(Hypertension. 1996;28:593-598.)
© 1996 American Heart Association, Inc.
Articles |
Insulin Resistance as an Independent Risk Factor for Carotid Wall Thickening
the Division of Atherosclerosis, Metabolism, and Clinical Nutrition, Department of Medicine, National Cardiovascular Center, Osaka, and Department of Applied Mathematics, Faculty of Science, Konan University (Y. Hattori), Kobe, Japan.
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Abstract |
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It has been reported that insulin resistance is associated with essential hypertension and that an aggregation of risk factors—hypertension, dyslipidemia, and glucose intolerance—together with insulin resistance leads to the more frequent appearance of coronary artery disease. We examined the relation between early asymptomatic atherosclerosis and these risk factors in 72 nondiabetic subjects with essential hypertension (41 men, 31 women) aged 50 to 59 years. Intima-media thickness and plaque formation of the carotid artery were assessed by B-mode ultrasonography, and insulin sensitivity was measured by the steady-state plasma glucose method. Lipoprotein profile was analyzed by ultracentrifugation. The intima-media thickness of the common carotid artery significantly correlated with systolic pressure; mean blood pressure; steady-state plasma glucose, indicating insulin resistance; fasting insulin; area under the curve of plasma insulin and glucose; body mass index; apolipoprotein B; apolipoprotein B in low-density lipoprotein; lower ratio of cholesterol to apolipoprotein B of low-density lipoprotein; and decreased high-density lipoprotein cholesterol. By multiple regression analysis, steady-state plasma glucose was the strongest risk, followed by lower high-density lipoprotein and systolic pressure. These three factors accounted for 54.9% of all the risk for increased intima-media thickness of the common carotid artery. In conclusion, insulin resistance was the strongest risk factor for carotid intima-media thickness, followed by lower high-density lipoprotein cholesterol and hypertension. An effort to maintain normal insulin sensitivity is essential for the prevention of early atheromatous lesions in essential hypertension.
Key Words: carotid arteries • hypertension, essential • insulin resistance • lipoproteins
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Introduction |
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Insulin resistance has been observed in essential hypertension.1 2 3 Impaired insulin sensitivity for glucose utilization has also been noted in subjects who have non–insulin-dependent diabetes mellitus,4 5 obesity,6 7 or hypertriglyceridemia8 or who smoke cigarettes.9 Hypertension, glucose intolerance, obesity, dyslipidemia, hyperinsulinemia, and smoking are all risk factors for atherosclerosis. The cluster of these risk factors based on insulin resistance has been described as syndrome X,10 or insulin resistance syndrome.11 Individuals with this syndrome are considered at high risk for cardiovascular disease.
Recently, we reported the existence of insulin insensitivity in subjects with stable effort and vasospastic angina12 as well as atherothrombotic cerebral infarction.13 Also, insulin resistance was reported in asymptomatic mild atherosclerosis of the carotid and femoral arteries.14 15 Atherosclerosis of the carotid artery shows an association with age,16 17 18 19 BP,1 2 3 dyslipidemia,17 19 20 diabetes mellitus,21 22 and smoking.19 No study has been reported to demonstrate an association between increased IMT of the carotid artery with insulin resistance in essential hypertension.
B-mode ultrasonography is a noninvasive technique that can directly visualize and assess the lumen and vessel wall of the carotid artery. Using this method, we analyzed the IMT of the common carotid artery and plaque formation in extracranial carotid arteries. IMT thickening indicates both an intimal atherosclerotic process and medial hypertrophy by the influence of pressure. Because of the increased IMT in subjects with familial hypercholesterolemia23 and progressive reduction in IMT by cholesterol-lowering treatment,24 IMT seems to be associated with the early phase of atherosclerosis. On the other hand, vascular wall hypertrophy also is likely to be related to increased IMT in hypertensive subjects.25 We also measured insulin sensitivity, insulin secretion, BP, glucose tolerance, lipoproteins, and apoB and compared the results with the degree of IMT and plaque formation of the carotid arteries.
Our main purpose in this study was to determine whether insulin insensitivity is a strong risk factor for carotid IMT thickening and plaque formation compared with other risk factors. Secondarily, because of the significant correlations between IMT and coronary or cerebrovascular disease,26 27 28 29 we evaluated the clinical significance of increased IMT in relation to insulin resistance in essential hypertension.
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Methods |
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Subjects
The clinical study was carried out in 72 subjects (41 men and 31 women) with essential hypertension (Table 1
). Because aging has been reported to be a strong risk factor for IMT and atherosclerosis of the carotid arteries,16 17 18 19 only subjects between the ages of 50 and 59 years were recruited. The inclusion criteria for this study were as follows: (1) hypertensive subjects, defined as having systolic and/or diastolic BP over 140 and 90 mm Hg, respectively; (2) nondiabetic subjects (exclusion of diabetes mellitus according to World Health Organization criteria 30 ); (3) body mass index less than 28.5 kg/m2; (4) serum triglycerides less than 3.39 mmol/L; (5) no familial hyperlipidemia; (6) no evidence of renal or liver dysfunction; (7) a negative exercise test; (8) no evidence of cerebrovascular, peripheral vascular, or endocrine disease; and (9) no drug treatment capable of reducing BP or influencing carbohydrate and lipid metabolism. Fourteen of the men and 10 of the women had a history of antihypertensive medications, but none had taken drugs at the start of the study (no medication period for hypertension >1 year).
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All subjects were interviewed about smoking habits. The total number of years of smoking was multiplied by the average number of cigarettes smoked daily. The product divided by 20 was expressed as pack years.
Procedures
With a mercury sphygmomanometer, systolic and diastolic BPs were measured by Korotkoff phases I and V, respectively. The mean of three measurements obtained on three different occasions with the subjects in the sitting position was used.
B-Mode Ultrasound Investigation of the Carotid Artery
Investigation of the carotid artery was performed with high-resolution B-mode ultrasonography (U-sonic model RT 2800 with 7.5-MHz mechanical sector transducer, Yokogawa Medical Systems). Subjects were examined while they were in the supine position. Both longitudinal and cross-sectional images were viewed. Three angles of longitudinal views were obtained: anterior oblique, lateral, and posterior oblique. Scanning lasted on average 20 minutes. All ultrasonographic assessments of carotid arteries were performed by a physician (M.S.) with no medical knowledge of the subjects.
The IMT of the carotid artery as defined by Pignoli et al31 32 was determined as the distance from the lumen-intima interface to the collagen-containing upper layer of the tonic adventitia (the distance between two echogenic lines separated by a hypoechoic or anechoic space). We used the same basic techniques as reported by Handa et al16 and Yamasaki and colleagues.33 34 The IMT of the common carotid artery was measured at 10, 20, and 30 mm proximal to the bifurcation in the anterior oblique, lateral, and posterior oblique longitudinal views. Internal and external carotid arteries were not examined because they were not accessible in all the subjects. Only the far wall was used. A mean IMT value for the 18 IMT values of bilateral common carotid arteries was calculated and was used as the IMT of the common carotid artery. We studied the reproducibility of the IMT measurement by repeating the scanning within 2 weeks in a randomly chosen subsample of 25 subjects. The second scannings were performed two times independently by the same physician (M.S.) and a different one (K.S.) with no medical information about the subjects. In 25 subjects, the mean absolute difference±SE between replicate scannings of the IMT were 0.02±0.01 and 0.02±0.01 mm for intraobserver and interobserver comparisons, respectively. The simple correlation coefficients between repeated determinations of IMT were .92 and .91 for intraobserver and interobserver analyses, respectively. A plaque was defined as a localized lesion with thickness (IMT) greater than 1.1 mm. No subject demonstrated plaque thickness more than 3.0 mm. Plaques in near and far walls of the bilateral common, internal, and external carotid arteries were evaluated.
Oral Glucose Tolerance Test
A standard 75-g oral glucose load was given to all subjects after overnight fasting. Plasma glucose and insulin levels were measured at 0, 30, 60, and 120 minutes during the test. Glucose tolerance was evaluated by World Health Organization criteria.30 The results are shown as AUCPG or AUCPI during the oral glucose tolerance test.
Insulin Sensitivity Test
Insulin sensitivity to glucose utilization was evaluated by a newly modified SSPG method5 with octreotide acetate (Sandostatin, Sandoz) after an overnight fast of at least 12 hours. Octreotide acetate (9.8 pmol in a bolus followed by a constant infusion of 73.5 pmol/h) and insulin (Novolin R, Novo Nordisk S/A; 45 pmol/kg [7.5 mU/kg] in a bolus followed by a constant infusion at 4.62 pmol/kg per minute [0.77 mU/kg per minute]) were infused intravenously for 2 hours. Glucose in a final 12% solution containing KCl (0.5 µmol/kg per minute) was infused at a rate of 0.033 mmol/kg per minute (6 mg/kg per minute) through an antecubital vein via a constant infusion pump. Blood samples were drawn routinely at 0, 30, and 120 minutes (9:00, 9:30, and 11:00 AM) for determination of glucose, insulin, electrolytes, and other substrates. Each lipoprotein fraction was measured at time 0. The glucose value at 120 minutes (SSPG) was used as a marker of insulin resistance to plasma glucose utilization. Plasma glucose was determined by the glucose oxidase method35 and plasma insulin by radioimmunoassay with a double antibody.36 Steady-state plasma insulin levels at 2 hours were 317±8.57 pmol/L (mean±SE).
Lipoprotein Analysis
Lipoprotein fractions were separated with a tabletop ultracentrifuge based on the method of Hatch and Lees.37 Blood samples for lipoprotein analysis were obtained at time 0 of the insulin sensitivity test. Two and one tenth milliliters of plasma with EDTA was mixed with 0.9 mL of each density of KBr solution and then centrifuged and separated into VLDL (including chylomicrons if present, density <1.006 g/mL), IDL (1.006<density<1.019 g/mL), LDL (1.019<density<1.063 g/mL), and HDL (density >1.063 g/mL) fractions with a tabletop ultracentrifuge (TL-100, Rotor TLA 100.3, Beckman Instruments). Cholesterol38 and triglycerides39 were determined by the enzymatic method. ApoB was determined by the highly sensitive latex method40 with the use of anti-apoB polyclonal antibody, which measures apoB accurately without the influence of elevated triglyceride levels.
The results are shown as cholesterol (millimoles per liter), triglycerides (millimoles per liter), and apoB (milligrams per deciliter) in each lipoprotein fraction. LDLchol/apoB was also calculated, a value that correlates with LDL particle size (cholesterol and apoB both in milligrams per deciliter).
The study protocol was approved by the ethics committee of the National Cardiovascular Center, and informed consent was obtained from all participants.
Statistical Analysis
Values are given as mean±SE. Probability values less than .05 (two-tailed tests) were defined as statistically significant. The Statistical Analysis System (SAS) was used.41 The significance of the mean difference between men and women was determined by Student's unpaired t test. The strength of the correlation between IMT and plaque number with respect to risk factors was assessed by Pearson's linear correlation and stepwise multiple regression analysis. Sex was coded as 0 for women and 1 for men. Because of the skewed distribution of triglyceride levels, their logarithms were entered into the regression equations.
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Results |
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Characteristics of men and women did not differ, except for smoking and total cholesterol. Pack year values were significantly higher and total cholesterol levels significantly lower in men than women (Table 1
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Simple Correlations Between IMT and Risk Factors of Atherosclerosis
Correlation coefficients were calculated between mean IMT and each risk factor. SSPG, fasting plasma insulin, AUCPI, AUCPG, systolic BP, mean BP, body mass index, HDL cholesterol, total apoB, LDL apoB, and LDLchol/apoB were all significantly correlated with IMT (Table 2). Age and IMT were not significantly correlated. No relation to IMT was noted with other factors (shown as P=NS in Table 2).
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Correlation coefficients were analyzed for men and women separately. The same significant correlations (P<.05) were observed between IMT and 10 factors: SSPG, fasting plasma insulin, AUCPI, AUCPG, systolic BP, body mass index, HDL cholesterol, total apoB, LDL apoB, and LDLchol/apoB (the Figure shows four typical factors). Mean BP was significantly correlated with IMT in all the subjects but was not significant in the analysis by sex.
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Relation of Risk Factors to IMT Analyzed by Stepwise Multiple Regression Analysis
We performed stepwise multiple regression analysis in all the subjects to evaluate the independent influence of the risk factors on IMT. We estimated and tested the joint contribution of age, sex, body mass index, pack years of smoking, systolic BP, diastolic BP, SSPG, AUCPG, AUCPI, VLDL triglycerides, IDL triglycerides, LDL cholesterol, HDL cholesterol, LDL apoB, and LDLchol/apoB to the variation of IMT. The three variables that remained significant in the equation were SSPG, systolic BP, and lower HDL cholesterol (Table 3). Values of partial R2 were 0.462 (SSPG), 0.053 (HDL cholesterol), and 0.034 (systolic BP). SSPG showed the highest contribution as a risk factor to IMT. These three factors accounted for 54.9% of the variability of IMT in the common carotid artery (R2=0.549, F=27.55, P=.0001). The same results were obtained if fasting plasma glucose, fasting plasma insulin, hemoglobin A1c, LDL triglycerides, HDL triglycerides, VLDL cholesterol, IDL cholesterol, VLDL apoB, and IDL apoB were added as independent variables.
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Discussion |
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High BP and low HDL cholesterol have already been reported as risk factors for increased IMT.17 18 42 Our study confirmed this but also demonstrated that insulin resistance is the strongest predictor of IMT in subjects with nondiabetic mild hypertension.
It has been reported that hypertensive individuals have higher IMT values compared with healthy subjects.25 43 Elevated BP is associated with IMT/atherosclerosis by hemodynamic factors, endothelial injury and/or dysfunction, and cell membrane abnormalities.44 Diffuse intimal thickening is thought to be the major alteration, although systolic BP is probably associated with IMT thickening in part because of arterial medial hypertrophy.25
Regarding insulin resistance and compensatory hyperinsulinemia, insulin resistance per se is probably directly associated with atherosclerosis, as suggested by the existence of insulin insensitivity in both effort and vasospastic angina12 and cerebral infarction with cortical artery stenosis.13 On the other hand, increased insulin may have a stimulatory effect on the proliferation of arterial smooth muscle cells.45 46
Among 72 subjects, the presence of plaque was observed in 27 subjects (38%), with the rest (45 subjects) having no plaque. Observed IMT thickening may include medial hypertrophy; however, 38% of these subjects exhibited plaque formation. Pure medial hypertrophy without intimal change is unlikely, and intimal change with atherosclerosis is supposed to be involved. IMT thickening in subjects with plaque was significantly higher than in subjects without plaque (1.10±0.03 versus 1.02±0.02 mm, P<.05); therefore, increases in IMT are most likely to be expressed in the early stage of local atherosclerosis. The same results were reported in a field study by other researchers.47 However, plaque number and risk factors were not correlated, as shown by either simple or multiple regression analysis.
Simple regression analysis by sex did not show any differing results between men and women. Stepwise multiple regression analysis was carried out including sex as an independent variable. Again, no difference between men and women was noted for IMT in this study. When stepwise analysis was performed in 41 men in the same model without sex as a factor (14 factors), SSPG, lower HDL cholesterol, and systolic BP remained significant (multiple R2=0.539, F=22.24, P=.0001). As for the results of stepwise analysis in women, SSPG and lower HDL cholesterol were significantly correlated with IMT, although probably because of the limited number of female subjects (n=31).
To correct for the skewed distribution of systolic BP, logarithms were entered into the regression equations for all subjects. The same results were obtained in both simple and multiple regression analyses. The simple correlation coefficient with IMT was .47 (P=.0001). In the multivariate analysis, SSPG, log(systolic BP), and HDL cholesterol remained as independent variables to IMT.
In this study, levels of cholesterol, apoB, and IDL triglycerides in hypertensive subjects were significantly higher than levels in healthy control subjects.48 LDLchol/apoB was inversely correlated with IMT by simple regression analysis, which means that small dense LDL is associated with increased IMT. Our laboratory has reported a low LDLchol/apoB ratio as a characteristic lipoprotein disorder in essential hypertension.48 Because small dense LDL particles are predictors of coronary artery disease and atherosclerosis,49 50 their presence might cause early atherosclerosis. In multiple regression analysis, LDLchol/apoB may be rejected on account of a significant simple correlation (r=.48, P=.0001) between HDL cholesterol and LDLchol/apoB in this study. Lower HDL cholesterol and LDLchol/apoB ratio were closely associated with insulin resistance as well as the intimal atheromatous process.
Regarding smoking, we noted no association with IMT in hypertensive subjects in this study, consistent with other reports.18 25 No association has been reported in the general population51 and in healthy subjects.52 On the other hand, significant relations were observed between smoking and carotid atherosclerosis, with definite stenosis in some studies.19 20 53 Pack year values were higher in men, but no difference was observed in IMT between men and women. The higher levels of total cholesterol in women might have potentiating effects on IMT thickening.
Insulin resistance in subjects with asymptomatic atherosclerosis was first reported by Laakso et al,14 who did not perform multivariate analysis. The same result was obtained by Agewall et al.15 They did not include age, BP, lipoprotein analysis, blood sugar, or insulin levels in the model for multiple regression analysis.
The present study has demonstrated that insulin resistance is the most powerful risk factor for increased IMT of the carotid artery compared with other risk factors in subjects with essential hypertension. An effort should be made to maintain normal insulin sensitivity for the protective effect on the atherosclerotic process that causes cardiovascular or cerebrovascular diseases.
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Selected Abbreviations and Acronyms |
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Acknowledgments |
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This study was supported by Special Coordination Funds for Promoting Science and Technology (Encouragement System of COE) from the Science and Technology Agency of Japan and a Grant for Scientific Research Expenses for Health and Welfare Program.
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Footnotes |
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Reprint requests to Masaaki Suzuki, MD, Division of Atherosclerosis, Metabolism, and Clinical Nutrition, Department of Medicine, National Cardiovascular Center, 5-7-1, Fujishirodai, Suita, Osaka 565, Japan.
Received January 4, 1996; first decision January 23, 1996; accepted May 13, 1996.
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 S. Abdelghaffar, M. El Amir, A. El Hadidi, and F. El Mougi Carotid Intima-Media Thickness: An Index for Subclinical Atherosclerosis in Type 1 Diabetes J Trop Pediatr, February 1, 2006; 52(1): 39 - 45. [Abstract] [Full Text] [PDF]
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 W. N. Kernan, S. E. Inzucchi, C. M. Viscoli, L. M. Brass, D. M. Bravata, G. I. Shulman, J. C. McVeety, and R. I. Horwitz Pioglitazone Improves Insulin Sensitivity Among Nondiabetic Patients With a Recent Transient Ischemic Attack or Ischemic Stroke Stroke, June 1, 2003; 34(6): 1431 - 1436. [Abstract] [Full Text] [PDF]
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 N. Ishizaka, Y. Ishizaka, E. Takahashi, T. Unuma, E.-i. Tooda, R. Nagai, M. Togo, K. Tsukamoto, H. Hashimoto, and M. Yamakado Association Between Insulin Resistance and Carotid Arteriosclerosis in Subjects With Normal Fasting Glucose and Normal Glucose Tolerance Arterioscler Thromb Vasc Biol, February 1, 2003; 23(2): 295 - 301. [Abstract] [Full Text] [PDF]
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W. N. Kernan, S. E. Inzucchi, C. M. Viscoli, L. M. Brass, D. M. Bravata, and R. I. Horwitz Insulin resistance and risk for stroke Neurology, September 24, 2002; 59(6): 809 - 815. [Abstract] [Full Text] [PDF]
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 D. E. Cooper, D. C. Goff Jr., R. A. Bell, D. Zaccaro, E. J. Mayer-Davis, and A. J. Karter Is Insulin Sensitivity a Causal Intermediate in the Relationship Between Alcohol Consumption and Carotid Atherosclerosis?: The Insulin Resistance and Atherosclerosis Study Diabetes Care, August 1, 2002; 25(8): 1425 - 1431. [Abstract] [Full Text] [PDF]
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 K. Bjorklund, L. Lind, B. Vessby, B. Andren, and H. Lithell Different Metabolic Predictors of White-Coat and Sustained Hypertension Over a 20-Year Follow-Up Period: A Population-Based Study of Elderly Men Circulation, July 2, 2002; 106(1): 63 - 68. [Abstract] [Full Text] [PDF]
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 S. I. McFarlane, M. Banerji, and J. R. Sowers Insulin Resistance and Cardiovascular Disease J. Clin. Endocrinol. Metab., February 1, 2001; 86(2): 713 - 718. [Full Text]
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D. Baldassarre, M. Amato, A. Bondioli, C. R. Sirtori, and E. Tremoli Carotid Artery Intima-Media Thickness Measured by Ultrasonography in Normal Clinical Practice Correlates Well With Atherosclerosis Risk Factors Stroke, October 1, 2000; 31(10): 2426 - 2430. [Abstract] [Full Text] [PDF]
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 H. Tomiyama, Y. Kimura, R. Okazaki, T. Kushiro, M. Abe, Y. Kuwabara, H. Yoshida, S. Kuwata, T. Kinouchi, and N. Doba Close Relationship of Abnormal Glucose Tolerance With Endothelial Dysfunction in Hypertension Hypertension, August 1, 2000; 36(2): 245 - 249. [Abstract] [Full Text] [PDF]
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 H.-M. Lakka, T. A. Lakka, J. Tuomilehto, J. Sivenius, and J. T. Salonen Hyperinsulinemia and the Risk of Cardiovascular Death and Acute Coronary and Cerebrovascular Events in Men: The Kuopio Ischaemic Heart Disease Risk Factor Study Arch Intern Med, April 24, 2000; 160(8): 1160 - 1168. [Abstract] [Full Text] [PDF]
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M. Suzuki, Y. Kimura, M. Tsushima, and Y. Harano Association of Insulin Resistance With Salt Sensitivity and Nocturnal Fall of Blood Pressure Hypertension, April 1, 2000; 35(4): 864 - 868. [Abstract] [Full Text] [PDF]
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M. Pyorala, H. Miettinen, P. Halonen, M. Laakso, and K. Pyorala Insulin Resistance Syndrome Predicts the Risk of Coronary Heart Disease and Stroke in Healthy Middle-Aged Men : The 22-Year Follow-Up Results of the Helsinki Policemen Study Arterioscler Thromb Vasc Biol, February 1, 2000; 20(2): 538 - 544. [Abstract] [Full Text] [PDF]
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J. Gariepy, J. Salomon, N. Denarie, F. Laskri, J. L. Megnien, J. Levenson, and A. Simon Sex and Topographic Differences in Associations Between Large-Artery Wall Thickness and Coronary Risk Profile in a French Working Cohort : The AXA Study Arterioscler Thromb Vasc Biol, April 1, 1998; 18(4): 584 - 590. [Abstract] [Full Text] [PDF]
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C. M. Burchfiel, D. S. Sharp, J. D. Curb, B. L. Rodriguez, R. D. Abbott, R. Arakaki, and K. Yano Hyperinsulinemia and Cardiovascular Disease in Elderly Men : The Honolulu Heart Program Arterioscler Thromb Vasc Biol, March 1, 1998; 18(3): 450 - 457. [Abstract] [Full Text] [PDF]
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C. J. O'Callaghan, K. Komersova, and W. J. Louis Acute Effects of Blood Pressure Elevation on Insulin Clearance in Normotensive Healthy Subjects Hypertension, January 1, 1998; 31(1): 104 - 109. [Abstract] [Full Text] [PDF]
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