Endocr. J./ K. Yoshiuchi et al.

: GA AND HbA1c IN T1 AND T2 DM

doi: 10.1507/endocrj/K07E-089

ORIGINAL

Glycated Albumin is a Better Indicator for Glucose Excursion than Glycated

Hemoglobin in Type 1 and Type 2 Diabetes

Kazutomi Yoshiuchi１, Munehide Matsuhisa１, Naoto Katakami１, Yoshihisa Nakatani１, Kenya

Sakamoto１, Takaaki Matsuoka１, Yutaka Umayahara2, Keisuke Kosugi2, Hideaki Kaneto１, Yoshimitsu
Yamasaki１ and Masatsugu Hori１

1 Department of Internal Medicine and Therapeutics, Osaka University Graduate School of Medicine,
Osaka, Japan
2 Department of Internal Medicine, Osaka Police Hospital, Osaka, Japan

Received October 10, 2007; Accepted February 26, 2008; Released online April 30, 2008

Correspondence to: Munehide Matsuhisa M.D., Ph.D., Department of Internal Medicine and
Therapeutics, Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita City 565-0871,
Japan

Abstract. To determine the impact of blood glucose profile, involving fluctuation and excursion of
blood glucose levels, on glycated proteins, we evaluated the association among the daily profile of
blood glucose, and glycated albumin (GA) and HbA1c levels in patients with type 1 diabetes (n=93)
and type 2 diabetes ( n=75). GA levels were strongly correlated with HbA1c levels in type 1 (r = 0.85,
P < 0.0001) and type 2 diabetes (r = 0.61, P < 0.0001), respectively. HbA1c levels were similar between
patients with type 1 and type 2 diabetes, while GA levels were significantly higher in type 1 diabetes.
Thus the ratio of GA levels to HbA1c levels was significantly higher in type 1 diabetes than that in type
2 diabetes (3.32 ± 0.36 vs. 2.89 ± 0.44, p < 0.001). The degrees of GA levels and HbA1c levels
correlated with maximum and mean blood glucose levels in patients with type 1 and type 2 diabetes.
Stepwise multivariate analysis revealed that GA levels independently correlated with maximum blood
glucose levels in type 1 diabetes (F=43.34, P<0.001) and type 2 diabetes (F=41.57, P<0.001). HbA1c
levels also independently correlated with maximum blood glucose levels in type 1 diabetes (F=34.78,
P<0.001), as well as being correlated with mean blood glucose levels in type 2 diabetes (F=11.28,
P<0.001). In summary, GA could be a better marker for glycemic control than glycated hemoglobin in
diabetic patients, especially for evaluating glycemic excursion, which is considered to be a major cause
of diabetic angiopathy.

Key words: Glycated albumin, HbA1c, Glycemic excursion

THE predominant component of glycated hemoglobin, HbA1c, is most widely used to

evaluate the long-term glycemic control and the risk for the development of complications
in patients with type 1 [1] and type 2 diabetes [2, 3]. Circulating glucose combines with
hemoglobin via a slow irreversible non-enzymatic reaction, the rate of which is
determined by serum glucose concentrations [4, 5]. However, glycated hemoglobin is
known to be affected by various conditions, especially by the modification of erythrocyte
survival and glycation. For example, lower HbA1c levels are observed in subjects with
shortened erythrocyte survival or decreased mean erythrocyte age. Hyperglycemia is also
known to reduce the survival of erythrocytes and to underestimate HbA1c levels in
diabetic patients under poor glycemic control [6, 7].
The Diabetes Control and Complications Trial demonstrated that intensive insulin
treatment markedly reduces the risk of retinopathy compared with conventional insulin
treatment in type 1 diabetic patients, even with identical levels of HbA1c [8]. The authors
suggested that intensive treatment with multiple insulin injections could decrease glucose

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doi: 10.1507/endocrj/K07E-089

fluctuation and excursion, and that such an effect on glucose profile might decrease the
incidence of diabetic micro-angiopathy. We also reported that postprandial glucose level is
a better predictor of diabetic retinopathy than HbA1c in type 2 diabetes [9]. In addition,
increased glycemic fluctuation and/or postprandial glucose excursion has been shown to
increase the risk for diabetic macro-angiopathy [10, 11]. Therefore a good indicator for
glucose fluctuation and excursion is necessary to predict the development of diabetic
complications.
Among various glycated proteins, serum glycated albumin (GA) has been reported to
be a useful and rapid indicator of glycemic control for diabetic patients, since the turnover
of serum albumin is much shorter (half-life of 17 days) than that of HbA1c [12, 13, 14].
Circulating albumin is strongly glycated at four sites of lysine residues, and the glycation
reaction occurs ten times more rapidly than the glycation of hemoglobin [15, 16]. It is,
therefore, possible that glycemic fluctuation and excursion could influence glycation
reaction in albumin strongly compared with hemoglobin.
In this study, we evaluated the effect of the daily profile of blood glucose levels on
GA and HbA1c levels in patients with type 1 and type 2 diabetes, because the glycemic
fluctuation and excursion in type 1 diabetes could be larger than that of type 2 diabetes.

Patients and Methods

Study subjects
Ninety-three patients with type 1 diabetes (28 males and 65 females, age 26.7 ± 7.4
years with a duration of diabetes of 15.6 ± 6.7 years) and 75 patients with type 2 diabetes
(54 males and 21 females, age 60.5 ± 10.6 years with a duration of diabetes of 13.0 ± 7.9
years) were enrolled in this study (Table 1). These patients were not suffering from
advanced micro- or macro- diabetic angiopathy. All patients with type 1 diabetes were
being treated with insulin injections at least 4 or 5 times daily. On the other hand, among
the type 2 diabetic patients, 38 and 37 patients were treated with oral anti-diabetic agents
and insulin, respectively. In these patients, treatment for diabetes went unchanged for at
least three months prior to enrolling in this study. After a full explanation of this study,
written informed consent was obtained from each subject. Furthermore, the study was
approved by the Ethical Committee for Human Studies at Osaka University Graduate
School of Medicine.

Evaluation of glycated proteins and daily glucose profile

HbA1c levels were determined using high performance liquid chromatography, and
glycated serum albumin levels were measured using the enzymatic glycated albumin assay
kit (Lucica GA-L, Asahi Kasei Pharma, Tokyo, Japan) [17]. The daily profile of glucose
levels was determined by self-monitored blood glucose testing before and 2-hours after
each meal and at bedtime on the day before blood sampling for glycated proteins, from
which data the mean blood glucose levels and the mean amplitude of glucose excursion
(MAGE) were calculated [18].

Statistical analysis
Data were presented as means ± SD. Data between the groups of type 1 and type 2
diabetes were compared by the Mann-Whitney U-test. Stepwise multivariate regression
analyses were performed to evaluate the relationship among glycated proteins and various
parameters of the diurnal glucose profile. For the stepwise multivariate regression analyses,
the F value for the inclusion and exclusion of variables was set at 4.0. The analysis was
performed with StatView computer program (Abacus Concepts, Berkeley, CA).

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doi: 10.1507/endocrj/K07E-089

Results
Age and body mass index (BMI) in type 1 diabetic patients were significantly lower
than those in type 2 diabetic patients, and the duration of diabetes in type 1 diabetic
patients was significantly longer than that in type 2 diabetic patients (Table 1). Fasting,
mean and maximum blood glucose levels, and MAGE determined from the daily blood
glucose profile were similar between type 1 and type 2 diabetes. However, the difference
between maximum and minimum blood glucose levels (ΔBG), representing glycemic
fluctuation, was significantly higher in type 1 diabetes than that in type 2 diabetes.
HbA1c levels were similar between type 1 and type 2 diabetes, while GA levels were
significantly higher in type 1 diabetes than that in type 2 diabetes. GA levels were strongly
correlated with HbA1c levels in type 1 (r = 0.85, P < 0.0001) and type 2 diabetic patients
(r = 0.61, P < 0.0001), respectively (Fig. 1). The ratio of GA levels to HbA1c levels in
type 1 diabetes was significantly higher than that of type 2 diabetes (P < 0.001).
A previous report demonstrated that BMI correlated negatively with GA [19], but we
could not find any correlation between BMI and GA or HbA1c in type 1 (GA, r = -0. 152;
HbA1c, r = -0.043) and type 2 diabetes (GA, r = -0. 178; HbA1c, r = 0.206). On the other
hand, the ratio of GA levels to HbA1c levels correlated negatively with BMI in type 2
diabetic patients (r = -0.466, P < 0.001), but not in type 1 diabetic ones (r = -0.231, P =
0.07).
In patients with type 1 diabetes, GA and HbA1c levels correlated with fasting, mean
and maximum glucose, MAGE and ΔBG levels (Table 2). On the other hand, in type 2
diabetes, GA levels correlated with fasting, mean and maximum glucose, and ΔBG levels,
and HbA1c levels correlated with mean and maximum glucose, and ΔBG levels. Stepwise
multivariate analysis revealed that GA levels independently correlated with maximum
blood glucose levels in type 1 and type 2 diabetes (Table 2). HbA1c levels also
independently correlated with maximum blood glucose levels in type 1 diabetes, while
HbA1c levels correlated with mean blood glucose levels in type 2 diabetes. Since ΔBG
were highly correlated with maximum glucose levels, ΔBG was excluded from stepwise
multivariate analysis.

Discussion
In the present study, GA levels were strongly correlated with HbA1c levels in type 1
and type 2 diabetes, and these glycated proteins were well correlated with mean blood
glucose levels determined from a 7-point blood glucose measurement per day. Thus GA
levels, as well as glycated hemoglobin levels, are a useful marker of glycemic control as
previously reported [14]. Since GA in patients with type 2 diabetes showed a better
correlation with various parameters of glycemic profiles than HbA1c, GA could be a more
accurate marker for evaluating glycemic control than HbA1c in these patients. In addition,
an independent determinant of GA was maximum glucose levels in type 2 diabetes, thus
GA might predominantly reflect glucose excursion. On the other hand, in type 1 diabetes,
both GA and HbA1c were similarly correlated with various parameters of glycemic
profiles, and were independently correlated with maximum glucose levels. However, the
coefficient and F-value of correlation of GA with maximum glucose levels were higher
than those of HbA1c in type 1 diabetes. Therefore, GA is a better marker for evaluating
glucose excursion than HbA1c in type 1 diabetes, as well as type 2 diabetes.
An independent determinant of HbA1c was maximum glucose in type 1 diabetes,
and mean blood glucose in type 2 diabetes. This finding implied that the impact of
glycemic excursion on HbA1c was stronger in type 1 diabetes than that in type 2 diabetes.
Monnier et al. demonstrated in type 2 diabetic patients that the contribution of
postprandial glucose excursion to glycated hemoglobin gradually decreased in contrast to
increase in HbA1c levels [20]. In the present study, however, the average HbA1c levels
were identical between type 1 and type 2 diabetic patients. We, therefore, speculated that

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 Endocr. J./ K. Yoshiuchi et al.: GA AND HbA1c IN T1 AND T2 DM
doi: 10.1507/endocrj/K07E-089

increased glycemic fluctuation in type 1 diabetic patients may increase the contribution of
postprandial glucose excursion to HbA1c levels.
Interestingly, the ratio of GA levels to HbA1c levels was significantly higher in type
1 diabetic patients than in type 2 diabetic patients. A previous report demonstrated that a
higher ratio of GA levels to HbA1c levels was observed in patients with poor glycemic
control than good glycemic control, and that acute glycemic control decreased this ratio
[14]. In the present study, mean blood glucose levels and glycated hemoglobin levels were
similar between type 1 and type 2 diabetic patients and treatment for diabetes remained
unchanged for at least three months prior to enrolling in this study. Thus acute change and
degree of glycemic control is unlikely to affect the ratio of GA levels to HbA1c levels in
this study. Moreover, Koga et al. recently reported that BMI negatively influenced
glycated albumin levels and the ratio of GA levels to HbA1c levels in diabetic patients
[19]. In the present study, we failed to find a correlation between BMI and GA levels in
patients with type 1 and type 2 diabetes, and BMI negatively correlated with the ratio of
GA levels to HbA1c levels only in type 2 diabetic patients. Thus, in patients with type 2
diabetes, higher BMI might partially contribute to lower ratio of GA levels to HbA1c
levels.

Since ΔBG and MAGE were the predominant determinants for the ratio of GA levels
to HbA1c levels among the various parameters of daily glucose profiles (F=25.4 and
F=4.8, respectively), large glucose fluctuation in type 1 diabetes could enhance the
glycation and oxidation reaction of albumin, which are known to be major reactions to
produce GA, and increase the ratio of GA levels to HbA1c levels. In addition,
hyperglycemia is known to reduce the survival of hemoglobin [6, 7], thus a higher glucose
fluctuation in type 1 diabetes may decrease HbA1c and increase the ratio of GA levels to
HbA1c levels.
In conclusion, GA could be a better marker for glycemic control than glycated
hemoglobin, especially for evaluating glycemic excursion in type 1 and type 2 diabetes.
Postprandial glucose excursion is known to be a risk factor for diabetic micro- and
macro-angiopathy in diabetic patients. Further studies are required to determine the
usefulness of GA as an indicator of diabetic complications.

Acknowledgements
We wish to thank Dr. Takuji Kouzuma (Asahi Kasei Pharma) for technical assistance
and critical discussion. We also thank Ms. Chikayo Yokogawa for excellent secretarial
work.

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Fig. 1. Correlation between glycated albumin and glycated hemoglobin in type 1 and
type 2 diabetes

T1DM T2DM

60

50 y = 3.525x - 1.5958
R 2 = 0.7301
GA (%) 40
y = 2.1588x + 5.7618
30 R 2 = 0.3723

20

10

0 2 4 6 8 10 12 14
HbA1c (%)

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 Endocr. J./ K. Yoshiuchi et al.: GA AND HbA1c IN T1 AND T2 DM
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Table 1. Patient characteristics

Type 1 diabetes Type 2 diabetes

Gender (Male/Female) 28/65 54/21

BMI 22.2±2.8 26.5±5.2**

Age (yrs) 27±7.4 60.5±10.6**

Duration (yrs) 16±6.7 13±7.9*

HbA1c (%) 7.8±1.4 8.1±1.2

GA (%) 25.8±5.6 23.1±4.4*

GA/HbA1c 3.32±0.36 2.89±0.44**

Fasting Blood Glucose (mg/dl) 146±71 147±42

Mean Blood Glucose (mg/dl) 170±57 174±68

Maximum Blood Glucose (mg/dl) 266±86 257±75

MAGE 132±66 119±55

⊿BG (maximum-minimum BG) (mg/dl) 178±73 133±58*

*P<0.05, **P<0.005 vs T1 DM

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Table 2. Association between glycated proteins and parameters of daily glucose profile
in patients with type 1 and type 2 diabetes
Type 1 diabetes Type 2 diabetes

Univariate Multivariate Univariate Multivariate

Factors Parameters R P F P R P F P

GA FBG 0.321 0.002 1.31 NE 0.446 <0.001 3.37 NE

MBG 0.535 <0.001 0.70 NE 0.601 <0.001 0.15 NE

MAXBG 0.568 <0.001 43.34 <0.001 0.605 <0.001 41.57 <0.001

MAGE 0.328 0.001 0.02 NE 0.219 0.060 0.153 NE

⊿BG 0.376 <0.001 0.452 <0.001

HbA1c FBG 0.352 <0.001 2.96 NE 0.107 NS

MBG 0.511 <0.001 1.24 NE 0.366 0.001 11.28 <0.001

MAXBG 0.526 <0.001 34.87 <0.001 0.359 0.001 0.43 NE

MAGE 0.346 <0.001 0.21 NE 0.172 NS

⊿BG 0.271 0.020 0.382 0.003

Pearson’s univariate correlation coefficients and stepwise multivariate regression analysis
were performed. P < 0.05. NS, not significant; NE, not entered