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Insulin resistance and coronary risk factors in Japanese type 2 diabetic patients with definite coronary artery disease
Diabetes Research and Clinical Practice 51 (2001) 181– 186 www.elsevier.com/locate/diabres
Insulin resistance and coronary risk factors in Japanese type 2 diabetic patients with definite coronary artery disease Kazunari Matsumoto *, Yoshihisa Kizaki, Satoki Fukae, Masako Tomihira, Yasunori Sera, Yukitaka Ueki, Tan Tominaga, Seibei Miyake Department of Internal Medicine, Sasebo Chuo Hospital, 15 Yamato-cho, Sasebo, Nagasaki 857 -1195, Japan Received 4 August 2000; accepted 25 September 2000
Abstract Insulin resistance is known as an important risk factor for coronary artery disease (CAD). However, CAD-related mortality in Japanese type 2 diabetics is lower than in Caucasians. To investigate whether insulin resistance is related to CAD in Japanese type 2 diabetics, we measured insulin sensitivity and several coronary risk factors in Japanese patients with type 2 diabetes with and without CAD. Thirty-three patients with definite CAD and 33 age- and sex-matched patients without CAD (control) were studied. Insulin sensitivity was assessed by the K index of insulin tolerance test (KITT). Clinical characteristics, classical risk factors, lipoprotein (a), and insulin sensitivity were compared between the two groups. Patients with CAD had a significantly longer duration of diabetes (9.0 9 1.4 vs. 5.5 90.9 years, P B0.05, respectively), were mostly hypertensive (69.7 vs. 39.4%, P B0.05), and more likely to be treated with insulin (45.5 vs. 18.2%, PB0.05) compared with the control. Concerning the metabolic parameters, patients with CAD had a significantly higher insulin resistance than control (2.40 9 0.15 vs. 3.23 9 0.17%/min, PB0.01, respectively), higher triglyceride (1.39 90.10 vs. 1.05 9 0.05 mmol/l, PB 0.05), lower HDL cholesterol (1.05 90.05 vs. 1.28 90.06 mmol/l, P B0.05), and higher lipoprotein (a) (27.5 9 4.3 vs. 17.4 9 2.0 mg/dl, P B 0.05). Multiple logistic regression analysis indicated that hypertension, insulin resistance, high lipoprotein (a) and triglyceride, and low HDL cholesterol were independently related to CAD. Our results suggest that insulin resistance per se is a significant risk factor for CAD in Japanese patients with type 2 diabetes. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Insulin resistance; Type 2 diabetes mellitus; Coronary artery disease; Insulin tolerance test; Insulin resistance syndrome
1. Introduction
* Corresponding author. Tel.: +81-956-337151; fax: + 81956-343241.
Recent studies have suggested that insulin resistance is related to classic coronary risk factors, such as glucose intolerance, hypertension, dyslipidemia, and obesity [1–3]. Moreover, both insulin resistance and/or hyperinsulinemia are recognized
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K. Matsumoto et al. / Diabetes Research and Clinical Practice 51 (2001) 181–186
as important and independent risk factors for coronary artery disease (CAD) [4 – 6]. Diabetes mellitus is a well-established risk factor for CAD, and is frequently complicated with other multiple coronary risk factors [7 – 9]. Therefore, it has been proposed that insulin resistance is a common pathogenic mechanism of both type 2 diabetes mellitus and CAD [10,11]. The diabetes –CAD link is primarily observed in the Caucasian population. However, in Japanese diabetic patients, the mortality associated with CAD is apparently lower than that of Caucasians [12,13]. To our knowledge, there are no studies that have previously investigated whether Japanese diabetic patients with CAD have a higher insulin resistance than those without CAD. In non-diabetic patients, compensatory hyperinsulinemia is a useful index of insulin resistance [14,15]. However, the degree of insulin resistance does not clearly correlate with serum insulin or C-peptide concentrations in type 2 diabetics [16]. Thus, direct measurement of insulin resistance is useful in the study of insulin resistance in diabetic patients. In the present study, we measured insulin resistance directly and assessed its role, together with those of several known coronary risk factors, in Japanese patients with type 2 diabetes with and without CAD.
2. Subjects and methods A total of 66 Japanese patients with type 2 diabetes gave informed consent to participate in the study. The study protocol was approved by the Ethics Committee of Sasebo Chuo Hospital. Type 2 diabetes was diagnosed according to the criteria of the Japan Diabetes Society [17]. Coronary artery disease was diagnosed based on a history of acute myocardial infarction with definite elevation of serum cardiac enzymes or effort angina pectoris confirmed by coronary angiography or a history of coronary intervention such as percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft (CABG).
Excluded from the study were patients who had heart failure, renal failure, liver disease, endocrine disease, intercurrent infections, or those who required bed rest. Patients with recent myocardial infarction or coronary intervention (within 6 months) were also excluded from the study. Hypertension was diagnosed when blood pressure was elevated ] 160/ ] 95 mmHg or by the use of antihypertensive agents. Patients were defined as current smokers or nonsmokers. Thirty-three patients were diagnosed with CAD, and the other 33 age- and sex-matched patients were recruited as control patients. In the type 2 diabetic patients with CAD, a positive history of myocardial infarction was identified in five patients, and of angina pectoris with coronary angiography in 14 patients, with PTCA in nine patients, and with CABG in five patients. Control patients did not have clinical symptoms of CAD, and had a normal Master two-step electrocardiogram.
2.1. Study protocol All patients were admitted to Sasebo Chuo Hospital. The treatment modality for diabetes provided for each patient was similar to that used in the outpatient department. Blood pressure was measured with a standard mercury sphygmomanometer after at least 10 min of rest. Insulin sensitivity was assessed by the K index of the short insulin tolerance test (KITT) as previously described [18,19]. Briefly, a bolus of regular insulin was infused, and blood samples were then obtained at 3, 6, 9, 12, and 15 min after insulin infusion. KITT was calculated using the formula KITT = 0.693/t1/2 [20]. The mean9SEM KITT value of 25 subjects with normal glucose tolerance was 5.039 0.14%/min [21]. In each patient, we also measured fasting glucose, fasting C-peptide, total cholesterol, triglyceride, HDL cholesterol, lipoprotein(a) [Lp(a)], and HbA1c using baseline blood samples.
2.2. Analytical methods Plasma glucose was measured with the glucose oxidase method (Kyoto-Daiichi Kagaku, Kyoto,
K. Matsumoto et al. / Diabetes Research and Clinical Practice 51 (2001) 181–186
Japan). Intra- and interassay coefficients of variations (CVs) were B1.5%. C-Peptide was measured with a commercial radioimmunoassay kit (Daiichi, Tokyo, Japan). Total cholesterol and triglyceride levels were measured with the enzymatic method (Kokusai Shiyaku, Kobe, Japan). HDL cholesterol was determined after isolation by a precipitation method (Kyowa, Tokyo, Japan). Lipoprotein(a) was measured with a commercial turbid immunoassay kit (Daiichi, Tokyo, Japan).
2.3. Statistical analysis Unpaired data were analyzed by the 2-test or Student’s t-test. Multiple logistic regression analysis was performed to evaluate the factor(s) that were independently related to CAD. A forward stepwise logistic regression was chosen, with a cut-off level of significance of 0.05. Data are presented as means9 SEM. Differences were considered statistically significant at P B0.05. Data were analyzed by SPSS 6.1 statistical package.
3. Results
3.1. Clinical characteristics As shown in Table 1, the duration of type 2 diabetes was significantly longer in patients with Table 1 Clinical characteristics of type 2 diabetic patients with and without coronary artery disease (CAD)a
Number (male/female) Age (years) Duration of diabetes (years) Body mass index (kg/m2) Prevalence of hypertension Prevalence of smoker Insulin treatment HbA1c (%)
Table 2 Continuous variables of coronary risk factors in type 2 diabetic patients with and without CADa
Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Fasting glucose (mmol/l) Fasting C-peptide (nmol/l) Total cholesterol (mmol/l) Triglyceride (mmol/l) HDL cholesterol (mmol/l) Lipoprotein(a) (mg/dl)
Patients with CAD
Patients without CAD
139 9 4
134 9 4
78 9 3
74 9 2
7.2 9 0.4
7.2 9 0.3
0.7 90.1
0.6 90.1
4.94 90.14
4.85 90.13
1.39 90.10* 1.05 90.05*
1.05 90.05 1.28 90.06
27.5 94.3*
17.4 92.0
a Data are means 9SEM. * PB0.05 versus patients without CAD.
CAD, compared with control patients. Body mass index tended to be higher in patients with CAD than control, albeit insignificantly. About 70% of the patients with CAD were hypertensive, and prevalence of hypertension in this group was significantly higher than the control. Prevalence of smoking was comparable between CAD patients and control. Concerning the modality of diabetes treatment, the percentage of patients treated by insulin was significantly higher in those with CAD than control. Glycosylated HbA1c levels were comparable between CAD patients and control.
Patients with CAD
Patients without CAD
3.2. Metabolic risk factors
33 (20/13) 65.89 1.3 9.0 91.4*
33 (23/10) 63.8 91.4 5.5 90.9
24.19 0.6
22.9 90.6
As shown in Table 2, systolic and diastolic blood pressures were comparable between patients with CAD and control. Fasting glucose levels, fasting C-peptide levels, and serum total cholesterol levels were also comparable between two groups. In contrast, serum levels of triglyceride were significantly higher in patients with CAD than control. Serum levels of HDL cholesterol were significantly lower in patients with CAD than control. Serum levels of Lp(a) were significantly higher in patients with CAD than control. Insulin sensitivity, expressed by KITT, in patients with CAD and control
23 (69.7%)*
13 (39.4%)
17 (51.5%) 15 (45.5%)* 8.590.3
13 (39.4%) 6 (18.2%) 9.1 9 0.3
Data are means 9SEM, or n (%). * PB0.05 versus patients without CAD. a
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terol, Lp(a), and KITT, as continuous variables; and sex, presence of hypertension, smoking status, and insulin therapy were included as categorical variables. Table 3 shows the results of the multiple logistic regression analysis. This model identified the presence of hypertension, insulin resistance (KITT), Lp(a), HDL cholesterol, and triglyceride as independent risk factors for CAD in Japanese type 2 diabetes. In this analysis, the negative values of KITT and HDL cholesterol were used because of the inverse relationship between these two variables and CAD. For example, a 1%/min lower KITT value was associated with a 4.20-fold increase in the odds ratio of CAD. The duration of diabetes and insulin treatment were not independently related to CAD. Fig. 1. Insulin sensitivity (KITT values) in diabetic patients with and without CAD. Open circles represent data from individual patients, and horizontal bars represent the mean value for the groups.
is shown in Fig. 1. KITT values were significantly lower in patients with CAD than control (2.409 0.15 vs. 3.2390.17%/min, P B0.01, respectively). Thus, patients with CAD have a high insulin resistance.
3.3. Multiple logistic regression analysis To determine the independent factors that are related to CAD in type 2 diabetic patients, we performed multiple logistic regression analysis. The following independent variables were included in the model: age, duration of diabetes, body mass index, fasting glucose, fasting C-peptide, total cholesterol, triglyceride, HDL-choles-
4. Discussion In the present study, we demonstrated that insulin sensitivity (KITT) in Japanese type 2 diabetic patients with CAD was significantly lower than in similar diabetic patients who were otherwise free of CAD. Furthermore, multiple logistic regression analysis identified insulin resistance as a significant and independent determinant of CAD. Thus, insulin resistance is an important and independent risk factor for CAD in Japanese type 2 diabetics, similar to their Caucasian counterparts [12,13]. In the same analysis, presence of hypertension, hypertriglyceridemia, and low HDL cholesterol levels were independently related to CAD. These clinical phenotypes are compatible with a state known as insulin resistance syndrome [3].
Table 3 Independent determinants of CAD based on multiple logistic regression analysisa Risk factor
Odds ratio
95% confidence interval
P-value
Hypertension (yes/no) Insulin resistance (KITT, 1%/min) Lipoprotein(a) (1 mmol/l) HDL cholesterol (1 mmol/l) Triglyceride (1 mmol/l)
4.61 4.20 4.46 16.6 4.94
1.16–18.4 1.59–11.1 0.82–24.3 1.21–228.7 0.82–29.7
0.030 0.004 0.084 0.036 0.081
a The negative values of KITT and HDL cholesterol were used in this analysis because of the inverse relationship between KITT, HDL cholesterol and CAD.
K. Matsumoto et al. / Diabetes Research and Clinical Practice 51 (2001) 181–186
Although the difference in body mass index (BMI) was not significant, BMI in patients with CAD tended to be higher than control. It is well known that visceral fat accumulation is closely related to insulin resistance and atherosclerosis such as CAD [22,23]. Unfortunately, our study did not evaluate the body fat distributions. We speculate, however, that slightly higher BMI in patients with CAD might be associated with visceral fat accumulation. Systolic and diastolic blood pressure were comparable in patients with and without CAD. However, the percentage of patients with hypertension was significantly higher in those with CAD than the control. This discrepant result may be explained by the use of antihypertensive drug in patients with hypertension. These results suggest that the hypertensive state may be a more important factor for CAD than absolute blood pressure. Thus, insulin resistance may be a likely pathogenic mechanism of hypertension in type 2 diabetes [1–3]. Fasting glucose and C-peptide were comparable in patients with CAD and the controls in our study. Therefore, it was difficult to distinguish CAD patients from type 2 diabetic patients by fasting glucose and C-peptide. In patients with diabetes, a direct measurement of insulin resistance may be useful to evaluate the relationship between insulin resistance and atherosclerotic vascular disease [24]. Inchiostro et al. reported that the KITT value in 36 type 2 diabetic Italian men with CAD was 2.4590.18%/min [24]. This value was almost identical in our Japanese type 2 diabetic patients with CAD (2.4090.15%/min). Thus, the degree of insulin resistance is comparable between Japanese and Italian. They also reported that BMI is independently related to CAD, but dyslipidemia (high triglyceride and low HDL cholesterol) is not [24]. Although the degree of insulin resistance was similar between the two populations, obesity may be manifested in Italian while dyslipidemia may be manifested in Japanese. Lp(a) is known as an important and independent risk factor for CAD in Caucasians [25,26]. In our study, Lp(a) was also significantly and independently related to CAD in Japanese type 2
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diabetics. We have previously reported the presence of a weak relationship between Lp(a) and arteriosclerosis obliterans or ischemic stroke [18,21]. Therefore, the effect of elevated serum Lp(a) may be more closely related to coronary arteries compared with peripheral arteries. Because the present study is a clinically-based investigation, the results cannot be applied to general Japanese type 2 diabetic patients. Furthermore, the present study was carried out on a relatively modest sample size and the results need to be confirmed in a larger population sample in a multi-center Japanese study. In conclusion, we have demonstrated in the present study that insulin resistance per se is a significant risk factor for CAD in Japanese type 2 diabetic patients. To prevent the development of CAD, correction of insulin resistance by exercise, body weight control, or use of insulin sensitizing drugs, is a potentially important clinical issue. References [1] G.M. Reaven, Role of insulin resistance in human disease, Diabetes 37 (1988) 1595– 1607. [2] N.M. Kaplan, The deadly quartet; upper body obesity, glucose intolerance, hypertriglyceridemia, and hypertension, Arch. Intern. Med. 149 (1989) 1514– 1520. [3] R.A. DeFronzo, E. Ferrannini, Insulin resistance; a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease, Diabetes Care 14 (1991) 173– 194. [4] J.P. Despres, B. Lamaeche, P. Mauriege, et al., Hyperinsulinemia as an independent risk factor for ischemic heart disease, N. Engl. J. Med. 334 (1996) 952– 957. [5] K. Shinozaki, M. Suzuki, M. Ikebuchi, Y. Hara, Y. Harano, Demonstration of insulin resistance in coronary artery disease documented with angiography, Diabetes Care 19 (1996) 1 – 7. [6] P. Lempiainen, L. Mykkanen, K. Pyorala, M. Laakso, J. Kuusisto, Insulin resistance syndrome predicts coronary heart disease events in elderly nondiabetic men, Circulation 100 (1999) 123– 128. [7] G. Paolisso, A. Gambardella, D. Galzerano, et al., Metabolic features of patients with and without coronary heart disease but with a superimposable cluster of cardiovascular risk factors, Coron. Artery Dis. 4 (1993) 1085– 1091. [8] M. Hanefeld, S. Fischer, U. Julius, et al., Risk factors for myocardial infarction and death in newly detected NIDDM; the Diabetes Intervention Study, 11-year follow-up, Diabetologia 39 (1996) 1577– 1583.
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K. Matsumoto et al. / Diabetes Research and Clinical Practice 51 (2001) 181–186 [18] K. Matsumoto, S. Miyake, M. Yano, et al., Insulin resistance and arteriosclerosis obliterans in patients with NIDDM, Diabetes Care 20 (1997) 1738– 1743. [19] K. Matsumoto, M. Yano, S. Miyake, et al., Effects of voglibose on glycemic excursions, insulin secretion, and insulin sensitivity in non-insulin-treated NIDDM patients, Diabetes Care 21 (1998) 256– 260. [20] E. Bonora, P. Moghetti, C. Zancanaro, et al., Estimates of in vivo insulin action in man; comparison of insulin tolerance tests with euglycemic and hyperglycemic glucose clamp studies, J. Clin. Endocrinol. Metab. 68 (1989) 374– 378. [21] K. Matsumoto, S. Miyake, M. Yano, et al., Insulin resistance and classic risk factors in type 2 diabetic patients with different subtypes of ischemic stroke, Diabetes Care 22 (1999) 1191– 1195. [22] S. Fujioka, Y. Matsuzawa, K. Tokunaga, S. Tarui, Contribution of intraabdominal fat accumulation to the impairment of glucose and lipid metabolism in human obesity, Metabolism 36 (1987) 54 – 59. [23] T. Nakamura, K. Tokunaga, I. Shimomura, et al., Contribution of visceral fat accumulation to the development of coronary artery disease in non-obese men, Atherosclerosis 107 (1994) 239– 246. [24] S. Inchiostro, G. Bertoli, G. Zanette, V. Donadon, Evidence of higher insulin resistance in NIDDM patients with ischemic heart disease, Diabetologia 37 (1994) 597– 603. [25] G. Utermann, The mysteries of lipoprotein (a), Science 246 (1989) 904– 910. [26] R.W. James, M. Boemi, C. Sirolla, L. Amadio, P. Fumelli, D. Pometta, Lipoprotein (a) and vascular disease in diabetic patients, Diabetologia 38 (1995) 711– 714.
[9] S.M. Haffner, S. Lehto, T. Ronnemaa, K. Pyorala, M. Laakso, Mortality from coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction, N. Engl. J. Med. 339 (1998) 229– 234. [10] M.P. Stern, Diabetes and cardiovascular disease. The ‘Common soil’ hypothesis, Diabetes 44 (1995) 369–374. [11] H. Taegtmeyer, Insulin resistance and atherosclerosis; common roots for two common diseases?, Circulation 93 (1996) 1777– 1779. [12] R. Takeda, M. Shimizu, Ischemic heart disease in patients with diabetes mellitus in Japan, Diab. Res. Clin. Pract. 24 (1994) S199– S203. [13] J.H. Fuller, L.K. Stevens, S. Wang, International variations in cardiovascular mortality associated with diabetes mellitus; the WHO multinational study of vascular disease in diabetes, Ann. Med. 28 (1996) 319–322. [14] P. Ducimetiere, E. Eschwege, L. Papoz, J.L. Richard, J.R. Claude, G. Rosselin, Relationship of plasma insulin level to the incidence of myocardial infarction and coronary heart disease mortality in middle-aged population, Diabetologia 19 (1980) 205–210. [15] K. Shinozaki, H. Naritomi, T. Shimizu, et al., Role of insulin resistance associated with compensatory hyperinsulinemia in ischemic stroke, Stroke 27 (1996) 37–43. [16] M. Laakso, How good a marker is insulin level for insulin resistance?, Am. J. Epidemiol. 137 (1993) 959–965. [17] T. Kuzuya, S. Nakagawa, J. Satoh, et al., Report of the Committee of Japan Diabetes Society on the classification and diagnostic criteria of diabetes mellitus, J. Japan Diab. Soc. 42 (1999) 385–404 in Japanese.
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Insulin resistance and coronary risk factors in Japanese type 2 diabetic patients with definite coronary artery disease Kazunari Matsumoto *, Yoshihisa Kizaki, Satoki Fukae, Masako Tomihira, Yasunori Sera, Yukitaka Ueki, Tan Tominaga, Seibei Miyake Department of Internal Medicine, Sasebo Chuo Hospital, 15 Yamato-cho, Sasebo, Nagasaki 857 -1195, Japan Received 4 August 2000; accepted 25 September 2000
Abstract Insulin resistance is known as an important risk factor for coronary artery disease (CAD). However, CAD-related mortality in Japanese type 2 diabetics is lower than in Caucasians. To investigate whether insulin resistance is related to CAD in Japanese type 2 diabetics, we measured insulin sensitivity and several coronary risk factors in Japanese patients with type 2 diabetes with and without CAD. Thirty-three patients with definite CAD and 33 age- and sex-matched patients without CAD (control) were studied. Insulin sensitivity was assessed by the K index of insulin tolerance test (KITT). Clinical characteristics, classical risk factors, lipoprotein (a), and insulin sensitivity were compared between the two groups. Patients with CAD had a significantly longer duration of diabetes (9.0 9 1.4 vs. 5.5 90.9 years, P B0.05, respectively), were mostly hypertensive (69.7 vs. 39.4%, P B0.05), and more likely to be treated with insulin (45.5 vs. 18.2%, PB0.05) compared with the control. Concerning the metabolic parameters, patients with CAD had a significantly higher insulin resistance than control (2.40 9 0.15 vs. 3.23 9 0.17%/min, PB0.01, respectively), higher triglyceride (1.39 90.10 vs. 1.05 9 0.05 mmol/l, PB 0.05), lower HDL cholesterol (1.05 90.05 vs. 1.28 90.06 mmol/l, P B0.05), and higher lipoprotein (a) (27.5 9 4.3 vs. 17.4 9 2.0 mg/dl, P B 0.05). Multiple logistic regression analysis indicated that hypertension, insulin resistance, high lipoprotein (a) and triglyceride, and low HDL cholesterol were independently related to CAD. Our results suggest that insulin resistance per se is a significant risk factor for CAD in Japanese patients with type 2 diabetes. © 2001 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Insulin resistance; Type 2 diabetes mellitus; Coronary artery disease; Insulin tolerance test; Insulin resistance syndrome
1. Introduction
* Corresponding author. Tel.: +81-956-337151; fax: + 81956-343241.
Recent studies have suggested that insulin resistance is related to classic coronary risk factors, such as glucose intolerance, hypertension, dyslipidemia, and obesity [1–3]. Moreover, both insulin resistance and/or hyperinsulinemia are recognized
0168-8227/01/$ - see front matter © 2001 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 1 6 8 - 8 2 2 7 ( 0 0 ) 0 0 2 2 8 - X
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as important and independent risk factors for coronary artery disease (CAD) [4 – 6]. Diabetes mellitus is a well-established risk factor for CAD, and is frequently complicated with other multiple coronary risk factors [7 – 9]. Therefore, it has been proposed that insulin resistance is a common pathogenic mechanism of both type 2 diabetes mellitus and CAD [10,11]. The diabetes –CAD link is primarily observed in the Caucasian population. However, in Japanese diabetic patients, the mortality associated with CAD is apparently lower than that of Caucasians [12,13]. To our knowledge, there are no studies that have previously investigated whether Japanese diabetic patients with CAD have a higher insulin resistance than those without CAD. In non-diabetic patients, compensatory hyperinsulinemia is a useful index of insulin resistance [14,15]. However, the degree of insulin resistance does not clearly correlate with serum insulin or C-peptide concentrations in type 2 diabetics [16]. Thus, direct measurement of insulin resistance is useful in the study of insulin resistance in diabetic patients. In the present study, we measured insulin resistance directly and assessed its role, together with those of several known coronary risk factors, in Japanese patients with type 2 diabetes with and without CAD.
2. Subjects and methods A total of 66 Japanese patients with type 2 diabetes gave informed consent to participate in the study. The study protocol was approved by the Ethics Committee of Sasebo Chuo Hospital. Type 2 diabetes was diagnosed according to the criteria of the Japan Diabetes Society [17]. Coronary artery disease was diagnosed based on a history of acute myocardial infarction with definite elevation of serum cardiac enzymes or effort angina pectoris confirmed by coronary angiography or a history of coronary intervention such as percutaneous transluminal coronary angioplasty (PTCA) and coronary artery bypass graft (CABG).
Excluded from the study were patients who had heart failure, renal failure, liver disease, endocrine disease, intercurrent infections, or those who required bed rest. Patients with recent myocardial infarction or coronary intervention (within 6 months) were also excluded from the study. Hypertension was diagnosed when blood pressure was elevated ] 160/ ] 95 mmHg or by the use of antihypertensive agents. Patients were defined as current smokers or nonsmokers. Thirty-three patients were diagnosed with CAD, and the other 33 age- and sex-matched patients were recruited as control patients. In the type 2 diabetic patients with CAD, a positive history of myocardial infarction was identified in five patients, and of angina pectoris with coronary angiography in 14 patients, with PTCA in nine patients, and with CABG in five patients. Control patients did not have clinical symptoms of CAD, and had a normal Master two-step electrocardiogram.
2.1. Study protocol All patients were admitted to Sasebo Chuo Hospital. The treatment modality for diabetes provided for each patient was similar to that used in the outpatient department. Blood pressure was measured with a standard mercury sphygmomanometer after at least 10 min of rest. Insulin sensitivity was assessed by the K index of the short insulin tolerance test (KITT) as previously described [18,19]. Briefly, a bolus of regular insulin was infused, and blood samples were then obtained at 3, 6, 9, 12, and 15 min after insulin infusion. KITT was calculated using the formula KITT = 0.693/t1/2 [20]. The mean9SEM KITT value of 25 subjects with normal glucose tolerance was 5.039 0.14%/min [21]. In each patient, we also measured fasting glucose, fasting C-peptide, total cholesterol, triglyceride, HDL cholesterol, lipoprotein(a) [Lp(a)], and HbA1c using baseline blood samples.
2.2. Analytical methods Plasma glucose was measured with the glucose oxidase method (Kyoto-Daiichi Kagaku, Kyoto,
K. Matsumoto et al. / Diabetes Research and Clinical Practice 51 (2001) 181–186
Japan). Intra- and interassay coefficients of variations (CVs) were B1.5%. C-Peptide was measured with a commercial radioimmunoassay kit (Daiichi, Tokyo, Japan). Total cholesterol and triglyceride levels were measured with the enzymatic method (Kokusai Shiyaku, Kobe, Japan). HDL cholesterol was determined after isolation by a precipitation method (Kyowa, Tokyo, Japan). Lipoprotein(a) was measured with a commercial turbid immunoassay kit (Daiichi, Tokyo, Japan).
2.3. Statistical analysis Unpaired data were analyzed by the 2-test or Student’s t-test. Multiple logistic regression analysis was performed to evaluate the factor(s) that were independently related to CAD. A forward stepwise logistic regression was chosen, with a cut-off level of significance of 0.05. Data are presented as means9 SEM. Differences were considered statistically significant at P B0.05. Data were analyzed by SPSS 6.1 statistical package.
3. Results
3.1. Clinical characteristics As shown in Table 1, the duration of type 2 diabetes was significantly longer in patients with Table 1 Clinical characteristics of type 2 diabetic patients with and without coronary artery disease (CAD)a
Number (male/female) Age (years) Duration of diabetes (years) Body mass index (kg/m2) Prevalence of hypertension Prevalence of smoker Insulin treatment HbA1c (%)
Table 2 Continuous variables of coronary risk factors in type 2 diabetic patients with and without CADa
Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg) Fasting glucose (mmol/l) Fasting C-peptide (nmol/l) Total cholesterol (mmol/l) Triglyceride (mmol/l) HDL cholesterol (mmol/l) Lipoprotein(a) (mg/dl)
Patients with CAD
Patients without CAD
139 9 4
134 9 4
78 9 3
74 9 2
7.2 9 0.4
7.2 9 0.3
0.7 90.1
0.6 90.1
4.94 90.14
4.85 90.13
1.39 90.10* 1.05 90.05*
1.05 90.05 1.28 90.06
27.5 94.3*
17.4 92.0
a Data are means 9SEM. * PB0.05 versus patients without CAD.
CAD, compared with control patients. Body mass index tended to be higher in patients with CAD than control, albeit insignificantly. About 70% of the patients with CAD were hypertensive, and prevalence of hypertension in this group was significantly higher than the control. Prevalence of smoking was comparable between CAD patients and control. Concerning the modality of diabetes treatment, the percentage of patients treated by insulin was significantly higher in those with CAD than control. Glycosylated HbA1c levels were comparable between CAD patients and control.
Patients with CAD
Patients without CAD
3.2. Metabolic risk factors
33 (20/13) 65.89 1.3 9.0 91.4*
33 (23/10) 63.8 91.4 5.5 90.9
24.19 0.6
22.9 90.6
As shown in Table 2, systolic and diastolic blood pressures were comparable between patients with CAD and control. Fasting glucose levels, fasting C-peptide levels, and serum total cholesterol levels were also comparable between two groups. In contrast, serum levels of triglyceride were significantly higher in patients with CAD than control. Serum levels of HDL cholesterol were significantly lower in patients with CAD than control. Serum levels of Lp(a) were significantly higher in patients with CAD than control. Insulin sensitivity, expressed by KITT, in patients with CAD and control
23 (69.7%)*
13 (39.4%)
17 (51.5%) 15 (45.5%)* 8.590.3
13 (39.4%) 6 (18.2%) 9.1 9 0.3
Data are means 9SEM, or n (%). * PB0.05 versus patients without CAD. a
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terol, Lp(a), and KITT, as continuous variables; and sex, presence of hypertension, smoking status, and insulin therapy were included as categorical variables. Table 3 shows the results of the multiple logistic regression analysis. This model identified the presence of hypertension, insulin resistance (KITT), Lp(a), HDL cholesterol, and triglyceride as independent risk factors for CAD in Japanese type 2 diabetes. In this analysis, the negative values of KITT and HDL cholesterol were used because of the inverse relationship between these two variables and CAD. For example, a 1%/min lower KITT value was associated with a 4.20-fold increase in the odds ratio of CAD. The duration of diabetes and insulin treatment were not independently related to CAD. Fig. 1. Insulin sensitivity (KITT values) in diabetic patients with and without CAD. Open circles represent data from individual patients, and horizontal bars represent the mean value for the groups.
is shown in Fig. 1. KITT values were significantly lower in patients with CAD than control (2.409 0.15 vs. 3.2390.17%/min, P B0.01, respectively). Thus, patients with CAD have a high insulin resistance.
3.3. Multiple logistic regression analysis To determine the independent factors that are related to CAD in type 2 diabetic patients, we performed multiple logistic regression analysis. The following independent variables were included in the model: age, duration of diabetes, body mass index, fasting glucose, fasting C-peptide, total cholesterol, triglyceride, HDL-choles-
4. Discussion In the present study, we demonstrated that insulin sensitivity (KITT) in Japanese type 2 diabetic patients with CAD was significantly lower than in similar diabetic patients who were otherwise free of CAD. Furthermore, multiple logistic regression analysis identified insulin resistance as a significant and independent determinant of CAD. Thus, insulin resistance is an important and independent risk factor for CAD in Japanese type 2 diabetics, similar to their Caucasian counterparts [12,13]. In the same analysis, presence of hypertension, hypertriglyceridemia, and low HDL cholesterol levels were independently related to CAD. These clinical phenotypes are compatible with a state known as insulin resistance syndrome [3].
Table 3 Independent determinants of CAD based on multiple logistic regression analysisa Risk factor
Odds ratio
95% confidence interval
P-value
Hypertension (yes/no) Insulin resistance (KITT, 1%/min) Lipoprotein(a) (1 mmol/l) HDL cholesterol (1 mmol/l) Triglyceride (1 mmol/l)
4.61 4.20 4.46 16.6 4.94
1.16–18.4 1.59–11.1 0.82–24.3 1.21–228.7 0.82–29.7
0.030 0.004 0.084 0.036 0.081
a The negative values of KITT and HDL cholesterol were used in this analysis because of the inverse relationship between KITT, HDL cholesterol and CAD.
K. Matsumoto et al. / Diabetes Research and Clinical Practice 51 (2001) 181–186
Although the difference in body mass index (BMI) was not significant, BMI in patients with CAD tended to be higher than control. It is well known that visceral fat accumulation is closely related to insulin resistance and atherosclerosis such as CAD [22,23]. Unfortunately, our study did not evaluate the body fat distributions. We speculate, however, that slightly higher BMI in patients with CAD might be associated with visceral fat accumulation. Systolic and diastolic blood pressure were comparable in patients with and without CAD. However, the percentage of patients with hypertension was significantly higher in those with CAD than the control. This discrepant result may be explained by the use of antihypertensive drug in patients with hypertension. These results suggest that the hypertensive state may be a more important factor for CAD than absolute blood pressure. Thus, insulin resistance may be a likely pathogenic mechanism of hypertension in type 2 diabetes [1–3]. Fasting glucose and C-peptide were comparable in patients with CAD and the controls in our study. Therefore, it was difficult to distinguish CAD patients from type 2 diabetic patients by fasting glucose and C-peptide. In patients with diabetes, a direct measurement of insulin resistance may be useful to evaluate the relationship between insulin resistance and atherosclerotic vascular disease [24]. Inchiostro et al. reported that the KITT value in 36 type 2 diabetic Italian men with CAD was 2.4590.18%/min [24]. This value was almost identical in our Japanese type 2 diabetic patients with CAD (2.4090.15%/min). Thus, the degree of insulin resistance is comparable between Japanese and Italian. They also reported that BMI is independently related to CAD, but dyslipidemia (high triglyceride and low HDL cholesterol) is not [24]. Although the degree of insulin resistance was similar between the two populations, obesity may be manifested in Italian while dyslipidemia may be manifested in Japanese. Lp(a) is known as an important and independent risk factor for CAD in Caucasians [25,26]. In our study, Lp(a) was also significantly and independently related to CAD in Japanese type 2
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