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Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Funding sources
  8. Competing interests
  9. Acknowledgements
  10. References
  11. Supporting Information

Aims

Elevated post-load plasma glucose levels may increase the risk of cardiovascular disease, even when they are within the normoglycaemic range. We examined the association of carotid artery intima-media thickness, a marker of early atherosclerosis, with glycaemic variables, including post-load plasma glucose levels, in Japanese subjects with normal glucose tolerance.

Methods

The study participants were 663 Japanese subjects with normal glucose tolerance (565 men, mean age 47 ± 9 years) who underwent both a 75-g oral glucose tolerance test and carotid artery intima-media thickness measurement by B-mode ultrasonography during a health examination. Associations between maximal common carotid artery intima-media thickness and fasting plasma glucose, 1-h and 2-h plasma glucose during an oral glucose tolerance test, and HbA1c were examined.

Results

The carotid artery intima-media thickness gradually increased across the tertiles of 1-h plasma glucose, 2-h plasma glucose and HbA1c. In multiple linear regression analysis, 2-h plasma glucose (β = 0.09, P = 0.012), as well as age, male gender, hypertension, dyslipidaemia, and current smoking were independent determinants of carotid artery intima-media thickness. In contrast, other glycaemic variables were not independent determinants of carotid artery intima-media thickness. The carotid artery intima-media thickness in hypertensive subjects with the highest tertile of 2-h plasma glucose [0.70 (95% CI 0.64–0.76) mm] was significantly greater than in normotensive subjects, with the lowest tertile of 2-h plasma glucose [0.60 (95% CI 0.58–0.63) mm, P = 0.037], even after adjusting for the multiple potential confounders.

Conclusions

The 2-h plasma glucose during an oral glucose tolerance test was positively and independently associated with carotid artery intima-media thickness in Japanese subjects with normal glucose tolerance. In particular, the combination of elevated 2-h plasma glucose and hypertension may contribute to an increased carotid artery intima-media thickness.

What's new?

  • The associations between maximal carotid artery intima-media thickness and several glycaemic variables were examined.
  • Study participants included 663 Japanese individuals with normal glucose tolerance.
  • Two-hour post-load glucose was an independent determinant of carotid artery intima-media thickness, whereas fasting plasma glucose, 1-h plasma glucose or HbA1c were not independent determinants.
  • A combination of high 2-h plasma glucose and hypertension was associated with increased carotid artery intima-media thickness.

Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Funding sources
  8. Competing interests
  9. Acknowledgements
  10. References
  11. Supporting Information

Diabetes is one of the established risk factors for atherosclerotic cardiovascular disease, including coronary heart disease and ischaemic stroke [1-3]. Several studies have also indicated that the risk of cardiovascular disease is increased in subjects with impaired fasting glucose and/or impaired glucose tolerance, a precursor state of diabetes [4, 5]. In addition, the Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE) study has reported that an elevation in 2-h post-load plasma glucose levels, even within the normoglycaemic range, during an oral glucose tolerance test is associated with an increased risk of cardiovascular disease [6]. These findings suggest that there is a need to evaluate the post-load plasma glucose levels and the extent of atherosclerosis, even in subjects with normal glucose tolerance.

Carotid artery intima-media thickness is a well-established marker of early atherosclerosis. A number of clinical and epidemiological studies have shown an increased carotid artery intima-media thickness to be an independent predictor of morbidity and mortality from cardiovascular disease [7-9]. Several previous studies examined the association between carotid artery intima-media thickness and glycaemic variables, including post-load plasma glucose levels, in subjects with normal glucose tolerance [10-13], in order to identify those more closely related to carotid artery intima-media thickness. However, thus far, those previous studies have not produced consistent results, possibly because: (1) fasting plasma glucose, post-load plasma glucose (1-h and 2-h plasma glucose during an oral glucose tolerance test) and HbA1c were not fully and simultaneously taken into account in the analysis; and (2) the characteristics of the study participants, such as ethnicity, differed among the studies. Given the fact that a slight elevation of post-load plasma glucose levels in normal glucose tolerance increases the risk of cardiovascular disease, it is important for the primary prevention of cardiovascular disease to further elucidate whether carotid artery intima-media thickness increases with the elevation of post-load plasma glucose levels in subjects with normal glucose tolerance. The purpose of the present study was to examine the relationship between carotid artery intima-media thickness and several glycaemic variables, including post-load plasma glucose levels, in Japanese subjects with normal glucose tolerance.

Subjects and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Funding sources
  8. Competing interests
  9. Acknowledgements
  10. References
  11. Supporting Information

Study subjects

In the present study, we analysed a database of subjects who underwent intensive health check-ups at Ota Memorial Hospital, Ota City, Gunma, Japan, between 2004 and 2010. All study subjects were local residents or workers employed in the car-manufacturing industry. If subjects underwent health check-ups ≥ 2 times during the study period, the data derived from the latest check-up were included in the analysis. From all the subjects in the database (n = 959), those with diabetes, impaired glucose tolerance or impaired fasting glucose were excluded from analysis (n = 268). In addition, those who had a history or presence of malignant disease, collagen disease or cardiovascular disease were also excluded (n = 28). Thus, the present analysis included 663 subjects (565 men, age range 28–79 years). This study was approved by the Institutional Review Board at Ota Memorial Hospital.

Measurements of variables

All subjects underwent an anthropometrical evaluation, including BMI, calculated as weight in kilograms divided by the square of height in meters. Systolic and diastolic blood pressures were measured twice by sphygmomanometer, consecutively after 5 min of quiet rest in the sitting position. The averages of systolic and diastolic blood pressures were used in the subsequent statistical analyses.

Venous blood was collected after the subjects had fasted overnight. Serum levels of triglycerides, LDL cholesterol, HDL cholesterol, C-reactive protein (CRP), creatinine and plasma glucose were measured using an automated analyser (AU2700; Olympus Co. Ltd., Tokyo, Japan). HbA1c was measured using the latex coagulating method. Because HbA1c values were recorded in our database in the form used by the Japan Diabetic Society, we converted them to National Glycohemoglobin Standardization Program (NGSP) values for the present study, in accordance with the following equation [14]: HbA1c (NGSP) (%) = 1.02 × HbA1c (Japan Diabetes Society) (%) + 0.25. Serum creatinine-based estimated glomerular filtration rate (eGFRCr) was calculated using the following equation, recommended by the Japanese Society of Nephrology [15]: eGFRCr = 194 × creatinine (mg/dl)–1.094 × age (years)–0.287 × 0.739 (if a woman).

Obesity was defined as BMI ≥ 25.0 kg/m2. Hypertension was defined as systolic blood pressure ≥ 140 mmHg, diastolic blood pressure ≥ 90 mmHg or use of anti-hypertensive medications. Dyslipidaemia was defined as LDL cholesterol ≥ 3.626 mmol/l (140 mg/dl), HDL cholesterol < 1.036 mmol/l (40 mg/dl) or triglyceride ≥ 1.695 mmol/l (150 mg/dl) or use of lipid-lowering medications. Chronic kidney disease was defined as eGFRCr < 60 ml min–1 1.73 m–2. An elevated CRP was defined as ≥ 1.0 mg/l.

Procedure of oral glucose tolerance test and the diagnosis of normal glucose tolerance

All subjects underwent an oral glucose tolerance test in the morning after overnight fasting. Blood samples were collected through an indwelling venous catheter, before, and 1 and 2 h after the ingestion of a standard dose (75 g) of glucose (Toleran G; Ajinomoto Pharmaceuticals Co., Tokyo, Japan) and respective plasma glucose levels were then measured. Based on the results of the oral glucose tolerance test and HbA1c, any subjects with diabetes, impaired glucose tolerance or impaired fasting glucose, defined according to the World Health Organization/International Diabetes Federation 2006 criteria [16] and the recommendations of the World Health Organization 2009 [17], were excluded from the present study. Namely, data analysis was restricted to the 663 subjects with normal glucose tolerance, defined as a fasting plasma glucose level ≤ 6.0 mmol/l (≤ 109 mg/dl), 2-h plasma glucose level during 75-g oral glucose tolerance test ≤ 7.7 mmol/l (≤ 139 mg/dl) and HbA1c level ≤ 46 mmol/mol (≤ 6.4%).

Measurement of carotid artery intima-media thickness

The carotid artery intima-media thickness was measured by high-resolution B-mode ultrasonography (Aplio SSA-700A; Toshiba Medical Systems Corporation, Tochigi, Japan) with a linear 12-MHz transducer. All measurements were performed and interpreted by experienced ultrasonographers who were blinded to all the subjects' clinical and laboratory characteristics. They had also been trained to increase measurement accuracy prior to the data collection period in the present study. The training was almost in line with the recommendations of the American Society of Echocardiography, although these were published after the start of the present data collection [18]. The measurement protocol included multiple longitudinal and transverse imaging of the common carotid artery. The thickness of the intima-media complex was assessed as described by Pignoli et al. [19]. The maximal carotid artery intima-media thickness value in the right and left common carotid arteries was used for the statistical analyses.

Statistical analysis

All statistical analyses were performed using the SPSS 16.0 statistical package (SPSS Inc., Tokyo, Japan). Continuous variables were expressed as the arithmetic mean ± sd, while those with a skewed distribution (triglycerides, CRP and carotid artery intima-media thickness) were expressed as geometric mean [95% confidence interval (CI)]. Categorical data were expressed as the percentage of the total. For triglycerides, CRP and carotid artery intima-media thickness, common log-transformed values were used for the statistical analyses. Pearson's moment correlation coefficient was analysed to determine the simple correlation between continuous variables. Correlations between continuous and dichotomous variables were analysed by the point biserial correlation coefficient, which is virtually identical to the Pearson's moment correlation coefficient. Analysis of variance with post hoc Bonferroni multiple comparisons was performed to compare the differences in carotid artery intima-media thickness among the tertiles of fasting plasma glucose [3.16–5.05, 5.11–5.44 and 5.49–6.05 mmol/l (57–91, 92–98 and 99–109 mg/dl)], 1-h plasma glucose [2.89–6.38, 6.44–8.27 and 8.33–13.32 mmol/l (52–115, 116–149 and 150–240 mg/dl)], 2-h plasma glucose [3.11–5.44, 5.49–6.38 and 6.49–7.71 mmol/l (56–98, 99–116 and 117–139 mg/dl)] and HbA1c (25–36, 37–39 and 40–45 mmol/mol (4.4–5.4, 5.5–5.7 and 5.8–6.3%)]. Analysis of covariance was also used to compare the differences in adjusted carotid artery intima-media thickness. Multiple linear regression analysis was used to examine the independent association between carotid artery intima-media thickness and glycaemic variables, after adjusting for the potential confounding factors. In the multivariate analysis, diastolic blood pressure was not used simultaneously with systolic blood pressure in order to avoid multicollinearity (r = 0.87 between systolic and diastolic blood pressure). A P-value < 0.05 was considered statistically significant.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Funding sources
  8. Competing interests
  9. Acknowledgements
  10. References
  11. Supporting Information

The characteristics of the study subjects are shown in Table 1. The mean age was 47 ± 9 years. The means of BMI, systolic and diastolic blood pressure and lipid profiles were within acceptable ranges. The geometric mean (95% CI) of carotid artery intima-media thickness was 0.63 (0.62–0.65) mm. The means of fasting plasma glucose, 1-h plasma glucose, 2-h plasma glucose and HbA1c were 5.22 ± 0.41 mmol/l (94 ± 7 mg/dl), 7.46 ± 1.99 mmol/l (134 ± 36 mg/dl), 5.90 ± 1.02 mmol/l (106 ± 18 mg/dl) and 37 ± 3.3 mmol/mol (5.5 ± 0.3%), respectively. The correlation coefficients among these four glycaemic variables, as well as their correlations with other studied variables, are shown in the Supporting Information (Table S1).

Table 1. Characteristics of study subjects (n = 663)
  1. Data are expressed as mean ± sd, geometric mean (95% CI) or number (percentage of the total).

  2. CRP, C-reactive protein; eGFRCr, creatinine-based estimated glomerular filtration rate.

Men, n (%)565 (85.2)
Age (years)47 ± 9
BMI (kg/m2)23.4 ± 3.0
Obesity n (%)176 (26.5)
Systolic blood pressure (mmHg)119 ± 15
Diastolic blood pressure (mmHg)72 ± 11
Hypertension, n (%)126 (19.0)
Medication for hypertension, n (%)69 (10.4)
Fasting plasma glucose (mmol/l)5.22 ± 0.41
1-h plasma glucose (mmol/l)7.46 ± 1.99
2-h plasma glucose (mmol/l)5.90 ± 1.02
HbA1c (mmol/mol)36.7 ± 3.0
(%)5.5 ± 0.3
LDL cholesterol (mmol/l)3.28 ± 0.74
HDL cholesterol (mmol/l)1.50 ± 0.36
Triglycerides (mmol/l)1.20 (1.18–1.21)
Dyslipidaemia, n (%)331 (49.9)
Medication for dyslipidaemia, n (%)35 (5.3)
eGFRCr (ml min–1 1.73 m–2)76.6 ± 13.1
Chronic kidney disease, n (%)58 (8.7)
Current smoking, n (%)259 (39.1)
CRP (mg/l)0.48 (0.44–0.52)
Elevated CRP, n (%)151 (22.8)
Carotid artery intima-media thickness (mm)0.63 (0.62–0.65)

Table 2 shows the differences in carotid artery intima-media thickness according to the tertile of each glycemic variable. The carotid artery intima-media thickness gradually increased across the tertiles of 1-h plasma glucose, 2-h plasma glucose and HbA1c, showing significant differences. The carotid artery intima-media thickness in the highest tertile of these three glycaemic variables was significantly higher than in the respective lowest tertile. The carotid artery intima-media thickness in the highest tertile of 2-h plasma glucose and HbA1c was also significantly higher than that in the corresponding middle tertile. In contrast, no significant differences in carotid artery intima-media thickness were observed among the tertiles of fasting plasma glucose. Differences in the characteristics of the study subjects among the tertiles of 2-h plasma glucose are presented in the Supporting Information (Table S2).

Table 2. Differences in carotid artery intima-media thickness according to the tertile of fasting plasma glucose, 1-h plasma glucose, 2-h plasma glucose and HbA1c
Fasting plasma glucose tertileCarotid artery intima-media thickness (mm)1-h plasma glucose tertileCarotid artery intima-media thickness (mm)2-h plasma glucose tertileCarotid artery intima-media thickness (mm)HbA1c tertileCarotid artery intima-media thickness (mm)
  1. Data are shown in geometric mean (95% CI). Fasting plasma glucose 3.16–5.05, 5.11–5.44 and 5.49–6.05 mmol/l (57–91, 92–98 and 99–109 mg/dl) in the lowest to the highest tertile, respectively; 1-h plasma glucose 2.89–6.38, 6.44–8.27 and 8.33–13.32 mmol/l (52–115, 116–149 and 150–240 mg/dl) in the lowest to the highest tertile, respectively; 2-h plasma glucose 3.11–5.44, 5.49–6.38 and 6.49–7.71 mmol/l (56–98, 99–116 and 117–139 mg/dl) in the lowest to the highest tertile, respectively; and HbA1c 25–36, 37–39 and 40–45 mmol/mol (4.4–5.4, 5.5–5.7 and 5.8–6.3%) in the lowest to the highest tertile, respectively.

  2. *P < 0.05 vs. lowest tertile, †P < 0.001 vs. lowest tertile and ‡P < 0.05 vs. middle tertile.

  3. ANOVA, analysis of variance.

Lowest0.62 (0.59–0.65)Lowest0.61 (0.58–0.63)Lowest0.60 (0.57–0.62)Lowest0.61 (0.58–0.64)
Middle0.63 (0.60–0.66)Middle0.63 (0.60–0.66)Middle0.62 (0.60–0.65)Middle0.62 (0.60–0.65)
Highest0.65 (0.62–0.69)Highest0.67 (0.63–0.70)*Highest0.68 (0.65–0.72)†‡Highest0.70 (0.66–0.75)†‡
P value (ANOVA)0.25P value (ANOVA)0.024P value (ANOVA)< 0.001P value (ANOVA)< 0.001

The simple correlation between carotid artery intima-media thickness and the studied variables is described in Table 3. The carotid artery intima-media thickness was significantly and positively correlated with 1-h plasma glucose, 2-h plasma glucose and HbA1c, but not fasting plasma glucose. The carotid artery intima-media thickness was also significantly correlated with age, BMI, systolic and diastolic blood pressure, hypertension, LDL and HDL cholesterol, triglycerides, dyslipidaemia, eGFRCr, chronic kidney disease and CRP.

Table 3. Pearson's correlation coefficient for the association between carotid artery intima-media thicknessa and each of the studied variables
Variables r P-value
  1. a

    Log-transformed values.

  2. CRP, C-reactive protein; eGFRCr, creatinine-based estimated glomerular filtration rate.

Sex (male = 1)–0.020.59
Age0.45< 0.001
BMI0.120.001
Obesity (yes = 1)0.050.22
Systolic blood pressure0.19< 0.001
Diastolic blood pressure0.17< 0.001
Hypertension (yes = 1)0.22< 0.001
Fasting plasma glucose0.050.21
1-h plasma glucose0.100.010
2-h plasma glucose0.15< 0.001
HbA1c0.15< 0.001
LDL cholesterol0.120.003
HDL cholesterol–0.110.004
Triglyceridesa0.18< 0.001
Dyslipidaemia (yes = 1)0.15< 0.001
eGFRCr–0.17< 0.001
Chronic kidney disease (yes = 1)0.16< 0.001
Current smoking (yes = 1)0.060.13
CRPa0.110.004

In a multiple linear regression analysis (Table 4), 2-h plasma glucose (β = 0.07, = 0.049) was an independent determinant of carotid artery intima-media thickness among the glycaemic variables studied in model 1, which was adjusted for age, sex, BMI, systolic blood pressure, LDL and HDL cholesterol, triglycerides, eGFRCr, CRP, current smoking, medication for hypertension and medication for dyslipidaemia. Among these variables, age (β = 0.44, < 0.001) and systolic blood pressure (β = 0.13, P < 0.001) were also independent determinants of carotid artery intima-media thickness. When diastolic blood pressure was entered in model 1 instead of systolic blood pressure, the results were materially maintained (data not shown). The 2-h plasma glucose (β = 0.09, P = 0.012), but not other glycaemic variables, was again an independent determinant of carotid artery intima-media thickness in model 2, which was adjusted for age, sex, current smoking and dichotomous variables (obesity, hypertension, dyslipidaemia, chronic kidney disease and elevated CRP) instead of the corresponding continuous variables. In model 2, age (β = 0.41, < 0.001), sex (β = 0.08, P = 0.037), hypertension (β = 0.08, = 0.021), dyslipidaemia (β = 0.08, = 0.023) and current smoking (β = 0.09, = 0.015) were independent determinants of carotid artery intima-media thickness apart from 2-h plasma glucose.

Table 4. Multiple linear regression analysis for the association between carotid artery intima-media thickness* and glycaemic variables
VariablesModel 1Model 2
βP-valueβP-value
  1. Model 1: adjusted for sex, age, BMI, systolic blood pressure, LDL cholesterol, HDL cholesterol, triglycerides*, eGFRCr, CRP*, current smoking, medication for hypertension and medication for dyslipidaemia. Diastolic blood pressure was not included in model 1 so as to avoid multicollinearity with systolic blood pressure.

  2. Model 2: adjusted for sex, age, obesity, hypertension, dyslipidaemia, current smoking, chronic kidney disease and elevated CRP. *Log-transformed values.

  3. CRP, C-reactive protein; eGFRCr, creatinine-based estimated glomerular filtration rate.

Fasting plasma glucose–0.050.19–0.040.28
1-h plasma glucose–0.020.520.010.82
2-h plasma glucose0.070.0490.090.012
HbA1c0.050.230.050.23

Hypertension has been reported to increase carotid artery intima-media thickness [20], and both systolic blood pressure and hypertension were associated with carotid artery intima-media thickness in the present study. In addition, there was no interaction between the tertile of 2-h plasma glucose and hypertension status for carotid artery intima-media thickness (P = 0.70 for interaction). Therefore, subjects were next divided into six groups according to the combination of the tertiles of 2-h plasma glucose and hypertension status, and the carotid artery intima-media thickness was compared among the groups. As shown in Fig. 1a, the carotid artery intima-media thickness differed significantly among the groups (P < 0.001). In the post hoc multiple comparisons, the carotid artery intima-media thickness was significantly higher in hypertensive subjects with the highest tertile of 2-h plasma glucose than in normotensive subjects with all tertiles of 2-h plasma glucose. The carotid artery intima-media thickness was also significantly higher in subjects with hypertension with the middle tertile of 2-h plasma glucose than in normotensive subjects with the lowest or middle tertile of 2-h plasma glucose. In addition, the carotid artery intima-media thickness in normotensive subjects with the highest tertile of 2-h plasma glucose was significantly higher than in those with the lowest tertile of 2-h plasma glucose. In an analysis of covariance, with adjustment for age, sex, obesity, dyslipidaemia, current smoking, chronic kidney disease and elevated CRP, the differences in the carotid artery intima-media thickness among the groups were attenuated but remained significant (P = 0.009, Fig. 1b). In the post hoc analysis, the carotid artery intima-media thickness in hypertensive subjects with the highest tertile of 2-h plasma glucose [0.70 (95% CI 0.64–0.76) mm] was significantly greater than in normotensive subjects with the lowest tertile of 2-h plasma glucose [0.60 (0.58–0.63) mm, P = 0.037].

image

Figure 1. Differences in (a) the unadjusted and (b) the adjusted carotid artery intima-media thickness among the six groups according to the combination of tertiles of 2-h plasma glucose and hypertension status. In part (b), carotid artery intima-media thickness was adjusted for age, sex, obesity, dyslipidaemia, current smoking, chronic kidney disease and elevated C-reactive protein. *P < 0.001 vs. normotensive subjects with the lowest tertile of 2-h plasma glucose, P < 0.001 vs. normotensive subjects with the middle tertile of 2-h plasma glucose and P = 0.024 vs. normotensive subjects with the highest tertile of 2-h plasma glucose. †P < 0.001 vs. normotensive subjects with the lowest tertile of 2-h plasma glucose and P = 0.005 vs. normotensive subjects with the middle tertile of 2-h plasma glucose. ‡P = 0.027 vs. normotensive subjects with the lowest tertile of 2-h plasma glucose. §P = 0.037 vs. normotensive subjects with the lowest tertile of 2-h plasma glucose. Error bars indicate 95% confidence intervals. ANCOVA, analysis of covariance; ANOVA, analysis of variance.

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Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Funding sources
  8. Competing interests
  9. Acknowledgements
  10. References
  11. Supporting Information

The present study demonstrated that the 2-h plasma glucose during the oral glucose tolerance test was independently and positively associated with carotid artery intima-media thickness in Japanese subjects with normal glucose tolerance who underwent intensive health check-ups. In contrast, other glycaemic variables used in the present study (fasting plasma glucose, 1-h plasma glucose or HbA1c) did not show any independent associations with carotid artery intima-media thickness. These results suggest a possible contribution of prolonged, slight elevation in non-fasting plasma glucose levels to the progression of early atherosclerosis in Japanese subjects with normal glucose tolerance.

The novelty of the present report is that it entered the fasting plasma glucose, post-load plasma glucose (1-h and 2-h plasma glucose during the oral glucose tolerance test) and HbA1c simultaneously in the analyses in order to fully examine the association between carotid artery intima-media thickness and these glycaemic variables in Japanese subjects with normal glucose tolerance. To our knowledge, four previous studies [10-13] have demonstrated a relationship between carotid artery intima-media thickness and glycaemic variables, including those obtained from the oral glucose tolerance test, in subjects with normal glucose tolerance. However, all the glycaemic variables used in the present study were not necessarily entered in the analyses in three of those four studies [10, 12, 13]. The remaining study, reported by Bobbert et al., used all these glycaemic variables in the analyses, which showed that HbA1c was the most informative marker with respect to carotid artery intima-media thickness [11]. This result appears to conflict with our present observations, but this discrepancy may be explained in part by the difference in the subjects' ethnicity (e.g. Caucasian vs. Asian), as well as other differences in the characteristics of the study participants, such as BMI (mean 23.5 kg/m2 in the present study vs. > 28 kg/m2 in the study by Bobbert et al.). These differences raise the possibility of dissimilar fluctuation patterns of plasma glucose levels during the oral glucose tolerance test, which may in turn result in the discrepant findings between the studies.

One possible mechanism by which elevated 2-h plasma glucose levels could be positively associated with carotid artery intima-media thickness is the involvement of hyperinsulinaemia and/or increased insulin resistance. Hyperinsulinaemia and/or increased insulin resistance impair endothelial function [21, 22], which is an initial step toward the progression of atherosclerosis. Indeed, hyperinsulinaemia and/or increased insulin resistance have been reported to be associated with the presence and the progression of coronary artery stenosis in patients with normal glucose tolerance [23-25]. The recent DECODE study [26] showed that normoglycaemic individuals with higher 2-h plasma glucose levels had elevated fasting insulin levels and increased insulin resistance. These previous observations may in part support our present findings for the association between an elevated 2-h plasma glucose level and an increased carotid artery intima-media thickness. However, serum insulin levels were not measured in the present study. Further studies are needed to address this issue.

Other than glycaemic variables, age and systolic (or diastolic) blood pressure were independently associated with carotid artery intima-media thickness. When hypertension and dyslipidaemia were entered in the model instead of blood pressure and lipid variables, they were also independently associated with carotid artery intima-media thickness. Because it is well known that advancing age, elevated blood pressure and dyslipidaemia are associated with an increase in carotid artery intima-media thickness [20, 27], our present findings are in line with previous observations. Regarding the strength of the association, carotid artery intima-media thickness had a much stronger association with age (β = 0.44) and a stronger association with systolic blood pressure (β = 0.13) than with 2-h plasma glucose (β = 0.07). These are convincing findings, because subjects with high plasma glucose or HbA1c levels (e.g. those with impaired fasting glucose, impaired glucose tolerance or diabetes) were excluded, while those with high blood pressure or the elderly were not excluded from the present study. Therefore, it is a very important finding that 2-h plasma glucose emerged as an independent determinant of carotid artery intima-media thickness, even in a population that only included subjects with normal glucose tolerance. In fact, the combination of hypertension and elevated 2-h plasma glucose appeared to significantly increase carotid artery intima-media thickness. From a clinical perspective, physicians should be aware that subjects with normal glucose tolerance who have a high normal value of 2-h plasma glucose and hypertension may be at risk for the progression of atherosclerosis, or may already have early atherosclerosis.

Earlier studies have shown inconsistent results regarding the association between CRP and carotid artery intima-media thickness [28-30]. We previously reported a significant association between CRP and carotid artery intima-media thickness using the same database as in the present study [31]. Nevertheless, the independent association in our previous report [31] was not observed in the present study. These seemingly discrepant findings may be attributable to the fact that the characteristics of the present study participants (only individuals with normal glucose tolerance) and the present statistical methods (multiple glycaemic variables, including post-load plasma glucose levels, entered in a multivariate analysis) were different from those in our previous study [31].

The present study has some potential limitations. First, the proportion of female participants was relatively small. Second, as noted above, the serum insulin levels were not measured. Third, detailed information about the medications used to treat hypertension and dyslipidaemia, such as their types and dosage, could not be obtained. Fourth, most participants had a carotid artery intima-media thickness of < 1.0 mm, which is one proposed cut-off level for identifying individuals at high risk for cardiovascular disease [32]. However, even carotid artery intima-media thickness values < 1.0 mm have been reported to be useful for cardiovascular risk prediction, beyond traditional cardiovascular risk factors [33]. Finally, this study was a cross-sectional investigation and the causal relationship between the cardiovascular risk variables and carotid artery intima-media thickness could not be clarified. Despite that our data suggested the association of 2-h plasma glucose with carotid artery intima-media thickness even in the patients with normal glucose tolerance, more evidence including cost–benefit analysis, is warranted to justify the clinical significance.

In conclusion, the present study showed that the 2-h plasma glucose level during the oral glucose tolerance test was positively and independently associated with carotid artery intima-media thickness. It also showed that hypertensive subjects with the highest tertile of 2-h plasma glucose had increased carotid artery intima-media thickness. Further research is required to determine whether an assessment of 2-h plasma glucose in patients with normal glucose tolerance improves clinical outcome.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Funding sources
  8. Competing interests
  9. Acknowledgements
  10. References
  11. Supporting Information

The authors would like to thank Dr Eitaro Kodani for his valuable suggestions for improving the manuscript.

References

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Funding sources
  8. Competing interests
  9. Acknowledgements
  10. References
  11. Supporting Information
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Supporting Information

  1. Top of page
  2. Abstract
  3. Introduction
  4. Subjects and methods
  5. Results
  6. Discussion
  7. Funding sources
  8. Competing interests
  9. Acknowledgements
  10. References
  11. Supporting Information
FilenameFormatSizeDescription
dme12288-sup-0001-TableS1.docxWord document20KTable S1. Correlation coefficient among the studied variables.
dme12288-sup-0002-TableS2.docxWord document18KTable S2. Characteristics of study subjects according to tertile of 2-h plasma glucose.

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