G, VanPhan C, Costa S, Conti M, Sandoli EP, Solerte B, Pozza G, Pontiroli AE, Reaven G. Alteration in nitric oxide/cyclic-GMP pathway in nondiabetic siblings of patients with Type 2 diabetes. J Clin Endocrinol Metab 2000; 85:2416 – 20. Zavaroni I, Piatti PM, Monti LD, Gasparini P, Barilli LA, Massironi P, Ardigo D, Valsecchi G, Delsignore R, Reaven GM. Plasma nitric oxide concentrations are elevated in insulin-resistance healthy subjects. Metabolism 2000;49:959 – 61. Balletshofer BM, Rittig K, Enderle MD, Volk A, Maerker E, Jacob S, Matthaei S, Rett K, H7ring HU. Endothelial dysfunction is detectable in young normotensive first-degree relatives of subjects with Type 2 diabetes in association with insulin resistance. Circulation 2000; 101:1780 – 4. Monti LD, Barlassina C, Citterio L, Galluccio E, Berzuini C, Setola E, Valsecchi G, Lucotti P, Pozza G, Bernardinelli L, Piatti P. Endothelial nitric oxide synthase polymorphisms are associated with Type 2 diabetes and the insulin resistance syndrome. Diabetes 2003;52: 1270 – 5. Petersen KF, Dufour S, Befroy D, Garcia R, Shulman GI. Impaired mitochondrial activity in the insulin-resistant offspring of patients with Type 2 diabetes. N Engl J Med 2004;350:664 – 71.