2014 ILEX PUBLISHING HOUSE, Bucharest, Roumania

http://www.jrdiabet.ro
Rom J Diabetes Nutr Metab Dis. 21(2):137-150
doi: 10.2478/rjdnmd-2014-0019

GLYCATED ALBUMIN MORE THAN THE MISSING LINK

IN THE EVALUATION OF DIABETES CONTROL
Ilie-Robert Dinu , Eugen Moa
University of Medicine and Pharmacy Craiova
received:

April 09, 2014

accepted:

April 29, 2014

available online:

June 15, 2014

Abstract
Diabetes mellitus represents a major public health problem in the world and glycemic
control is very important in subjects with diabetes. Glycation of many proteins is
increased in subjects with diabetes compared with persons without diabetes. Glycated
albumin (GA) has emerged as a possible glycation index for intermediate-term diabetes
control. There is evidence that GA can be considered a better parameter than glycated
haemoglobin in many conditions including pregnancy, chronic kidney disease, liver
diseases and anemia. Several reports indicate that GA plays a role in the pathogeny of
diabetes complications, mainly in diabetic nephropathy and retinopathy. There are
several limitations for using GA including the lack of standardization in the laboratories.
Several studies are needed in order to understand the place of GA in the pathogeny of
diabetes complications and the role in assessing the metabolic control.
key words: glycated albumin, glycated hemoglobin, diabetes, complications
to be involved both in the development but also
Introduction
in the progression of chronic diabetes
Diabetes mellitus represents a major public complications [4]. From all of the glycated
health problem in the world with an increasing proteins, the glycated hemoglobin (HbA1c) is
prevalence and important medical and social used as the gold standard index of glycemic
consequences. According to the sixth edition of control in clinics and in study design. In the last
the IDF Atlas, there are 382 million people with years, the glycated albumin (GA) has emerged as
diabetes in the world and the number will rise to a possible glycation index for evaluation of
592 million by 2035 [1]. Glycemic control is intermediate-term diabetes control. This review
very important in subjects with diabetes. Many focuses on the role of the GA in the assessment
large trials have indicated that strict glycemic of metabolic control, the methods for its
control can reduce the risk of development of measurement and its possible role in diabetes
complications.
complications in diabetic patients [2,3].
It is known that glycation of many proteins
The glycation of albumin
is increased in subjects with diabetes compared
Most of the proteins in the human body can
with persons without diabetes. Some of the
glycated proteins are used for the evaluation of be glycated. Glucose molecules can join to
diabetes control and some of them are suggested

1 Tabaci Street, Craiova, Romania, 200642; Tel: 0040740243654

corresponding author e-mail: drdinurobert@yahoo.com
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protein molecules to form stable ketoamines

through glycation, a non-enzymatic mechanism.
The high content of lysine and arginine in the
primary structure of albumin makes this protein
a potential target for glycation. GA is a
ketoamine formed via a non-enzymatic glycation
reaction of serum albumin [5].
Albumin is one of the most abundant
proteins in blood plasma. It is produced in
hepatocytes and it constitutes about half of the
blood serum protein. It is soluble and
monomeric. The albumin reference range in
blood is 3.4 to 5.4 g/dL. The serum half-life of
albumin is approximately 20 days and its
molecular mass is 67 kDa. Approximately 10%
of the albumin in normal human serum is
modified by nonenzymatic glycosylation,
primarily at the epsilon-amino group of lysine
residue 525 [6].
Glycation and oxidation are the most
common major non-enzymatic mechanisms.

Non-enzymatic glycation, also called Maillard

reaction, is a process in which glucose reacts
spontaneously with amine containing molecules,
such as proteins. The reaction proceeds through
many stages; initially, glucosylamines (Schiff
bases) are formed, then fructosamines (Amadori
compounds),
and
aminoaldoses
(Heyns
compounds) and ultimately it leads to the
formation of irreversible glycation end products.
They include crosslinks, aromatic heterocycles,
and other oxidized compounds, that are
generally named advanced glycation end
products (AGEs). The concentration levels of
these products are very elevated in diabetes, and
several data from numerous studies suggest that
non-enzymatic glycation and AGE formation is
important in the etiology of diabetes
complications [7].
The glycation of hemoglobin and the
formation of glycated hemoglobin are
represented in Figure 1.

Figure 1. Non-enzymatic glycation of hemoglobin (adapted from [8]).

The glycation of albumin implies a slow,

non-enzymatic reaction initially when glucose or
its derivatives are attached to free amine groups
of albumin, leading to formation of stable
ketoamine (Figure 2).

138

Methods for the measurement of GA

There are several methods used in the
isolation and quantification of GA. They include
(a) enzymatic assay, (b) high-performance liquid
chromatography
(HPLC)
and
affinity

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chromatography, (c) immunoassay, including

quantification by radio-immunoassay, (d)
enzyme-linked immunosorbent assay (ELISA),

(e) enzyme-linked boronate immunoassay

(ELBIA),
(f)
colorimetry,
and
(g)
electrochemical [9].

Figure 2. Non-enzymatic glycation of albumin (adapted from [4]).

In the United States, most of the laboratories

use affinity chromatography and state reference
values for GA in the range of 0.63.0%. Few
laboratories perform an enzymatic assay
indicating a GA reference range of 1116%.
Almost half the scientific and clinical reports
regarding GA measurement in the last decades
indicate normal GA values of 2.6% or lower,
consistent with the majority of reference
laboratories. Almost a quarter of these reports
indicate normal values in the range of 59%.
Other reports indicate normal values between
1020%, in line with the enzymatic reference
determination. Overall, typical GA values for
subjects with diabetes are 25 times above the
normal values for a given reporting method [9].
Monoclonal isolation associated with ELISA
but also immunonephelemetry (turbidimetric)
and gel electrophoresis with bromcresol green
(BCG) showed GA values in a lower range of
reported values. Other assays have replaced the
thiobarbituric acid (TBA) method including
nitroblue tetrazolium and 2-keto-glucose with
hydrazine. Improvement of BCG has led to the
Hitachi automated BCG-dye binding analyzer
and it indicates results in agreement with another
reported method for the quantification of
nonglycated human serum albumin using lateral

chromatography
and
immunofluorescence
[9,10].
Recently, a user friendly, automated
enzymatic assay (Lucica GA-L kit, Asahi Kasei
Pharma, Tokyo, Japan) for determining GA has
been developed. It can be used with automated
general biochemical analyzers, and the kit
reagents are liquid, making prior preparation
unnecessary. Because both serum and plasma
samples can be used, GA can be analyzed along
with other parameters such as glucose,
cholesterol and triglycerides, without requiring a
separate blood collection. A separate sample of
whole blood is required for HbA1c. Also, the
assay is stable even for samples stored for a long
period of time (frozen for 1923 years).
Moreover, this assay offers reproductivity and
specificity. This assay has correlated very highly
(r = 0.99) with values for GA obtained by the
HPLC assay [7,11].
GA in the screening for diabetes
Because of the increasing prevalence of
diabetes in the world, new methods for the
screening of diabetes are necessary. Nowadays
only blood glucose levels and recently
introduced criteria of HbA1c are used for the
diagnosis of diabetes. In order to test the utility

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139

of GA for diagnosing diabetes, a communitybased population study was done in Japan - the
Kyushu and Okinawa Population Study (KOPS)
[12]. The study indicated that GA levels did not
differ by sex, while HbA1c levels were
significantly higher in men than in women. The
Atherosclerosis Risk in Communities (ARIC)
study in the United States also showed
significant differences between sex in HbA1c,
but no such significant difference in GA [13].
Thus, when evaluating GA one does not have to
take gender into account.
The ARIC study demonstrated that GA was
strongly associated with the subsequent risk of
diabetes, and the association remained
significant after adjustment for fasting glucose or
HbA1c level [13]. KOPS, based on a community
population of healthy Japanese participants with
no history of diabetes, showed that a GA level of

15.5% is best for discriminating patients with

diabetes from those without diabetes. This cutoff value had a sensitivity of 83.3% and a
specificity of 83.3% in a receiver operating
characteristic (ROC) analysis where the area
under the ROC curve was 0.91 [12]. According
to the KOPS findings, fasting plasma glucose
concentrations of 100 mg/dL (5.56 mmol/L),
110 mg/dL (6.11 mmol/L), and 126 mg/dL (7.00
mmol/L) corresponded to HbA1c (National
Glycohemoglobin Standardization Program:
NGSP) and GA levels of 5.6% (38 mmol/mol),
5.9% (41 mmol/mol) and 6.3% (45 mmol/mol),
and 15.0%, 15.7% and 16.9%, respectively
(Table 1). The GA:HbA1c (NGSP) ratio was
2.68. These data indicate that GA is a useful
marker for the screening of diabetes in a routine
medical evaluation [7].

Table 1. Correspondence of the hemoglobin A1c (HbA1c), glycated albumin (GA), and fasting plasma glucose (FPG)
levels in the participants from the KOPS study (adapted from [7]).

HbA1c (%) (NGSP)

GA (%)

FPG
100 mg/dL
5.56 mmol/L
5.6
15.0

Ma et al. assessed the validity of GA in

screening of subjects with undiagnosed diabetes
in a Chinese population. They also determined
the role of the combination of FPG and GA in
enhancing the efficacy of diabetes screening
[14]. The authors concluded that GA is a highly
sensitive and convenient test for diabetes
screening and a GA value of 17.1%, the optimal
cut-off point in these subjects, identified a very
high proportion of potentially diabetic
individuals. Moreover, the dual criteria of FPG
6.1mmol/L and GA 17.1% increased the
sensitivity of diabetes screening and it would
avoid the majority of oral glucose tolerance tests.
[14].

140

110 mg/dL
6.11 mmol/L
5.9
15.7

126 mg/dL
7.00 mmol/L
6.3
16.9

GA in assessing the glycemic control

Diabetes monitoring is generally managed
by combining daily self-monitoring of blood
glucose (SMBG) measurements with physicianassessed HbA1c levels every 36 months. Many
reports have indicated the utility of A1C as a
long-term glycemic index. The half-life of the
red blood cells containing hemoglobin is
approximately 120 days and the relative quantity
of glycated hemoglobin in a patients blood
indicates the average glycemic value over a
period of a few months. The use of A1c test as a
gold standard happened because it has been
shown to predict the risk of developing diabetes
complications [9].

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The use of short-term indicators of glycemic

control for people with diabetes is no longer
limited to the assessment of glucose in blood,
plasma, serum, or other body fluids. Serum 1,5anhydroglucitol (1,5-AG) is known as a
nonprotein marker for monitoring short-term
glycemic control and it has been used for more
than a decade in Japan under the name
GlycoMark. It could reflect glucoses
competitive inhibition of the reabsorption of 1,5AG in the kidney tubule and it represents
diabetic status over a 24 hours period [15]. In a
study that included subjects with type 1 and type
2 diabetes showing good to moderate control,
1,5-AG was able to reflect postprandial glycemic
excursions better than either A1C or the
intermediate indicator, fructosamine (FA).
Nevertheless, it is not recommended for
monitoring gestational diabetes, because of the
instability of renal hemodynamics during
pregnancy. Another marker for short-term
control is apolipoprotein B, a component of lowdensity lipoproteins (LDLs), that also becomes
glycated. This protein is very important because
of its involvement in atherogenesis. The half-life
of circulating LDLs is 35 days, so the glycated
LDL level reflects mean glycemia over the
preceding week [9].
In the last 1520 years, many reports have
indicated the use of serum protein indicators,
specifically FA and GA, as a method to evaluate
glycemic status over 24 weeks, reflecting the
half-lives of these molecules in serum.
Fructosamine represents the sum of all
ketoamine linkages that result from the glycation
of circulating serum proteins and the name
comes from the chemical similarity to fructose.
The measurement of FA was easily automated
and this assay was relatively inexpensive to
perform. FA measurement remains popular in
some countries outside the United States [16].
The experience gathered with FA testing has

indicated the potential benefit of an intermediate

index to retrospectively evaluate changes in diet
and metabolic control and to allow a rapid
evaluation of changes in medication dosages [9].
Several authors indicated that the
concentration of GA in serum, having a half-life
of 1219 days, would represent an excellent
index of recent ambient glycemia [17]. Albumin
can be easily measured in the blood and it would
fill the time gap between SMBG and A1C at
approximately 1 month.
Changes in Short-Term Glycemic Status
Several studies have shown that GA is a
better marker than HbA1c for monitoring shortterm variations of glycemic control during
treatment, for patients with type 1 and type 2
diabetes [18]. Thus, GA measurement can play
an important role in guiding the control of
glycemia, serving as an intermediate-term index.
Studies based on self-monitoring of blood
glucose and continuous glucose monitoring have
found GA levels to better reflect glycemic
fluctuation [19].
Numerous data indicate that postprandial
glucose level is a better predictor than HbA1c of
diabetic retinopathy in type-2 diabetes [20].
Postprandial hyperglycemia is generally caused
by inadequate endogenous insulin secretion [21].
Even among patients with similar HbA1c levels,
GA
reflects
adequately
postprandial
hyperglycemia [19]. In addition, GA levels are
reported to be better correlated than HbA1c with
the severity of cardiovascular disease, and better
indicate glycemic fluctuations [9]. The
measurement of GA has great merit in terms of
glycemic control, especially for postprandial
hyperglycemia and glycemic fluctuation.
Since the half-life of albumin is shorter than
that of erythrocytes, GA changes more rapidly in
cases where the status of glycemic control is
modified during short term [22]. To evaluate the

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141

usefulness of GA, intensive insulin therapy was

performed as the initial treatment in 8 patients
with type 2 diabetes mellitus with poor glycemic
control [23]. It was noted only a mild decrease in
averaged HbA1C from 10.9% to 10.0%, while
averaged GA decreased markedly from 35.6% to
25.0%. The changes of HbA1C and GA during 2
weeks were -0.9% and -10.6%, respectively, and
the decrease of GA was approximately 10 times
greater than that of HbA1C. When glycemic
control changes shortly due to the start or change
of diabetes treatment, GA is a more suitable
index of glycemic control than HbA1C [4].
On the other hand, GA increases prior to
HbA1C when glycemic control status worsens
during short term. Therefore in such conditions,
GA allows to detect at an earlier stage the
worsening of glycemic control. It is known that
HbA1C remains normal or only mildly elevated
at the diagnosis of fulminant type 1 diabetes
mellitus in which pancreatic cells are rapidly
destroyed, resulting in an increase in plasma
glucose and ketoacidosis in the very short term.
Koga and Kasayama examined HbA1C and GA
at diagnosis in patients with fulminant type 1
diabetes mellitus [4]. Due to the increase of
plasma glucose during very short term, the
extent of the elevation of GA was larger than
that of HbA1C at the diagnosis of fulminant type
1 diabetes mellitus. As a result, the GA/HbA1C
ratio was significantly higher in patients with
fulminant type 1 diabetes mellitus at diagnosis
than those with untreated type 2 diabetes
mellitus. When a GA/HbA1C ratio 3.2 is
regarded as a cutoff value, the sensitivity and
specificity of differentiating fulminant type 1
diabetes mellitus at diagnosis from untreated
type 2 diabetes mellitus were 97% and 98%,
respectively [4]. Therefore, the authors
suggested that a high GA/HbA1C ratio is helpful
for diagnosing fulminant type 1 diabetes
mellitus.

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Evaluation of Postprandial
Hyperglycemia
Several epidemiological studies have shown
that postload hyperglycemia becomes a risk
factor for cardiovascular diseases. The DECODE
study [24] or Funagata study [25] revealed that
postload plasma glucose in the glucose tolerance
test is a more potent risk factor for
cardiovascular events than fasting plasma
glucose. Furthermore, it has been reported that
administration of the glucosidase inhibitor
acarbose to patients with impaired glucose
tolerance or diabetes mellitus was associated
with cardiovascular risk reduction (STOPNIDDM trial) [26].
HbA1C is considered primarily to be an
index which reflects the mean plasma glucose
levels. Several recent reports suggested that GA
is an index which more strongly reflects
postprandial plasma glucose rather than mean
plasma glucose. In general, plasma glucose
fluctuates over a greater range in patients with
type 1 diabetes mellitus compared with patients
with type 2 diabetes mellitus. In view of this
phenomenon, in patients with type 1 diabetes
mellitus and those with type 2 diabetes mellitus
who show no difference in HbA1C value, the
GA value is significantly higher in the former.
The authors speculated that GA may more
strongly reflect postprandial plasma glucose and
range of plasma glucose fluctuations than
HbA1C [4].
When relationship between HbA1C and GA
was examined in patients with type 2 diabetes
mellitus, GA/HbA1C ratio was significantly
higher in subjects receiving insulin treatment
than in patients receiving diet therapy or oral
hypoglycemic drugs [27]. Insulin secretion
determined by the homeostasis model
assessment pancreatic cell function (HOMA%) was significantly lower in the patients
receiving insulin treatment than that in the

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patients not receiving insulin treatment. There

was a significant inverse correlation in
GA/HbA1C ratio and HOMA-%, reflecting
decreased endogenous insulin secretion involved
in increased value of the GA/HbA1C ratio. Thus,
it was suggested that a decrease in the insulin
secretion increases the glycemic excursion,
causing increase of the GA/HbA1C ratio.
Recently, plasma glucose levels throughout
the day can be measured by means of the
continuous glucose monitor (CGM) system. A
study on the relationship between the CGM
system data and the index of glycemic control
was reported. Among the patients with diabetes
mellitus showing poor glycemic control, GA
indicated a more potent relationship with
differences of plasma glucose levels and plasma
glucose fluctuation index than HbA1C and 1,5AG [28].
GA in monitoring glycemic excursions
during pregnancy
Women with pre-gestational diabetes but
also their fetuses are at very high risk of
developing complications compared with the
pregnant women without diabetes, including
spontaneous abortion, hypertensive disorders
and preterm labor. Women with gestational
diabetes mellitus (GDM) also can develop
similar complications, usually not of the same
magnitude. Gestational diabetes mellitus
represents ~90% of cases of pregnancies
complicated by diabetes, with potentially longreaching consequences that include high risk of
subsequently developing type 2 diabetes for both
mother and child [29].
In pregnant women displaying diabetes
mellitus and those with gestational diabetes,
intensive glycemic control during pregnancy is
needed to lower the associated risks. Phelps et
al. [30] showed biphasic changes in HbA1C
levels during pregnancy, with HbA1C levels
lowest at gestational week 24. One of the

reasons why HbA1C decreases from the first

trimester to the second trimester of pregnancy is
considered to be the decrease in plasma glucose
levels, but the reason why HbA1C increases
again from the second trimester to the third
trimester is unknown. Sanaka, et al. [31]
reported that HbA1C increases from the second
trimester to the third trimester of pregnancy in
non-diabetic cases, whereas GA does not vary
much during this period. Therefore, it was
suggested that HbA1C might exhibit high values
independent of plasma glucose levels from the
second trimester to the third trimester during
pregnancy.
It is known that iron demand is increased
and iron deficiency often occurs in the third
trimester of pregnancy. Transferrin saturation
and serum ferritin decreased from the second
trimester to the third trimester of pregnancy, and
thus most women became iron deficient in the
third trimester. Since HbA1C showed significant
inverse correlations with these values, it can be
concluded that the increase of HbA1C in the
third trimester of pregnancy was caused by iron
deficiency [32]. In pregnant women with
diabetes mellitus, HbA1C increased and
transferrin saturation and serum ferritin
decreased from the second trimester to the third
trimester of pregnancy, while GA showed no
significant change. Since HbA1C again showed
a significant inverse correlation with transferrin
saturation, it was concluded that, in pregnant
women with diabetes mellitus, HbA1C increases
due to iron deficiency in the third trimester [33].
Moreover, a long period of time is needed to
modify the HbA1c value. These findings suggest
that HbA1C is not an appropriate index of
glycemic control during pregnancy. Meanwhile,
GA is not affected by iron deficiency and has the
advantage of reflecting the short-term status of
glycemic control, and is thus considered to be a
preferable index of glycemic control during

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143

pregnancy. Since the threshold of reabsorption

of glucose decreases in renal tubules, resulting in
renal glycosuria during pregnancy, serum 1,5AG indicates a low value [34]. Therefore, serum
1,5-AG is inadequate as an index of glycemic
control during pregnancy.
GA and Chronic Kidney Disease (CKD)
Unlike the randomized interventional studies
in the general population without established
CKD, no data exist in established diabetic CKD
concerning the impact of tight glycemic control
on future morbidity and mortality. Data on the
effect of long-term glycemic control are very
limited and whether tight glucose regulation is
beneficial and correlates with the risk of death or
hospitalization in diabetic patients with ESRD
(End Stage Renal Disease) remains controversial
[35]. There is some evidence from observational
studies that good glycemic control, assessed
using glycated hemoglobin (HbA1c) as a
marker, prevents progression of nephropathy,
reduces morbidity and improves survival in
patients with advanced CKD and in people
requiring haemodialysis (HD) [36]. More
recently, Drechsler et al. [37] demonstrated in
the post hoc analysis of a four-dimensional study
in diabetic HD patients a 2-fold increase in the
risk of sudden death in the group with poor
glycaemic control (HbA1c > 8%) compared to a
good glycemic-controlled group (HbA1c 6%).
However, risk of myocardial infarction and
mortality (excluding sudden death) did not differ
between groups.
While HbA1c has proven to be a reliable
prognostic marker in the general diabetic
population, it may not be valid in patients with
diabetes and CKD. Whether HbA1c corresponds
to the same mean glucose concentrations in
people with ESRD is debated [38]. Several
features present in CKD have a significant
impact on HbA1c concentrations and its values

144

may be falsely low. Besides glucose, HbA1c is

influenced by other factors including
hemoglobin, the lifespan of the red blood cells
(RBCs), recombinant human erythropoietin
(rHuEpo), the uraemic environment and blood
transfusions. In patients with CKD, and
particularly those on HD, the RBC lifespan is
significantly reduced with 2050% [39]. The
subsequent increased rate of hemoglobin
turnover leads to decreased exposure time to
ambient glucose that in turn lowers the extent of
non-enzymatic
binding of
glucose
to
hemoglobin. This results in reduced value for
HbA1c. Thus, in subjects with CKD and a
shortened RBC lifespan, lower HbA1c levels are
observed than would be expected from measured
glucose control [40].
Furthermore, when erythropoietin is
administered to patients with renal anemia,
HbA1C shows even lower values because
lifespan of erythrocytes is shortened [38].
Meanwhile, it has been reported that GA is a
useful index of glycemic control in hemodialysis
patients with diabetes because GA is not affected
by renal anemia [38]. Additionally, in the
examination of patients with diabetes mellitus
receiving peritoneal dialysis, it was shown that
GA reflects properly the status of glycemic
control whereas HbA1C does not [41].
Iron deficiency elevates the level of HbA1c
independently of glucose and hemoglobin levels
[42]. However, once treatment is initiated with
iron supplementation, HbA1c concentrations
decrease significantly as a result of the
production of immature cells. In CKD, an
increased amount of carbamylated hemoglobin is
formed under uraemic conditions. This acquired
form of hemoglobin interferes with some HbA1c
assays
(only
charge-dependent
assays),
predominantly by incomplete separation of the
carbamylated hemoglobin fraction, resulting in
an overestimation of HbA1c values. The

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interference is significant when urea levels

exceed 30mmol/L [43]. Moreover, other
hemoglobin modifications occur due to various
molecules that accumulate in CKD such as
advanced glycation end-products, which may
bind to hemoglobin and causing more potential
interference [43].
In contrast, in patients with diabetic
nephropathy (stage III or IV) presenting marked
proteinuria, it should be noted that GA shows a
lower value relative to plasma glucose levels as a
result of the increased turnover of albumin
metabolism. Observations of 98 hemodialysis
patients with diabetes mellitus for 11 years
indicated that the prognosis in the group with a
GA value 29.0% at the start of hemodialysis
was significantly poorer than that in the group
with a GA value <29.0% [44].
These results show that glycemic control
status in hemodialysis patients with diabetes is
also involved in their prognosis, and that
glycemic control status should be judged by GA,
not by HbA1C.
GA and anemia
HbA1C presents lower values in relation to
glycemia in patients with hemolytic anemia,
because lifespan of erythrocytes is shortened in
these patients. On the other hand, patients with
iron deficiency anemia present higher HbA1C
values relative to plasma glucose levels [45].
HbA1C also shows higher levels in relation to
glycemia even in iron deficient state without
anemia [46]. Iron deficiency anemia is the most
frequently seen anemia.
Since
approximately
one
half
of
premenopausal women are in iron deficient
status, a great number of premenopausal women
present high HbA1C values relative to plasma
glucose levels [45]. On the other hand, when
patients with iron deficiency anemia are treated
with iron supplements, HbA1C decreases

because lifespan of erythrocytes shortens [47]. In

contrast, GA is not influenced by these
conditions, and thus GA is a preferable index of
glycemic control in premenopausal women who
frequently suffer from iron deficiency anemia
[47].
GA and chronic liver diseases
Liver is a pivotal organ regulating plasma
glucose levels and glucose metabolic
abnormalities occur frequently in patients with
chronic liver diseases, such as chronic hepatitis
and liver cirrhosis. In patients with liver disease,
about 70-90% are diagnosed with impaired
glucose tolerance and 30-60% of them have
diabetes mellitus [48]. It is important to achieve
and keep a good glycemic control because
chronic liver disease (CLD) patients with poor
glycemic control have been shown to exhibit a
poor prognosis [4].
HbA1C is apparently lower in relation to
glycemia because of the shortened half-life of
erythrocytes [49] caused by the hypersplenism in
these patients. On the contrary, GA and
fructosamine levels are apparently higher in
relation to glycemia in these patients because of
prolonged half-life of serum albumin originating
from reduced synthesis of albumin in vivo [50].
Therefore, it is difficult to monitor glycemic
control status accurately in patients with liver
disease, because none of the known markers
reflects it precisely. Several authors investigated
the relationship between plasma glucose levels
and glycemic control markers in these CLD
patients [50]. In comparison with HbA1C
estimated from the mean plasma glucose levels
[53], measured HbA1C showed lower values
while GA/3 (GA indicates approximately 3
times the value of HbA1C, thus the HbA1C
value can be predicted from GA/3) showed
higher values in CLD patients. The discrepancy
between HbA1C or GA/3 and estimated HbA1C

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145

increased when hepatic function decreased.

Instead, HbA1C calculated as the mean of
HbA1C and GA/3 was found closely matched
with HbA1C estimated from the mean plasma
glucose levels. Therefore, calculated HbA1C is
useful as an index of glycemic control in these
patients [4].
In Table 2 are summarized the most
common diseases and pathologic conditions
where GA assessment is recommended (adapted
from [4])
Table 2. The common diseases and pathologic conditions
where GA assessment is recommended.
1)
2)
3)
4)
5)
6)
7)
8)
9)
10)
11)
12)
13)

At rapid improvement or aggravation of glycemic

control status
At onset of fulminant type 1 diabetes mellitus
Type 1 diabetes mellitus
Type 2 diabetes mellitus under insulin therapy
Patients with marked postprandial hyperglycemia
(e.g., gastrectomy)
Patients treated with drugs targeting postprandial
hyperglycemia
Hemolytic
anemia,
hemorrhage,
blood
transfusion, etc.
Variant hemoglobin
Chronic renal failure (in particular, receiving
hemodialysis)
Liver cirrhosis (calculation of CLD-HbA1C)
Iron deficiency anemia, iron deficiency status
Treatment phase of iron deficiency anemia
Pregnant women, premenopausal women

GA is involved in the pathogenesis of

diabetes complications
Beyond its role in assessing hyperglycemia,
GA has been directly implicated in the
development of several major complications of
diabetes, especially in nephropathy, because of
its interaction with receptors on mesangial cells.
Several blockade experiments in mice have
indicated that the interaction of GA with
mesangial cell receptors, independent of the
actions of hyperglycemia, can impact
albuminuria and mesangial expansion that are
hallmarks of diabetic nephropathy [9]. The
macrophages in the artery walls can also
recognize GA via specific receptors and they can
146

stimulate inflammatory responses, leading to the

development of atheroma plaques.
Carotid artery intima media thickness (IMT)
is commonly used to evaluate atherosclerosis in
large epidemiological studies. Significant
positive correlations have been established
between the HbA1c and IMT levels and between
the IMT level and the severity of coronary heart
disease (CHD) [51]. Limited data are available
for the association between the GA level and
atherosclerotic disease. Carotid artery IMT was
measured by ultrasound for 1575 participants of
the KOPS Study [52]. The max-IMT was
dened as a maximum value that included the
values for the plaque and the six points of mean
IMT on either side. The max-IMT increased
steadily for participants with a GA level
19.0%. The participants with a GA level
19.0% had a significantly higher IMT (1.109
0.562 mm) than those with a GA level < 14.0%
(0.757 0.317 mm) (P < 0.0001) [52]. A
retrospective Korean study has also shown that
GA is related to the development of diabetic
atherosclerosis, using carotid artery IMT
assessment by ultrasound [53]. Finally, a
prospective Chinese study demonstrated the
superiority of the measurement of the serum GA
level in comparison with the HbA1c level for
evaluating the relative risk for the development
and progression of coronary disease in type 2
diabetic patients [54].
Increased blood levels of GA have been
related to diabetic retinopathy and to
Alzheimers disease via the cerebrospinal fluid.
It is interesting that several reports involve
hypothyroidism and glucose oscillations, where
A1C did not identify the diabetic episode, but
other shorter term indicator did [9].
Several studies indicated that human serum
contains antibodies against glycated proteins
including GA [55]. However, further
investigations on the presence of antibodies

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against glycated proteins are needed in diabetes

patients with or without diabetic complications.
If characterized, these antibodies would be very
useful in early diagnosis of the disease.
Other studies correlated the levels of GA or
the GA/HbA1c ratio with the progression of
liver fibrosis in hepatitis B virus- or hepatitis C
virus-positive [56,57].
Limitations of GA
The GA level is significantly correlated with
HbA1c level (NGSP). However, some
discrepancies exist between the levels of HbA1c
and GA in certain pathologic disease states
including anemia, chronic liver diseases, and
nephrotic syndrome. Although GA is not
influenced by anemia and variant hemoglobin, it
is influenced in patients with disorders of
albumin metabolism. GA shows lower values in
relation to glycemia in patients with nephrotic
syndrome,
hyperthyroidism
[58],
and
glucocorticoid administration in which albumin
metabolism increases. Meanwhile, GA presents
higher values relative to plasma glucose levels in
patients with liver cirrhosis and hypothyroidism
in which albumin metabolism decreases [58].
In obese subjects, GA values were found to
be lower in relation to glycemia [59]. It is known
that chronic micro-inflammation is generated by
inflammatory
cytokines
secreted
from
adipocytes in obese subjects, and a significant
positive correlation was noted between BMI and
high sensitive C-reactive protein. Moreover, a
significant inverse correlation between high
sensitive C-reactive protein and GA was
observed [59]. Based on these results, Koga et
al. proposed the theory that chronic microinflammation increases albumin catabolism in
obese subjects, and, as a result of the shortened
half life of albumin, GA decreases relative to
plasma glucose levels [59]. It has been shown
that GA was lower in relation to plasma glucose

levels in smokers, hyperuricemic patients,

hypertriglyceridemia and men with nonalcoholic
fatty liver disease (NAFLD) with high alanine
aminotransferase (ALT) levels in whom chronic
inflammation is evoked [4].
GA is significantly lower in infants than
adults. GA levels in infants significantly increase
with age [60]. This can be explained by the fact
that the plasma glucose level of infants is lower
than that of adults, and that higher albumin
metabolism is associated with a lower GA
levels.
Despite the ongoing debates about the
interpretation of HbA1c, there is no consensus
on a suitable cut-off value for HbA1c across
different racial or ethnic populations. In the
ARIC study, differences between the AfricanAmerican and the Caucasian population in GA,
fructosamine, and 1,5-AG levels parallel the
differences in HbA1c among both non-diabetic
and diabetic subjects [61]. The findings may
imply a similarity between GA and HbA1c on
racial and ethnic differences.
Future perspectives
There are few studies regarding GA
although the last years brought to light the
numerous roles of GA in the pathogeny of
diabetes complications and its usefulness in
evaluating the metabolic control. Many studies
have to be done in order to establish the cut-off
values and a standardized method for its
evaluation before endorsing it as powerful tool
in the hand of clinicians.
Conclusions
GA represents a useful parameter for the
evaluation of glycemic control for a medium
period of time, almost a month. It represents the
missing link between SMBG and HbA1c is
supposed to have also implications in the
pathogenesis of the complications of diabetes
mellitus. Due to its properties, it appears to be a

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147

better indicator for metabolic control in several

conditions such as pregnancy, chronic kidney
disease, anemia and liver disease. Numerous

studies are requested in order to fully understand

this molecule and its role in evaluating and
worsening diabetes.

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