Age-adjusted glycated albumin: a more robust parameter to establish glycaemic control in neonatal diabetes mellitus

Abstract

Background

We previously reported that glycated albumin (GA) levels increased in an age-dependent manner in infancy. In order to determine whether this phenomenon is true from infancy to adulthood, we investigated the GA levels in non-diabetic subjects of a wide range of age.

Methods

GA levels of 376 non-diabetic subjects [average age, 31.8 ± 23.8 years (4 days–78 years)] were determined. A relationship between GA and logarithmically transformed age [log(age)] was analysed.

Results

GA levels were significantly positively correlated with log(age) [R = 0.865, P < 0.0001, GA = 1.77 × log(day) + 6.55]. Based on a regression line, we established the formula for adjusting GA levels according to age.

Conclusion

We showed that GA increases with age from infancy to adulthood and that normal GA levels are demonstrated as a simple regression formula with log(age). This formula allowing us to use the adult reference range has the potential for treatment monitoring of diabetic patients regardless of age.

Introduction

Glycated albumin (GA) is one of the indexes of glycaemic control and reflects the status of glycaemic control changes for 2–4 weeks. ¹ The principal advantage of GA against glycosylated haemoglobin (HbA1c), which is widely used as an indicator for glycaemic control, ² is that GA is not affected by both haemoglobin metabolism and a variant haemoglobin. ¹ On the other hand, GA has been reported to be inadequate to assess the glycaemic control of diabetic patients with albumin metabolism disorders. ¹ For example, in nephrotic syndrome, hyperthyroidism and glucocorticoid therapy, which increases albumin metabolism, GA is apparently low. In contrast, GA is apparently high in liver cirrhosis and hypothyroidism, which decreases albumin metabolism. We previously reported that GA, but not HbA1c, reflects glycaemic control in patients with neonatal diabetes mellitus (NDM) whose disease onset is within six months of age, because in this period fetal haemoglobin is high and gradually decreases. ³ On the other hand, we have also found that GA in healthy infants within one year of age is low and correlated with logarithmically transformed age [log(age)]. ⁴ However, there is no study to investigate whether the phenomenon that GA is correlated with log(age) is true from infancy to adulthood so far. If there is a significant correlation between them, it is possible to calculate age-adjusted GA (Aa-GA), which enables us to use the adult reference value when assessing glycaemic control for patients at any age. Thus, we investigated the GA levels in non-diabetic subjects of a wide range of age.

Subjects and methods

Study subjects

A total of 376 non-diabetic subjects [236 males, 140 females; average age, 31.8 ± 23.8 years (4 days–78 years)] were selected. Of these 376 subjects, 78 were infants (58 cases were previously reported ⁴ ); 86, children and 212, adults. ⁵ For non-diabetic children, the subjects as follows were used: patients with growth hormone therapy, developmental disability or obesity, of which plasma glucose and HbA1c levels were within normal range. We excluded those participants with thyroid disease, liver disease, renal disease, anaemia or administration of glucocorticoid. The data of the infants and children were collected from October 2010 to November 2011 and from January 2012 to May 2012, respectively.

This study was approved by the Ethics Committee at Asahikawa Medical University. All subjects and/or subjects’ parents provided written informed consent.

Laboratory measurements

Serum GA was determined using Hitachi 7600 autoanalyzer (Hitachi Instruments Service Co., Tokyo, Japan) by enzymatic method using albumin-specific proteinase, ketoamine oxidase and albumin assay reagent (Lucica GA-L; Asahi Kasei Pharma Co., Tokyo, Japan). Inter-assay coefficient variations (CV) in the data collection for the infants were 4.55% and 5.56%, respectively, as determined in two representive samples. Inter-assay CV in the data collection for the children were 2.14% and 1.87%, respectively, as well. The adult reference value for GA is 14.0 ± 1.1% (range, 11.7–16.2%), where inter-assay CV were 1.38% and 1.32%, respectively as determined in two representive samples. ⁵

Statistical analysis

Simple regression analyses were employed to assess the association between continuous variables. On the basis of the regression lines of GA and log(age), Aa-GA was calculated: Aa-GA was derived from the equation of multiplying the adult mean value of GA (14.0% as described above) by that regression formula. All analyses were conducted using SPSS 20 at a significance level of P < 0.05.

Results

GA levels were significantly correlated with log(age) in 376 non-diabetic subjects (R = 0.865; P < 0.0001). Figure 1 shows the regression line and equation. By using this equation, we established the formula for Aa-GA by using the following equations.

$\text{Aa-GA}=\text{GA}\times 14.0/[1.77\times \log (\text{age})\hspace{1em}(\text{days})+6.55]\hspace{1em}\text{or}\text{Aa-GA}=\text{GA}\times 14.0/[1.77\times \log (\text{age})\hspace{1em}(\text{years})+11.1]$

Figure 1.

Correlation between glycated albumin (GA) and logarithmically transformed age [log(age)] in 376 non-diabetic subjects (age range, 4 days–78 years) are depicted. The actual data were plotted on a lin-log graph (using a logarithmic scale on the x-axis). The grey column represents the reference range of GA for the adults (11.7–16.2%). The broken line represents the average GA value for the adults (14.0%).

Discussion

We previously reported a significant positive correlation between GA and log(age) in healthy infants of up to one year of age. ⁴ Our current study broadened the analysis to include adults, and we found that a significant positive correlation exists between GA and log(age). It is well known that GA levels are influenced by albumin metabolism. ¹ As GA is measured as a ratio of glycated to total albumin, it is not generally affected by the serum albumin levels. However, serum albumin was significantly positively correlated with GA or log(age) in healthy infants. ⁴ Both the low GA levels and positive correlation between serum albumin and GA in infants can be explained because of probably accelerated albumin metabolism. Increased albumin biosynthesis has been shown in a dynamic study using an isotope. ⁶ Protein synthesis rate was also reported to be more than twice as fast as that in adults. ⁷ During fetal and neonatal development, weight increases rapidly in parallel with protein gain, which results from a difference between protein synthesis and breakdown (i.e. protein turnover). ⁷ More rapid growth and protein gain were repoted to be associated with higher rates of protein turnover.^7,8 Accordingly, albumin metabolism is speculated to have a negative correlation with log(age).

Many measured parameters show various patterns of gradual increase or decrease concurrent with growth from childhood. ⁹ Nevertheless, most studies for age-related change are limited in children. It might be interesting to determine whether changes similar to that of GA can be detected for some parameters from infancy to the aged.

There is a danger of assessing NDM patients with poor glycaemic control state as good if the adult reference range of GA is used because GA levels in infants are lower than in adults. Therefore, we have previously proposed that GA levels should be compared with age-dependent reference range in order to make accurate assessments regarding glycaemic control. ⁴ However, one problem with this method was that an age-dependent reference range is always necessary for judgment of the GA levels in NDM patients.

Because GA showed strong positive correlation with log(age), Aa-GA is well adapted for comparison with the adult reference range and can be a useful indicator for glycaemic control in NDM patients. One advantage of using Aa-GA levels is that it can be easily calculated from measured GA levels and age without using age-dependent reference range. Another advantage of using Aa-GA levels is that long-term trends of glycaemic control can be compared.

In conclusion, GA in non-diabetic subjects is strongly positively correlated with log(age). Consequently, Aa-GA allowing us to use the same adult reference range has the potential for treatment monitoring of diabetic patients, especially NDM patients, regardless of age.