ga in evaluation of diabetes control

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

corresponding author e-mail: drdinurobert@yahoo.com

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

Introduction

Diabetes mellitus represents a major public

health problem in the world with an increasing

prevalence and important medical and social

consequences. According to the sixth edition of

the IDF Atlas, there are 382 million people with

diabetes in the world and the number will rise to

592 million by 2035 [1]. Glycemic control is

very important in subjects with diabetes. Many

large trials have indicated that strict glycemic

control can reduce the risk of development of

complications in diabetic patients [2,3].

It is known that glycation of many proteins

is increased in subjects with diabetes compared

with persons without diabetes. Some of the

glycated proteins are used for the evaluation of

diabetes control and some of them are suggested

to be involved both in the development but also

in the progression of chronic diabetes

complications [4]. From all of the glycated

proteins, the glycated hemoglobin (HbA1c) is

used as the gold standard index of glycemic

control in clinics and in study design. In the last

years, the glycated albumin (GA) has emerged as

a possible glycation index for evaluation of

intermediate-term diabetes control. This review

focuses on the role of the GA in the assessment

of metabolic control, the methods for its

measurement and its possible role in diabetes

complications.

The glycation of albumin

Most of the proteins in the human body can

be glycated. Glucose molecules can join to

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

UnauthenticatedDownload Date | 5/27/15 6:36 PM

138 Romanian Journal of Diabetes Nutrition & Metabolic Diseases / Vol. 21 / no. 2 / 2014

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).

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


Romanian Journal of Diabetes Nutrition & Metabolic Diseases / Vol. 21 / no. 2 / 2014 139

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



of GA for diagnosing diabetes, a community-

based 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 cut-

off 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]).

FPG

100 mg/dL 110 mg/dL 126 mg/dL

5.56 mmol/L 6.11 mmol/L 7.00 mmol/L

HbA1c (%) (NGSP) 5.6 5.9 6.3

GA (%) 15.0 15.7 16.9

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].

GA in assessing the glycemic control

Diabetes monitoring is generally managed

by combining daily self-monitoring of blood

glucose (SMBG) measurements with physician-

assessed 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].



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 1,5-

anhydroglucitol (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 1,5-

AG 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 low-

density 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 short-

term 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



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.

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 (STOP-

NIDDM 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



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 1,5-

AG [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 long-

reaching 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



pregnancy. Since the threshold of reabsorption

of glucose decreases in renal tubules, resulting in

renal glycosuria during pregnancy, serum 1,5-

AG 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

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



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


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) At rapid improvement or aggravation of glycemic

control status

2) At onset of fulminant type 1 diabetes mellitus

3) Type 1 diabetes mellitus

4) Type 2 diabetes mellitus under insulin therapy

5) Patients with marked postprandial hyperglycemia

(e.g., gastrectomy)

6) Patients treated with drugs targeting postprandial

hyperglycemia

7) Hemolytic anemia, hemorrhage, blood

transfusion, etc.

8) Variant hemoglobin

9) Chronic renal failure (in particular, receiving

hemodialysis)

10) Liver cirrhosis (calculation of CLD-HbA1C)

11) Iron deficiency anemia, iron deficiency status

12) Treatment phase of iron deficiency anemia

13) 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

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



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 micro-

inflammation 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 African-

American 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



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.

REFERENCES

1. International Diabetes Federation. IDF

Diabetes Atlas, 6th edn. Brussels, Belgium: International

Diabetes Federation, 2013. http://www.idf.org/

diabetesatlas.

2. The Diabetes Control and Complications Trial

Research Group. The effect of intensive treatment of

diabetes on the development and progression of long term

complications in insulin dependent diabetes mellitus. N

Eng J Med 329: 977-86, 1993.

3. UK prospective Diabetes Group. Intensive

blood glucose control with sulphonylurea or insulin

compared with conventional treatment and risk of

complications in patients with type 2 diabetes (UKPDS

33). Lancet 352: 837-53, 1998.

4. Koga M, Kasayama S. Clinical impact of

glycated albumin as another glycemic control marker.

Endocr J 57: 751-762, 2010.

5. Kim KJ, Lee BW. The roles of glycated albumin

as intermediate glycation index and pathogenic protein.

Diab Metab J 36: 98107, 2012.

6. Mukherjee B, Patra S, Das AK. Glycated

albumin and glycated hemoglobin- A comparison. Int J of

Biomed Res 4: 381386, 2013.

7. Furusyo N, Hayashi J. Glycated albumin and

diabetes mellitus. Biochem Biophys Acta 1830: 5509

5514, 2013.

8. Hinzmann R, Schlaeger C, Tran CT. What do

we need beyond hemoglobin A1c to get the complete

picture of glycemia in people with diabetes? Int J Med Sci

9: 665-681, 2012.

9. Roohk HV, Zaidi AR. A review of glycated

albumin as an intermediate glycation index for controlling

diabetes. J Diabetes Sci Technol 2: 11141121, 2008.

10. Choi S, Choi EY, Kim DJ et al. A rapid, simple

measurement of human albumin in whole blood using a

fluorescence immunoassay (I). Clin Chim Acta 339: 147

156, 2004.

11. Kohzuma T, Koga M. Lucica GA-L glycated

albumin assay kit: a new diagnostic test for diabetes

mellitus, Mol Diagn Ther 14: 4951, 2010.

12. Furusyo N, Koga T, Ai M et al. Utility of

glycated albumin for the diagnosis of diabetes mellitus in a

Japanese population study: results from the Kyushu and

Okinawa Population Study (KOPS), Diabetologia 54:

30283036, 2011.

13. Selvin E, Francis LM, Ballantyne CM et al.

Nontraditional markers of glycemia: associations with

microvascular conditions, Diabetes Care 34: 960967,

2011.

14. Ma XJ, Pan JM, Bao YQ et al. Combined

assessment of glycated albumin and fasting plasma

glucose improves the detection of diabetes in Chinese

subjects. Clin Exp Pharmacol Physiol 37: 974979, 2010.

15. Dungan KM, Buse JB, Largay J et al. 1,5-

anhydroglucitol and postprandial hyperglycemia as

measured by continuous glucose monitoring system in

moderately controlled patients with diabetes. Diabetes

Care 29: 12141219, 2006.

16. Carter AW, Borchardt N, Cooney M et al.

Dual-test monitoring of hyperglycemia using daily glucose

and weekly fructosamine values. Diabetes Technol Ther 3:

399403, 2001.

17. Cohen MP, Clements RS. Measuring glycated

proteins: clinical and methodological aspects. Diabetes

Technol Ther 1: 5770, 1999.

18. Yoshiuchi K, Matsuhisa M, Katakami N et al.

Glycated albumin is a better indicator for glucose

excursion than glycated hemoglobin in type 1 and type 2

diabetes. Endocr J 55: 503507, 2008.

19. Suwa T, Ohta A, Matsui T et al. Relationship

between clinical markers of glycemia and glucose

excursion evaluated by continuous glucose monitoring

(CGM), Endocr J 57: 135140, 2010.

20. Shiraiwa T, Kaneto H, Miyatsuka T et al.

Postprandial hyperglycemia is a better predictor of the

progression of diabetic retinopathy than HbA1c in

Japanese type 2 diabetic patients, Diabetes Care 28: 2806

2807, 2005.

21. Jones AG, Besser RE, Shields BM et al.

Assessment of endogenous insulin secretion in insulin



treated diabetes predicts postprandial glucose and

treatment response to prandial insulin, BMC Endocr

Disord 12: 6, 2012.

22. Takahashi S, Uchino H, Shimizu T et al.

Comparison of glycated albumin (GA) and glycated

hemoglobin (HbA1C) in type 2 diabetic patients:

usefulness of GA for evaluation of short-term changes in

glycemic control. Endocr J 54: 139-144, 2007.

23. Kohzuma T, Koga M. Lucica GA-L glycated

albumin assay kit: A new diagnostic test for diabetes

mellitus. Mol Diagn Ther 14: 49-51, 2010.

24. The DECODE study group. Glucose tolerance

and mortality: comparison of WHO and American

Diabetes Association diagnostic criteria. Lancet 354: 617-

621, 1999.

25. Tominaga M, Eguchi H, Manaka H et al.

Impaired glucose tolerance is a risk factor for

cardiovascular disease, but not impaired fasting glucose.

The Funagata Diabetes Study. Diabetes Care 22: 920-924,

1999.

26. Chiasson JL, Josse RG, Gomis R et al. STOP-

NIDDM Trial Research Group. Acarbose treatment and

the risk of cardiovascular disease and hypertension in

patients with impaired glucose tolerance: the STOP-

NIDDM trial. JAMA 290: 486-494, 2003.

27. Koga M, Murai J, Saito H et al. Glycated

albumin and glycated hemoglobin are differently

influenced by endogeneous insulin secretion in patients

with type 2 diabetes mellitus. Diabetes Care 33: 270-272,

2010.

28. Suwa T, Ohta A, Matsui T et al. Relationship

between clinical markers of glycemia and glucose

excursion evaluated by continuous glucose monitoring

(CGM). Endocr J 57: 135-140, 2010.

29. Seshiah V, Balaji V, Srinivasan A et al.

Comparison of Glycated Albumin (GA) and Glycosylated

Hemoglobin (A1C) in monitoring glycemic excursions

during pregnancy. Open J Obstet Gynecol 3: 47-50, 2013.

30. Phelps RL, Honig GR, Green D et al. Biphasic

changes in haemoglobin A1c concentrations during

normal human pregnancy. Am J Obstet Gynecol 147: 651-

653, 1983.

31. Sanaka M. Management of pregnant patients

with diabetes mellitus. Diabetes J 34: 127-135, 2006.

32. Hashimoto K, Noguchi S, Morimoto Y et al.

A1C but not serum glycated albumin is elevated in late

pregnancy owing to iron deficiency. Diabetes Care 31:

1945-1948, 2008.

33. Hashimoto K, Osugi T, Noguchi S et al. A1C

but not serum glycated albumin is elevated because of iron

deficiency in late pregnancy in diabetic women. Diabetes

Care 33: 509-511, 2010.

34. Tetsuo M, Hamada T, Yoshimatsu K et al.

Serum levels of 1,5-anhydro-Dglucitol during the normal

and diabetic pregnancy and puerperium. Acta Obstet

Gynecol Scand 69: 479-485, 1990.

35. Okada T, Nakao T, Matsumoto H et al.

Association between markers of glycemic control,

cardiovascular complications and survival in type 2

diabetic patients with end-stage renal disease. Intern Med

46: 807814, 2007.

36. Kalantar-Zadeh K, Kopple JD, Regidor DL et

al. A1C and survival in maintenance hemodialysis

patients. Diabetes Care 30: 10491055, 2007.

37. Drechsler C, Krane V, Ritz E et al. Glycemic

control and cardiovascular events in diabetic hemodialysis

patients. Circulation 120: 24212428, 2009.

38. Peacock T, Shihabi Z, Bleyer A et al.

Comparison of glycated albumin and hemoglobin A1c

levels in diabetic subjects on hemodialysis. Kidney Int 73:

10621068, 2008.

39. Vos FE, Schollum JB, Coulter CV et al. Red

blood cell survival in patients on long-term dialysis. Am J

Kidney Dis 58: 591598, 2011.

40. Vos FE, Schollum JB, Walker RJ. Glycated

albumin is the preferred marker for assessing glycemic

control in advanced chronic kidney disease. NDT Plus 4:

368375, 2011.

41. Freedman BI, Shenoy RN, Planer JA et al.

Comparison of glycated albumin and hemoglobin A1c

concentrations in diabetic subjects on peritoneal and

hemodialysis. Perit Dial Int 30: 72-79, 2010.

42. Kim C, Bullard KM, Herman WH et al.

Association between iron deficiency and A1C Levels

among adults without diabetes in the National Health and

Nutrition Examination Survey, 1999-2006. Diabetes Care

33: 780785, 2010.

43. Weykamp CW, Penders TJ, Siebelder CW et

al. Interference of carbamylated and acetylated

hemoglobins in assays of glycohemoglobin by HPLC,

electrophoresis, affinity chromatography, and enzyme

immunoassay. Clin Chem 39: 138142, 1993.



44. Fukuoka K, Nakao K, Morimoto H et al.

Glycated albumin levels predict long-term survival in

diabetic patients undergoing haemodialysis. Nephrology

13: 278-283, 2008.

45. Kim C, Bullard KM, Herman WH et al.

Association between iron deficiency and A1C Levels

among adults without diabetes in the National Health and

Nutrition Examination Survey, 1999-2006. Diabetes Care

33: 780-785, 2010.

46. Koga M, Morita S, Saito H et al. Association of

erythrocyte indices with glycated haemoglobin in pre-

menopausal women. Diabetic Med 24: 843-847, 2007.

47. Koga M, Murai J, Saito H et al. Usefullness of

glycated albumin as a glycemic control marker after iron

treatment for diabetic patients with iron deficiency anemia.

J Jpn Diab Soc 52: 341-345, 2009.

48. Kingston ME, Ali MA, Atiyeh M et al. Diabetes

mellitus in chronic active hepatitis and cirrhosis.

Gastroenterology 87: 688-694, 1984.

49. Nomura Y, Nanjo K, Miyano M et al.

Hemoglobin A1 in cirrhosis of the liver. Diabetes Res 11:

177-180, 1989.

50. Bando Y, Tachibana Y, Fukuoka K et al.

Clinical study of long-term glycemic control makers in

patients with chronic liver disease. J Jpn Diab Soc 40: 17-

24, 1997.

51. Bobbert T, Mai K, Fischer-Rosinsky A et al.

A1C is associated with intima-media thickness in

individuals with normal glucose tolerance. Diabetes Care

33: 203204, 2010.

52. Furusyo N, Koga T, Ai M et al. Plasma glycated

albumin level and atherosclerosis: results from the Kyushu

and Okinawa Population Study (KOPS). Int J Cardiol 167:

2066-2072, 2013.

53. Song SO, Kim KJ, Lee BW et al. Serum

glycated albumin predicts the progression of carotid

arterial atherosclerosis. Atherosclerosis 225: 450455,

2012.

54. Pu LJ, Lu L, Shen WF et al. Increased serum

glycated albumin level is associated with the presence and

severity of coronary artery disease in type 2 diabetic

patients. Circ J 71: 10671073, 2007.

55. Ansari NA, Dash D. Amadori glycated proteins:

role in production of autoantibodies in diabetes mellitus

and effect of inhibitors on non-enzymatic glycation. Aging

Dis 4: 5056, 2013.

56. Enomoto H, Aizawa N, Nakamura H et al. An

increased ratio of glycated albumin to HbA1c is associated

with the degree of liver fibrosis in hepatitis B virus-

positive patients. Gastroenterol Res Pract 2014: 351396,

2014.

57. Aizawa N, Enomoto H, Imanishi H et al.

Elevation of the glycated albuminto glycated hemoglobin

ratio during the progression of hepatitis C virus related

liver fibrosis. World J Hepatol 4: 1117, 2012.

58. Koga M, Murai J, Saito H et al. Effect of

thyroid hormone on serum glycated albumin levels: Study

on non-diabetic subjects. Diabetes Res Clin Pract 84: 163-

167, 2009.

59. Koga M, Otsuki M, Matsumoto S et al.

Negative association of obesity and its related chronic

inflammation with serum glycated albumin but not

glycated hemoglobin levels. Clin Chim Acta 378: 48-52,

2007.

60. Suzuki S, Koga M, Niizeki N et al. Glycated

albumin is lower in infants than in adults and correlated

with both age and serum albumin. Pediatr Diabetes 14:

2530, 2013.

61. Selvin E, Steffes MW, Ballantyne CM et al.

Racial differences in glycemic markers: a cross-sectional

analysis of community-based data. Ann Intern Med 154:

303309, 2011.


ga in evaluation of diabetes control

abstract diabetes mellitus

glycated proteins

glycated albumin ga

glycated haemoglobin

glycation of albumin

strict glycemic control

rom j diabetes nutr

glycated hemoglobin

Documents

testing and evaluation in education ga 3113 lecture 1

evaluation of the medicare diabetes prevention program

evaluation on the effectiveness of diabetes nurse clinic...

an economic evaluation of diabetes mellitus management in

self management - diabetes initiative · • jon liebman,...

cvd project evaluation: baseline diabetes study … re cvd...

diabetes high risk foot services - ministry of...

evaluation of a diabetes self-management program …

clinical evaluation of diabetes

euclipse ga, utrecht september 2010...euclipse ga, utrecht...

6|18 evaluation and impact measurement · diabetes adult...

against diabetes crusade july 2012.pdf · the centres have...

diabetes...innledning helsedirektoratet ga i 2016 ut nye...

national diabetes prevention program submitting evaluation...

evaluation of a diabetes care coordination program for...

an evaluation of the diabetes conversation map ™ program...

ga sixth grade evaluation kit

evaluation of postural control among diabetes mellitus...

evaluation of a peer-education program for diabetes … ·...

evaluation of diabetes mhealth apps 2017