Atherosclerosis 225 (2012) 450e455

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Atherosclerosis
journal homepage: www.elsevier.com/locate/atherosclerosis

Serum glycated albumin predicts the progression of carotid arterial

atherosclerosis
Sun Ok Song a, Kwang Joon Kim a, b, Byung-Wan Lee a, *, Eun Seok Kang a, Bong Soo Cha a, Hyun Chul Lee a
a
Division of Endocrinology and Metabolism, Department of Internal Medicine, Severance Hospital, Yonsei University College of Medicine, 134 Shinchon-dong, Seodaemun-gu,
Seoul 120-752, Republic of Korea
b
Severance Executive Healthcare Clinic, Severance Hospital, Yonsei University Health System, Seoul, Republic of Korea

a r t i c l e i n f o a b s t r a c t

Article history: Introduction: We investigated the association between the ratio of serum glycated albumin (GA) levels to
Received 22 June 2012 hyperglycemic levels (GA/A1c ratio) and the progression of carotid artery atherosclerosis.
Received in revised form Methods: For this retrospective longitudinal study we recruited patients who had undergone carotid IMT
24 August 2012
measurement twice and been tested consecutively for both A1c and GA levels every 3 or 6 months. The
Accepted 6 September 2012
Available online 18 September 2012
subjects were classified into two groups based on non-progression (group I) and progression (group II) of
carotid IMT. Mean values of A1c and GA and the GA/A1c ratio were compared between groups.
Results: Of the 218 subjects (122 men and 96 women), group II (n¼77) showed significantly higher
Keywords:
Glycated albumin
baseline systolic BP, eGFR, GA, GA/A1c ratio, and progression of carotid IMT (D IMT) than group I (n ¼
Type 2 diabetes 141). The mean A1c level tended to be higher in group II than in group I (p ¼ 0.054). By Spearman's
Carotid intima media correlation test, baseline diastolic BP, total cholesterol, triglyceride, GA, and GA/A1c were significantly
Thickness associated with D IMT in group II but not in group I. In multivariate regression analysis, serum level of GA
GA/A1c ratio and GA/HbA1c ratio predicted progression of IMT after adjustment for other risk factors in both models
applied.
Conclusion: We suggest that glycated albumin is not only a useful glycemic index but also might be an
atherogenic protein in the development of diabetic atherosclerosis.
Ó 2012 Elsevier Ireland Ltd. All rights reserved.

1. Introduction
Atherosclerosis is a major vascular complication in type 2 dia-
betes (T2D) and can have severe consequences such as coronary
heart disease or stroke. Among the known risk factors for athero-
sclerosis, there is controversy over the role of advanced glycated
end product (AGE)-mediated vascular inflammation in the devel-
opment or progression of atherosclerosis in patients with T2D [1,2].
The utility of glycated albumin (GA) as an intermediate term (2e3
weeks) parameter for glucose monitoring and as a useful and rapid
glycation index for glucose fluctuation and excursion is well
recognized [3], but there is growing evidence that GA, a precursor
of AGEs, is also associated with enhanced oxidative stress and
endothelial injury resulting in atherosclerosis in diabetic subjects
[2,4,5,6]. In a recent cross-sectional study, we demonstrated that an
increased GA level is associated with atherosclerotic plaque
formation assessed by carotid intima media thickness (IMT) in type
2 diabetic subjects without evidence of coronary heart disease and
peripheral arterial disease documented by cardiac MRI and ABI [7].
Although an association between carotid IMT progression and
several common risk variables such as hyperlipidemia, hyperten-
sion, and hyperglycemia has been widely demonstrated [8], few
clinical studies have been performed on the role of GA in predicting
diabetic vascular complications.
In this study, we hypothesized that, in addition to higher glyce-
mic indices, increased glycation indices might also predict or reflect
an increase or progression of carotid IMT. Based on this hypothesis,
we aimed to investigate the association between carotid artery
atherosclerosis and an elevated ratio of GA levels relative to hyper-
glycemic levels (measured by glycated hemoglobin or A1c levels) by
adopting the GA/A1c ratio used for controlling hyperglycemia.
2. Methods
2.1. Subjects and research design

This study was a retrospective longitudinal study on type 2 dia-

* Corresponding author. Tel.: þ82 2 2228 1938; fax: þ82 2 393 6884. betic subjects who were registered on the Severance Hospital Dia-
E-mail address: bwanlee@yuhs.ac (B.-W. Lee). betes Complications Registry between March 2009 and April 2012.

0021-9150/$ e see front matter Ó 2012 Elsevier Ireland Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.atherosclerosis.2012.09.005
 S.O. Song et al. / Atherosclerosis 225 (2012) 450e455
We recruited adult subjects who satisfied the following criteria: (1)
had undergone carotid IMT measurement twice in this period; and
(2) had been tested consecutively for both A1c and GA every 3 or 6
months. Exclusion criteria included patients unavailable for repeat
GA analysis within a 6-month period. We defined the positive values
of D IMT (D IMT ¼ follow-up IMT  baseline IMT) as progression of
carotid IMT, and even or negative D IMT as non-progression. Based on
this definition, we classified the subjects into non-progression and
progression of carotid IMT during the time interval of carotid IMT
measurements. The study protocol was approved by the ethics
committee of Yonsei University College of Medicine.
2.2. Laboratory assessments
Blood samples were collected from subjects after an overnight
fast. Plasma glucose was measured using the glucose oxidase
method. Plasma triglycerides, total cholesterol, high-density lipo-
protein cholesterol (HDL cholesterol), blood urea nitrogen, creati-
nine, AST, and ALT levels were assayed using a routine Hitachi 7600
autoanalyzer (Hitachi Instruments Service, Tokyo, Japan). Low-
density lipoprotein cholesterol (LDL cholesterol) was calculated
using the Friedewald equation. Serum glycated albumin (GA) was
determined by an enzymatic method using an albumin-specific
proteinase, ketamine oxidase, albumin assay reagents (LUCICA
GA-L, Asahi Kasei Pharma Co., Tokyo, Japan), and a Hitachi 7699 P
module autoanalyzer. The coefficient of variation (CV) was 1.43%.
Serum glycated hemoglobin (HbA1c; henceforth described as A1c)
was measured by high-performance liquid chromatography (HPLC)
using a Variant II Turbo system (Bio-Rad Laboratories, Hercules,
CA). The reference interval was between 4.0 and 6.0% for A1c and
between 11.0 and 16.0% for GA.
The average of A1c (henceforth referred to as mean A1c), GA
(mean GA), and GA/A1c ratio (mean GA/A1c) were calculated by the
sum of every measured values in each indices divided by the
numbers of values throughout the study period.
2.3. Measurement of intima media thickness (IMT)
The change in IMT (mm) (D IMT ¼ follow-up IMT  baseline IMT)
during the study period was calculated. IMT measurement has been
described in detail in previous reports [7]. Briefly, common carotid
arterial ultrasound examinations were conducted by two specialized
technicians using an Aloka ProSound ALPHA 10 (HITACHI, Tokyo,
Japan) with a 13 MHz linear probe. All measurements were recorded
with the subject in a supine position with the head elevated to 45
and tilted to either side by 30 . We performed B mode examinations
1.5 cm proximal to the carotid bifurcation on the far wall of the
common carotid artery and on both sides. IMT was defined as the
distance between the mediaeadventitia interface and the lumene
intima interface. Average IMT was the mean value of computer-based
points in the region, and maximal IMT was the IMT value at the
maximal point of the region [9]. Reproducibility was further tested
for carotid IMT measurements: inter-observer coefficient of variation
(CV) was 2.11%, and the day-to-day coefficient of variation was 2.06%.
Plaques were defined according to the Mannheim consensus [10], in
which a plaque is diagnosed when the vessel wall thickness is greater
than 1.5 mm or when the vessel wall appears to be at least .5 mm or
50% thicker than the surrounding wall.
2.4. Statistical analysis
All statistical analyses were performed with PASW statistics soft-
ware (version 18.0; SPSS Inc., Chicago, IL). We performed the Kol-
mogoroveSmirnov test to identify whether the data are not normally
distributed. Because of their non-normal distribution, all continuous
451
variables were expressed as medians (interquartile range). Discrete
variables were expressed as percentages. Statistical comparisons
between groups with and without carotid artery IMT progression
were performed using the ManneWhitney U test or c2 test which are
non-parametric statistical methods. Spearman’s correlation coeffi-
cient, a type of non-parametric correlation analysis, was used to
determine the relationship between IMT changes and the continuous
variables. Multivariate logistic regression analysis was used to esti-
mate multiple correlations between carotid artery IMT changes and
clinical and laboratory risk factors. c2 test was used for comparison of
carotid IMT changes according to the progression or regression of IMT
level. Data with p value <.05 were considered significant.
3. Results
3.1. Characteristics of the study participants
A total of 218 subjects (122 men and 96 women; median age,
62.0 [interquartile range (IQR), 53.0e68.0] years) were finally
enrolled in this study. The enrolled subjects were classified into
non-progression (group I, n ¼ 141) and progression (group II,
n ¼ 77) of carotid IMT during the time interval of carotid IMT
measurements. The median duration of diabetes was 6.00 (3.00e
12.0) years. The median levels of serum A1c, GA, and the value of
GA/A1c were 7.00% (6.40e7.95), 14.6% (16.9e20.9), and 2.17 (2.45e
2.76), respectively. The median BMI of the study subjects was 25.3
(23.3e27.5) kg/m2. Table 1 shows the demographic and laboratory
characteristics between the two groups, focusing on glucose
metabolism and cardiovascular risk variables. The median age (62
(IQR 53.0e68.0) vs. 62 (IQR 53.8e69.3)) and gender (52.5% vs.
62.3%) were relatively similar between patients with non-
progression (group I) and progression (group II) of IMT, respec-
tively. Except for SBP and parameters for glycemic indices, there
were no differences in other anthropometric characteristics
between two groups. Systolic blood pressure was higher in group II
(129 (IQR 119.0e142.3)) than in group I (125 (IQR 118.0e137.0),
p ¼ 0.032). Compared to group I without-progression of carotid
IMT, the baseline GA (16.3% (IQR 14.2e20.5) vs. 18.1% (IQR 15.7e
23.4), p ¼ 0.016), baseline GA/A1c ratio (2.40 (IQR 2.14e2.69) vs.
2.49 (IQR 30e2.91), p ¼ 0.013), the mean GA over the study period
(15.8%(IQR 14.1e18.6) vs. 17.5% (IQR 14.8e21.7), p ¼ 0.011) and
mean GA/A1c ratio (2.34 (IQR 2.13e2.54) vs. 2.49 (IQR 2.19e2.85),
p ¼ 0.019) were significantly higher in group II with progression of
carotid IMT. However, baseline A1c (6.8% (IQR 6.4e7.8), 7.2% (IQR
6.6e8.1), p ¼ 0.157) and mean A1c across the study period (6.9%
(IQR 6.5e7.5) vs. 7.08 (IQR 7.7e7.9), p ¼ 0.054) were not signifi-
cantly different between the groups (Table 1 and Fig. 2). Regarding
to the correlation of GA with A1c, which is the golden standard for
glycemic index, a strong linear relationship was observed between
mean serum GA and mean A1c levels in all patients in the
progression and non-progression groups (r ¼ .767, .749 and .783,
respectively, p < 0.001) (Fig. 1).
We also ascertained the subjects rank in each percentile for
baseline A1c (10, 25, 50, 75, 90) and compared glycemic indices,
baseline GA, baseline GA/A1c, mean GA, and mean GA/A1c between
group I and group II (Supplementary Figure S1). Baseline GA, mean
GA/A1c, mean GA, and mean GA/A1c were higher in group II than in
group I for every percentile of baseline HbA1c.
4. Association of carotid IMT progression with glycemic
indices and cardiovascular risk variables
Table 2 and Supplementary Figure S2 show Spearman’s corre-
lation coefficients between carotid IMT changes (D IMT) and the
variables for glycemic indices and cardiovascular risks in enrolled
452 S.O. Song et al. / Atherosclerosis 225 (2012) 450e455

Table 1
Participants characteristics stratified by carotid IMT progression.

All patients (n ¼ 218) Carotid IMT P value

Group I (Non progressioin, n ¼ 141) Group II (Progression, n ¼ 77)

Age (years) 62.0 [53.0e68.0 ] 62.0 [53.0e68.0 ] 62.0 [53.8e69.3 ] .364
Male sex (n,%) 122 (56%) 74 (52.5%) 48 (62.3%) .160
DM duration (years) 6.0 [3.0e12.0 ] 6.0 [3.0e12.0 ] 7.0 [3.0e14.3 ] .519
Smoking (n, %) 107 (49.7%) 64 (45.4%) 43 (55.8%) .141
BMI (kg/m2) 25.3 [23.3e27.5 ] 25.3 [23.3e27.4 ] 24.3 [23.0e27.4 ] .440
Waist-to-hip ratio .92 [.88e.96 ] .92 [.87e.96 ] .93 [.89e.96 ] .156
Follow up (months) 24.0 [21.0e27.0 ] 24.0 [21.0 27.0 ] 24.0 [21.0 27.0 ] .668
SBP (mmHg) 126.0 [119.0e138.0 ] 125 .0 [118.0e137.0 ] 129.0 [119.0e142.3 ] .032
DBP (mmHg) 73.0 [68.0e80.5 ] 73.0 [67.0e80.0 ] 73.0 [68.0e82.0 ] .798
baseline A1c (%) 7.00 [6.40e7.95 ] 6.80 [6.40e7.83 ] 7.20 [6.60e8.10 ] .157
baseline GA (%) 14.6 [16.9e20.9 ] 16.3 [14.2e20.5 ] 18.1 [15.7e23.4 ] .016
baseline GA/A1c 2.17 [2.45e2.76 ] 2.40 [2.14e2.69 ] 2.48 [2.30e2.91 ] .013
Mean A1c 6.95 [6.50e7.58 ] 6.90 [6.45e7.46 ] 7.08 [6.68e7.87 ] .054
Mean GA 16.4 [14.2e19.7 ] 15.8 [14.1e18.6 ] 17.5 [14.8e21.7 ] .011
Mean GA/A1c 2.39 [2.14e2.58 ] 2.13 [2.34e2.54 ] 2.19 [2.49e2.85 ] .019
baseline mean IMT .72 [.63e.83 ] .72 [.64e.83 ] .72 [.62e.85 ] .961
baseline max IMT .87 [.74e1.03 ] .87 [.74e1.03 ] .86 [.73e1.05 ] .793
follow-up mean IMT .71 [.61e.83 ] .67 [.60e.78 ] .76 [.67e.91 ] <.001
follow-up max IMT .70 [.81e.96 ] .77 [.67e.89 ] .90 [.77e1.13 ] <.001
D mean IMT .01 [.05e.03 ] .04 [.07 w .01 ] .04 [.01e.08 ] <.001
D max IMT .04 [.11e.01 ] .08 [.13 w .05 ] .03 [.00e.11 ] <.001
Creatinine .90 [.78e1.09 ] .89 [.76e1.02 ] .96 [.80e1.18 ] .002
eGFR 82.0 [70.9e93.2 ] 83.9 [73.1e95.8 ] 80.9 [64.2e89.5 ] .004
Total protein (g/dL) 7.10 [6.80e7.40 ] 7.10 [6.78e7.40 ] 7.20 [6.80e7.50 ] .313
Albumin (g/dL) 4.50 [4.30e4.80 ] 4.50 [4.30e4.80 ] 4.50 [4.30e4.80 ] .514
AST 21.0 [17.0e26.0 ] 20.0 [16.8e25.3 ] 21.5 [16.8e28.8 ] .739
ALT 22.0 [15.0e32.0 ] 21.0 [15.0e30.0 ] 23.0 [16.0e36.0 ] .420
Total cholesterol (mg/dL) 166.0 [144.0e196.0 ] 166.0 [141.8e199.8 ] 165.0 [146.8e188.5 ] .814
TG (mg/dL) 124.0 [37.0e176.0 ] 121.5 [86.0e174.5 ] 124.5 [96.5e179.3 ] .751
HDL (mg/dL) 43.0 [37.0e54.5 ] 43.5 [37.0e54.3 ] 43.0 [35.8e54.3 ] .308
LDL (mg/dL) 91.4 [71.6e117.0 ] 91.5 [69.6e118.9 ] 91.2 [73.8e111.7 ] .879

Data presented as median [IQR] for continuous variables with non-normal distribution and n (%) for categorical variables.

subjects. In all subjects, all glycemic indices (baseline and mean
A1c, GA and GA/A1c, respectively) were significantly but weakly
associated with D IMT. The baseline GA (p ¼ 0.02) and GA/A1c ratio
(p ¼ 0.04) showed significant association with D IMT in group II, but
not in group I (p ¼ 0.426, .709, respectively). However, baseline A1c
and mean A1c did not correlate with D IMT, and, mean GA and GA/
A1c across the study period showed only a weakly associated
tendency (p ¼ 0.098, and .064, respectively) in group II.
4.1. Factors associated with progression of carotid artery IMT
For the multivariate regression analysis, IMT change (D IMT)
(mm) was used as a dependent variable, and baseline A1c, GA, and
GA/A1c, and mean A1c, GA and GA/A1c values from this study and
conventional risk variables were entered as independent variables
(Table 3). In this analysis, we used two statistical models with
different independent variables. In model 1, we adopted SBP, eGFR,
and the glycemic indices. To avoid confounding factors and to
investigate the effects of serum GA, A1c and GA/A1c ratio on IMT
progression, we controlled for SBP and eGFR. Baseline GA/A1c (OR
1.741, p ¼ 0.024), mean GA (OR 1.067, p ¼ 0.010), and mean GA/A1c
ratio (OR 2.255, p ¼ 0.010) were independently correlated with IMT
progression. In model 2, we included classical atherosclerosis risk
factors such as age, gender, BMI, and LDL cholesterol in addition to
the variables in included in model 1. Baseline GA/A1c ratio, mean
GA, and mean GA/A1c ratio were independently correlated with

Fig. 1. (A) correlation between A1c and GA in each group; all patients: R ¼ .744, p < 0.001 Group I: R ¼ .719, p < 0.001 Group II: R ¼ .779, p < 0.001.(B). Correlation between mean
A1c and mean GA in each group; all patients: R ¼ .767, p < 0.001 Group I: R ¼ .749, p < 0.001 Group II: R ¼ .783, p < 0.001.
 S.O. Song et al. / Atherosclerosis 225 (2012) 450e455 453

Fig. 2. Glycemic indices between two groups with or without carotid IMT progression.

D IMT in both models. Of the glycemic indices, a high GA level and physiological aspects of the GA/A1c ratio in type 2 diabetic subjects,
a high GA/A1c ratio were correlated with D IMT after multivariate the observation that the GA/A1c ratio increases more rapidly than
adjustment for other risk factors in both models 1 and 2 (Table 3 the A1c level may be attributed to more marked increases in GA
and Supplementary Table S1). levels relative to A1c levels and to certain diabetic conditions such
as poorly controlled glucose and insulin deficient status [3,15]. The
4.2. Area under curve of glycemic indices for predicting carotid IMT more rapid increase in GA relative to A1c reflects the fact that the
progression rate of non-enzymatic glycation of proteins in the circulation is
approximately nine times faster than that of human hemoglobin,
We calculated the AUC of glycemic indices for D IMT prediction which resides in erythrocytes, and the glycation of albumin is
(Fig. 3). Except for baseline A1c (p ¼ 0.157) and mean A1c across the therefore approximately 10-fold greater than that of hemoglobin
study period (p ¼ 0.053), the AUCs for other glycemic indices were [14,16,17]. However, the practical implications of an increased or
statistically significant. Among baseline glycemic indices, baseline decreased GA/A1c ratio with respect to the development of diabetic
GA/A1c ratio presented the largest AUC for D IMT (p ¼ 0.010, vascular complications have not been well investigated.
AUC ¼ .618). In respect to average glycemic values over study Based on the knowledge that increased serum GA is associated
period, mean GA had the largest AUC for D IMT (p ¼ 0.011, with diabetic vascular complications [13], we hypothesized that
AUC ¼ .621). The cut-off values of baseline GA, GA/A1c ratio, and increased GA levels might be associated with progression of
A1c were 15.5%, 2.274, and 6.9%, respectively. In addition, cut-off atherosclerosis. To test this hypothesis, we adopted the GA/A1c
values of mean GA, GA/A1c ratio, and A1c over the study period ratio used for adjusting conventional glucose levels and measured
were 16.3%, 2.47, and 6.81% respectively. progressive changes of carotid IMT (D IMT) as an end-point of
atherosclerosis. We investigated the following: (1) variables that
5. Discussion differ between patients with progression and non-progression of
carotid IMT; (2) whether conventional CVD risk factors and glyce-
In diabetic subjects, exposure of circulating proteins to hyper- mic indices measured by the standard glycemic index of A1c, gly-
glycemia is inevitable, resulting in protein glycation. Among such cated albumin, and GA/A1c ratio are associated with the
glycated proteins, there is growing evidence supporting the progression of carotid IMT; and (3) which variables could predict
atherogenic effects of GA, a precursor of AGEs, in diabetic subjects the progression of carotid IMT.
[2,4,5,6,11,12,13]. Among glycation indices for glucose monitoring, We compared glucose metabolism parameters and cardiovas-
the current golden standard is hemoglobin A1c. However, some cular risk variables according to carotid IMT progression and non-
discrepancies exist between the levels of A1c and glycated albumin progression. The patients with carotid IMT progression showed
(GA) in certain pathologic disease states including anemia, liver increased SBP, increased baseline and mean GA and GA/A1c ratio,
cirrhosis, and nephritic syndrome [14]. With respect to the and reduced renal function. Although the levels of A1c were not
significantly different between the groups, the levels of GA and
ratio of GA/A1c were significantly different.
Table 2 With respect to independent correlates of carotid IMT
Associations of cardiovascular risk factors with carotid IMT progression.
progression, a positive D IMT was associated with all glycemic
All patients Group I Group II indices in all patients, although baseline A1c only tended to be
b p-value b p-value b p-value associated with progression of carotid IMT in our study population.
Age .011 .874 .161 .057 .047 .686 Other CVD risk factors such as age, BMI, WH ratio, BP, and choles-
BMI .059 .383 .011 .898 .109 .344 terol showed no association with positive D IMT. The lack of asso-
WH ratio .025 .719 .013 .875 .227 .049 ciation between these CVD risk factors including A1c and a positive
SBP .100 .140 .037 .663 .191 .096 D IMT could be due to the characteristics of our study population. In
DBP .020 .764 .014 .873 .235 .040
baseline A1c .186 .006 .156 .064 .220 .055
our diabetic patients, well-controlled plasma glucose (median A1c,
baseline GA .206 .002 .068 .426 .342 .002 7.00%, IQR 6.40e7.95), blood pressure (median SBP, 126 mmHg, IQR
baseline GA/A1c .190 .006 .032 .709 .336 .004 119.0e138.0) and cholesterol (median LDL-C, 91.4 mg/dL, IQR 71.6e
mean A1c .184 .007 .130 .126 .140 .223 117.0), as well as the early stage of disease (median duration of
mean GA .172 .011 .025 .770 .190 .098
diabetes, 6.0 years, IQR 3.0e12.0) might explain the lack of asso-
mean GA/A1c .139 .040 .034 .685 .212 .064
creatinine .084 .218 .137 .106 .100 .388 ciation of these factors with the progression of carotid IMT.
eGFR .073 .283 .161 .056 .013 .910 With respect to predictors for carotid IMT progression, the
T.chol .039 .568 .002 .982 .342 .002 association between initial and mean GA levels and carotid IMT
TG .129 .058 .135 .112 .313 .006 progression was maintained after multivariate adjustment. Multi-
HDL .028 .682 .053 .533 .002 .985
variable logistic regression analysis investigating factors that affect
LDL .008 .903 .020 .811 .071 .540
the progression of carotid IMT showed that SBP, eGFR, baseline GA/
454 S.O. Song et al. / Atherosclerosis 225 (2012) 450e455

Table 3
Multivariable logistic regression models for associations of cardiovascular risk factors with carotid IMT progression.

A B C

OR 95% CI for OR P value OR 95% CI for OR P value OR 95% CI for OR P value

Model 1
SBP 1.022 1.003e1.042 .022 1.022 1.003e1.042 .021 1.024 1.004e1.043 .016
eGFR .979 .965e.994 .006 .978 .964e.993 .003 .980 .966e.995 .007
Baseline A1c
Baseline GA
Baseline GA/A1c 1.741 1.074e2.821 .024
Mean A1c
Mean GA 1.067 1.016e1.121 .010
Mean GA/A1c 2.255 1.216e4.183 .010
Model 2
Age .996 .966e1.027 .801 .998 .968e1.029 .910 .995 .965e1.026 .758
Gender .807 .442e1.472 .484 .809 .442e1.480 .492 .828 .452e1.516 .540
BMI .989 .925e1.058 .750 .992 .928e1.061 .820 .995 .930e1.065 .891
SBP 1.021 1.001e1.040 .036 1.021 1.002e1.040 .034 1.022 1.003e1.042 .027
eGFR .980 .963e.997 .018 .979 .962e.996 .015 .980 .963e.997 .021
LDL 1.001 .993e1.009 .792 1.001 .993e1.009 .833 1.001 .993e1.010 .736
Baseline A1c
Baseline GA
Baseline GA/A1c 1.680 1.013e2.788 .045
Mean A1c
Mean GA 1.063 1.010e1.119 .018
Mean GA/A1c 2.213 1.148e4.265 .018

A1c ratio, mean GA, and mean GA/A1c ratio were independently
correlated with carotid IMT progression in this study population.
When we analyzed our data using only serum A1c as a glycemic
parameter rather than serum GA and GA/A1c ratio, no correlation
with IMT progression was found with any of the analytic models. In
this regard, we suggest that GA level might be a more powerful
parameter in predicting carotid IMT progression than conventional
golden standard glycemic index of hemoglobin A1c. Regarding to
significance of GA/A1c ratio compared to GA or A1c alone, simple
discrepancies between the levels of GA and A1c are attributed to
certain pathologic conditions, such as chronic renal failure and
anemia, or to rapid glucose changes such as developing time of
fulminant type 1 diabetes and periods of intensified glucose
lowering medication. Glucose excursion is a well-known factor for
atherosclerosis, especially carotid intima-media thickness [18,19].
Because GA, even among similar A1c levels, better reflects post-
prandial hyperglycemia, which is mainly caused by inadequate or
dysfunctional endogenous insulin secretion [6], clinical significance
of GA/A1c ratio over GA or A1c alone are not only a value of adjusted
conventional glucose levels but is also a better reflection of glucose
fluctuation, postprandial hyperglycemia, and dysfunctional insulin
secretory function [15].
In understanding the pathogenic effects of glycated albumin
(GA) on diabetic vascular complications, it is necessary to consider
that GA results from early-stage Amadori-modified reaction prod-
ucts formed from Schiff’s base adducts [14], and is regarded as
a precursor of AGEs [5]. In addition, albumin, synthesized mainly in
the liver, constitutes 50e60% of the total protein in the plasma of
healthy subjects. Physiologically, it is a pivotal antioxidant in
human serum [20]. Therefore, glycation and accompanying oxida-
tion of albumin leads to a loss of antioxidant activity and generates
an atherogenic protein in patients with diabetes [6]. This could
explain why a higher level of GA is related to vascular complications
in diabetes [5,12].

Fig. 3. ROC Curve of each glycemic indices predicting IMT progression.

 S.O. Song et al. / Atherosclerosis 225 (2012) 450e455
Our study has some limitations. First of all, this was a retro-
spective study conducted at a single center. Second, although other
variables such as medications taken by the study subjects and
smoking habits might affect the levels of GA, we did not analyze
their influence on GA because our attention was focused on the
clinical relevance of a higher GA/A1c ratio to atherosclerosis.
However, previous studies have demonstrated that smoking, sta-
tins, and oral hypoglycemic agents are associated with serum levels
of GA [6,14,21,22,23,24] and this should be considered in future
studies.
Based on the findings of the present study, we conclude that
serum GA has two main clinical implications in diabetic subjects:
first, similar to previous reports [3,13,15,25], GA is strongly corre-
lated with A1c (r ¼ .744, p < 0.001) which confers utility for the
glycemic index; second, GA might be an atherogenic protein in
diabetic subjects because our study demonstrates a significant
association between progression of IMT (D IMT) and glycated
albumin-related parameters. This results of this experiment are in
accord with the earlier one [13]. We postulate that new parameters
or equations to predict CVD using serum GA and GA/A1c ratio might
be developed in future studies with a larger study population.
Funding
This study was supported by a faculty research grant from
Yonsei University College of Medicine, 2012 (6-2012-0009).
Acknowledgments
Statistical analyses in this study were supported by Jieun Kim
(Basic Research Assistant Professor) and Min Woong Kang
(Research Assistant) at Biostatistics Collaboration Unit, Yonsei
University College of Medicine, Seoul, Korea.
Dong-Su Jang, B,A., (Research Assistant, Department of
Anatomy, Yonsei University College of Medicine, Seoul, Korea)
supplied figures for our requests.
The authors greatly appreciate the expert technical assistance
and help of them.
Appendix A. Supplementary material
Supplementary data associated with this article can be found, in
the online version, at http://dx.doi.org/10.1016/j.atherosclerosis.
2012.09.005.
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