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Abstract

Background

The Japanese Red Cross Society measures levels of glycated albumin (GA), an indicator of mean blood glucose levels, in blood obtained from all donors.

Methods

Changes in mean GA levels and the percentage of cases of prediabetes from 2009 to 2018 were investigated in approximately 4.2 million, healthy, first-time blood donors aged 16–64 years, and the seasonal characteristics of GA and the association of the GA level with body mass index (BMI) were clarified.

Results

Mean GA levels decreased over the decade, with a decrease of 0.42–0.77% in male and 0.39–0.49% in female donors in the groups categorised by age. The percentage of prediabetes cases also decreased over the decade, with the largest decrease in those in their 60s. GA levels were higher in the warm season than in the cold season. In 2018, the seasonal difference in the GA level was 0.48% (95% confidence interval [CI] 0.45–0.50%) for male and 0.45% (95% CI 0.41–0.48%) for female donors. GA had a linear negative correlation with BMI in the younger generation. A trend of increasing GA with BMI was noted in those in their 30s and older.

Conclusions

Mean GA levels and the percentage of prediabetic cases have decreased, possibly resulting from public health promotion efforts and early diagnosis of diabetes mellitus. The present data on GA seasonal variation, showing higher levels in the warm season, and the association between BMI and GA may be useful for clinical practice.

Keywords

Glycemic marker prediabetes state body mass index public health

Introduction

Type 2 diabetes mellitus is a multifactorial condition, arising from a combination of genetic susceptibility and environmental influences, which include, but are not limited to, dietary habits, such as overconsumption, and a lack of appropriate physical activity. Additional risk factors such as obesity, stress, and ageing also contribute to the development of the disease. The prevalence of diabetes mellitus is clearly increasing worldwide, with an increasing number of prediabetic patients also expected. The prevention and treatment of diabetes mellitus and its related complications are not only a medical issue but also an important social issue.

HbA1c and glycated albumin (GA) are the indicators of mean blood glucose levels in diabetic persons and healthy individuals. HbA1c has long been used as the gold standard for predicting blood glucose levels. HbA1c and GA indicate the percentage of glycation of haemoglobin and of albumin, respectively; GA levels are about three times higher than corresponding HbA1c levels.¹ Whereas HbA1c reflects the blood glucose status over a month or two leading up to the test, GA reflects the mean blood glucose level for the last two to 4 weeks. The difference between the HbA1c and GA levels is attributed to albumin’s structure, which contains more amino acids that undergo glycation and more rapid metabolism of albumin than haemoglobin.² Therefore, the GA level is a useful parameter for monitoring the effectiveness of diabetes mellitus treatment, because it more accurately reflects acute changes in the mean blood glucose level occurring over a shorter timescale than the HbA1c level.³

It has also been demonstrated that GA reflects postprandial hyperglycaemia more than HbA1c.^3–5 In addition, HbA1c shows a value dissociated from the actual blood glucose state in individuals with haemoglobin variants, kidney failure, or anaemia.^1,6–9 In this context, GA could be preferentially used to monitor blood glucose in patients who are anaemic due to kidney insufficiency, pregnancy, or cancer treatment.¹ In contrast, GA shows divergent values in patients with liver cirrhosis or nephrotic syndrome due to changes in the albumin turnover rate. A low GA level has also been reported in severe obesity.¹⁰

The Japanese Red Cross Society (JRCS) informs all blood donors of their test results for peripheral blood cell counts, liver function tests including alanine aminotransferase, gamma-glutamyltranspeptidase, total cholesterol, albumin, the ratio of albumin to globulin, and total protein. In 2009, it added the GA test and started informing blood donors of the results of their GA tests so that they could use the data for their health management.¹¹ Of individuals with diabetes mellitus, those taking oral medications for diabetes mellitus, on insulin therapy, and/or with diabetic complications are excluded as blood donors in Japan. Therefore, individuals with diabetes mellitus on exercise or diet therapy, as well as those with prediabetes, can donate their blood. Thus, analysis of the GA test results of blood donors is expected to clarify the status of mild diabetes mellitus and prediabetes in Japan.

We previously analysed the GA test results of blood donors in 2009 and found that the mean GA level increased with increasing age. The percentage of those with prediabetes also increased with age.¹¹ The effect of blood donation on GA levels has not been reported. However, because up to 600 mL of plasma is collected per blood donation, blood donation could, in principle, affect GA levels. Therefore, the present analysis was restricted to first-time blood donors. The present cross-sectional study using a large dataset of over 4 million first-time blood donors in Japan aimed to analyse 10-year trends in GA levels, potentially providing valuable insights into demographic changes in prediabetes. In addition, the relationship of GA levels with the body mass index (BMI) and the seasonal variation of GA levels were analysed.

Methods

Study population and data analysis

To evaluate the 10-year trend of GA levels and analyse the association of GA levels with BMI, 4,292,606 (2,651,319 male and 1,641,287 female) donors who donated blood for the first time between financial year (FY) 2009 and FY2018 were selected for this study. The participants were aged between 16 and 64 years at the time of blood donation and were divided into six age groups: 16–19 years of age; four 10-year strata from 20 to 59 years of age; and 60–64 years of age.

To examine seasonal variation in GA levels, all donors who donated blood for the first time in FY2009 and FY2018 (889,300 [545,119 male and 344,181 female] donors) were analysed. As for the characteristics of the GA levels of blood donors, data analysis was performed with descriptive statistics using means, standard deviations, and 95% confidence intervals. EZR, a modified version of R commander designed to add statistical functions that are frequently used in the field of biostatistics, was used for all statistical analyses.¹²

Blood donors

JRCS is the only organisation that provides all allogeneic blood components nationwide to medical facilities. In the JRCS regulation, healthy people aged between 16 and 64 years are eligible for first-time blood donation. Detailed eligibility for blood donation was further judged through questionnaires and medical examination by the doctor responsible for the whole donation process. For individuals with diabetes mellitus, those requiring insulin injections and/or oral antidiabetic medications or those with diabetic complications were not eligible for blood donation. Therefore, individuals with diabetes mellitus on only exercise and diet therapy, as well as those with prediabetes, can donate their blood. These inclusion and exclusion criteria regarding diabetic status for blood donation were consistent throughout the study period. Eligibility for blood donation also depends on the type of blood components and the collection volume. The minimum body weight of male or female individuals required for 200-mL whole blood donation and aphaeresis blood collection of platelets and plasma is 45 kg or 40 kg, respectively, and 50 kg for both sexes for 400-mL whole blood collection. The BMI is calculated by dividing weight in kilogrammes by the square of height in metres. The donor height and weight values used in this study were mostly self-reported.

Glycated albumin (GA) measurement and report of its value to donors

The measurement of GA was conducted with an enzymatic method, using the reagent LUCIKA GA-L (Asahi Kasei Pharma, Tokyo, Japan) and the automatic clinical chemistry analyser LABOSPECT08 (Hitachi High-Technologies, Tokyo, Japan)^13,14 in 10 JRCS testing laboratories across the country. Quality control was performed on a daily basis at the start and end of analyser operation in all laboratories using control materials that were shared among them. There are as yet no official definitions of suspected diabetes mellitus and prediabetes based on the GA level. Since GA levels are basically approximately three times higher than corresponding HbA1c levels,^1,15,16 the JRCS has, therefore, categorised the GA levels by using three times the reference range for HbA1c defined by the Japan Diabetes Society (Japan Diabetes Society (JDS) value)^1,15,17 as follows: a GA value <15.6% is defined as normal; 15.6%≤GA <16.5% as normal high (health guidance needed); 16.5%≤GA <18.3% as prediabetes (consultation recommended); and GA ≥18.3% as diabetes mellitus.^11,18 The criterion for the ‘prediabetes’ category outlined in this study is largely similar to that for impaired glucose tolerance (IGT).¹⁹

Together with the results of gamma-glutamyl transpeptidase (ɤ-GTP), alanine aminotransferase (ALT), etc., the GA test results are reported to all blood donors in ‘the blood test result letter’, in which we describe the details of how to interpret the GA test result, as follows: ‘the GA level is indicative of the mean blood glucose level in approximately the last 2 weeks. A GA level <16.5% can be judged normal. If you have a GA level above the normal range, we recommend having a consultation at a medical institution. If you have a GA level ranging from 15.6% to 16.5%, which is the upper border of the normal range, careful attention is needed’.

Ethical approval

The study protocol was approved by the Japanese Red Cross Society Research Ethics Committee (2019-003). All methods in the study were performed according to the Japanese Ethical Guidelines for Medical and Health Research Involving Human Subjects and the principles laid down in the Declaration of Helsinki. All blood donors provided their informed consent through an opt-out approach using methods approved by the Japanese Red Cross Society Research Ethics Committee.

Results

Study population

GA levels were evaluated in a total of about 4.3 million donors who donated blood for the first time during the 10 years from 2009 to 2018. Of the total, 33,663 (0.78%) blood donors were classified as having prediabetes or diabetes mellitus, with GA levels that exceeded the reference value of 16.5%. Moreover, 11,455 men (0.27%) and 3740 women (0.09%) were considered to have diabetes mellitus with a GA of 18.3% or higher (Table S1).

Changes over a decade

Changes in mean GA levels

The mean GA levels increased as donor age increased, except for donors in their 20s, and this trend was observed in every year examined (Table S2). The mean GA levels showed a decreasing trend over the 10 years from 2009 to 2018, with similar trends for both sexes and all age groups. For males, the change in GA levels over the 10 years was greater in the older age group; the largest decrease in the mean GA was observed in those in their 60s, with a 0.8% decrease (mean difference 95% CI 0.618–0.916%) compared with 0.4% (mean difference 95% CI 0.407–0.425%) for those in their teens. For females, in contrast, the decrease in the mean GA ranged from 0.4% to 0.5% over all age groups (95% CI 0.383–0.404% and 0.348–0.617% for those in their teens and their 60s, respectively). For both males and females, the largest decrease occurred from 2011 to 2012 for all age groups (Figure 1, Table S2).

Figure 1.

Decadal changes in mean glycated albumin (GA) by age. This figure shows the change in mean GA for each age group of first-time donors from 2009 to 2018. The blue diamonds show data for teens (age 16 to 19 years), the orange squares show data for those in their 20s, the green triangles show data for those in their 30s, the red circles show data for those in their 40s, the yellow inverted triangles show data for those in their 50s, and the purple hexagons show data for those in their 60s (age 60 to 64 years). All years are financial years. The upper and lower 95% confidence intervals are shown as error bars that extend above and below the top of the mean GA. Since the 95% CI for those in their teens to those in their 40s is less than 0.05, it is not shown in the figure.

Changes in the percentage of donors with high GA levels

Over the 10-year period from 2009 to 2018, the rates of GA ≥18.3%, indicating diabetes mellitus, and 16.5%≤GA <18.3%, indicating prediabetes, decreased across all age groups and both sexes. The absolute decline in percentage points for GA in the prediabetes range (16.5%≤GA <18.3%) increased with age. The decline in those in their teens was 0.04 and 0.20 percentage points for males and females, respectively (95% CI 0.018–0.067 percentage points and 0.150–0.250 percentage points for males and females, respectively). In contrast, the decline in those in their 60s was 2.65 and 2.34 percentage points for males and females, respectively (95% CI 1.58–3.72 percentage points and 1.13–3.56 percentage points for males and females, respectively). The absolute percentage point decline in each age group was greater in females than in males, except for those in their 60s (Figure 2, Table S1).

Figure 2.

Decadal changes in the percentage of individuals with prediabetes by age. This figure shows the change in percentage of individuals with prediabetes (16.5%≤ glycated albumin (GA) < 18.3%) for each age group of first-time donors from 2009 to 2018. The blue diamonds show data for teens (age 16 to 19 years), the orange squares show data for those in their 20s, the green triangles show data for those in their 30s, the red circles show data for those in their 40s, the yellow inverted triangles show data for those in their 50s, and the purple hexagons show data for those in their 60s (age 60 to 64 years). All years are financial years. The 95% confidence intervals for all points are less than 0.01 and are therefore not shown in the figure.

Changes in BMI

There was a slight increase in BMI for all age groups and both sexes between 2009 and 2018. The increase in BMI was 0.05 kg/m² for males and 0.23 kg/m² for females (95% CI: 0.036–0.072 kg/m² and 0.211–0.251 kg/m² for males and females, respectively). There was no increasing or decreasing trend with age. Females in their 30s had the largest increase of 0.8 kg/m². Males in their teens and females in their 50s and 60s had a smaller increase of 0.1 kg/m² (Table S2).

Association between GA and BMI

In younger age groups from their teens to 30s, both males and females tended to have lower mean GA levels in the higher BMI category. For those in their teens and 20s, mean GA decreased linearly as BMI increased. This trend was less clear for those in their 30s, particularly for males. For those in their 40s or older, except for females in their 60s, the trend changed to increasing GA with BMI >25 kg/m². The increasing trend in mean GA levels in obese individuals was observed in both males and females, but was stronger in males. At BMI <25 kg/m², females had higher GA levels than males at all ages, contributing to the higher average GA levels in females (Figure 3, Table S3).

Figure 3.

Glycated albumin (GA) levels by donor BMI and age group. The blue diamonds show data for teens (age 16 to 19 years), the orange squares show data for those in their 20s, the green triangles show data for those in their 30s, the red circles show data for those in their 40s, the yellow inverted triangles show data for those in their 50s, and the purple hexagons show data for those in their 60s (age 60 to 64 years). All years are financial years. The body mass index (BMI) is calculated by dividing weight in kilogrammes by the square of the height in metres. The upper and lower 95% confidence intervals are shown as error bars that extend above and below the mean GA.

Seasonal changes in GA

GA levels were higher in the warm season and lower in the cold season. The trend was similar in males and females and in 2009 and 2018, although GA levels were lower overall in 2018 than in 2009 (Figure 4, Table S4). In 2018, males had a mean GA of 13.16% in August and 12.68% in January (difference 0.48%; 95% CI 0.448–0.502%). Females had a mean GA of 13.68% in September and 13.23% in January (difference 0.45%; 95% CI 0.411–0.478%). The same seasonal variation was seen in all age groups (Table S5). Seasonal variations in GA levels and in mean temperatures in Tokyo showed similar trends (Figure 4, Table S4).

Figure 4.

Seasonal variation in mean glycated albumin (GA). The orange triangles show female values in 2009, the red inverted triangles show female values in 2018, the light blue squares show male values in 2009, the blue circles show male values in 2018, and the green bar shows average temperatures in Tokyo in 2018. The 95% confidence intervals for all points are less than 0.03 and therefore not shown in the figure.

Discussion

In this study, a large amount of data on GA levels over a 10-year period was collected that had been measured with the same reagents and instruments using the same standard in the routine testing of the JRCS for all blood donors. Approximately 4.3 million first-time donors, representing approximately 3% of the Japanese population, were included in the analysis. This is also the first study to show the 10-year change and seasonal characteristics of the mean GA value of healthy blood donors. The JRCS informs all blood donors of their biochemical test results, including GA test results. Overall, 0.78% of first-time donors who had judged themselves healthy received GA results indicating diabetes mellitus. In particular, it was estimated that there were 1600 young blood donors under the age of 29 years who had diabetes mellitus over the 10-year period. In this regard, GA testing of blood donations is contributing to identifying new patients with diabetes mellitus and encouraging them to seek earlier physician consultation.

The decline in GA over the 10-year period is possibly due to the effect of the lifestyle health check-ups and health guidance measures implemented by the Japanese government, although there is no direct evidence to prove this. These strategies started in April 2008 to prevent lifestyle-related diseases for people aged 40 years and older. Lifestyle health check-ups are specialised check-ups that look for symptoms of metabolic syndrome. Lifestyle health guidance is provided to persons who show a risk of lifestyle-related illness based on the check-up results. It is expected that improving lifestyle habits can prevent illness.

In July 2010, the diagnostic criteria for diabetes mellitus were changed in Japan.²⁰ The changes enabled diagnosis of diabetes mellitus based on HbA1c and blood glucose results. The changes aimed to promote early diagnosis and treatment of diabetes mellitus in Japan. Such a nationwide introduction of this precautionary strategy may have enabled identification of diabetic individuals among those who might otherwise have been selected to donate blood due to the lack of a diabetes mellitus diagnosis. Therefore, it is possible that such individuals voluntarily avoid visiting blood donation sites, or that they may be identified as having diabetes mellitus at the pre-donation interview and subsequently do not donate blood. These conditions may explain the largest decrease in GA levels from FY2011 to FY2012 confirmed in the current study, possibly due to the successful early diagnosis and therapeutic interventions for individuals with diabetes mellitus after the implementation of the revised diagnostic criteria in 2010. However, the study also showed a decrease in the percentages of prediabetes defined as 16.5%≤GA <18.3% and normal high as 15.6%≤GA <16.5% (Figure 2, Table S1). Individuals within these GA ranges would not consult a physician like those with a risk of diabetes mellitus. Therefore, the 10-year decline in GA levels cannot be explained by diagnostic criteria changes alone.

In contrast, the National Health and Nutrition Survey (NHNS) in Japan, a nationwide, representative survey of the general population conducted annually involving approximately 20,000 individuals, with blood tests performed on a subset of approximately 4000 participants each year, has shown that HbA1c levels in persons not on medication for diabetes mellitus have remained almost unchanged over 10 years.²¹ The 10-year decline in GA levels might be the result of capturing a more detailed trend, although no clear evidence is available.

A negative correlation of GA with BMI has already been reported.²² The current study reported detailed age-specific GA and BMI correlations using data obtained from >4 million people. A previous study demonstrated that GA shows decreasing values as BMI increases due to the increased albumin metabolism or turnover in individuals with a high BMI.²³ However, obesity is known to bring about hyperinsulinemia and insulin resistance.²⁴ Young people can produce enough insulin to compensate for the increasing insulin resistance as they reach a high BMI, which eventually helps them show GA levels inversely proportional to BMI. In contrast, when elderly people reach a high BMI, they may have such considerable insulin resistance that their endogenous insulin production is unable to keep pace due to their long-lasting hyperinsulinemia. This status could explain the increased GA levels in elderly people with higher BMIs. Decreased insulin production capacity due to ageing or impaired β-cell function also likely contributes to this tendency. The trend of increasing GA levels due to obesity was found to be stronger in male than in female donors in the present study. This observation fits with previous reports that insulin resistance is higher in obese males than obese females.^25,26 The increase in BMI over the 10 years analysed in the present study was modest. Therefore, the change in BMI was not significant enough to affect the decrease in GA levels over the 10 years (Table S2).

HbA1c has been reported to be higher in cooler seasons and lower in warmer seasons.^27–30 Interestingly, unlike seasonal changes in HbA1c, GA levels tended to be higher in warmer seasons and lower in cooler seasons. Some reports indicated that oral glucose tolerance test (OGTT) results are worse in summer.^31–33 It is presumed that the GA levels that reflect postprandial hyperglycemia to some degree had a similar trend.

Seasonal variations in GA levels seem to correlate with temperatures in Japan, suggesting an effect of temperature, for which the reason is not clear. The seasonal variation was basically the same in 2009 and 2018 (Figure 4). No seasonal changes in GA in diabetic outpatients were reported from a longitudinal cohort study including >2000 subjects,³⁴ in contrast to the present cross-sectional study involving nearly 900,000 blood samples from healthy individuals.

The previous study indicated that healthy young men had elevated postprandial serum glucose and insulin levels at high temperatures.³¹ Heat exposure may induce insulin counterregulatory hormones including adrenaline, glucagon, cortisol, and growth hormone.^32,35 Gestational diabetes is more common in summer,^36,37 and heat exposure was related to hospitalisations for hyperglycaemic emergencies such as diabetic ketoacidosis (DKA) and hyperosmolar hyperglycaemic state (HHS).^38,39

The incidence of diabetes mellitus in the United States and the worldwide prevalence of glucose intolerance were found to be higher as outdoor temperatures increased.⁴⁰ Brown adipose tissue activity, which is responsible for effectively lowering blood glucose levels, is negatively correlated with outdoor temperature.^41–43 Though one cannot draw conclusions about causal relationships from the present study along with these previous reports, the results nevertheless support each other.

The GA/HbA1c ratio is used to indicate postprandial hyperglycemia and insulin secretion (HOMA-β),^44–47 but differences in seasonal trends in GA and HbA1c levels may affect results in summer and winter. The trend in the monthly distribution of the number of blood donors did not change significantly over the 10-year period, confirming that the 10-year decrease in the mean GA was not caused by a monthly imbalance of blood donors. Analysis of the mean GA for the same months in 2009, 2012, 2015, and 2018 also showed a downward trend over the 10-year period (Table S6).

Multivariate analysis was not performed because of the lack of information on potential confounders that may typically affect GA levels other than age, sex, and BMI. The present study, instead, presents data from a cross-sectional study examining >4,000,000 blood samples. Detailed questionnaires administered to blood donors about their health status certainly concentrate them into a highly healthy population (blood donor effect).^48,49 Thus, the GA levels and the prevalence of prediabetes in the general population in Japan may be higher than the levels reported here.

Conclusion

GA testing at the time of blood donation is contributing to identifying new patients with diabetes mellitus, and the JRCS is continuing this testing as a blood donor service. Since the subjective symptoms of early diabetes mellitus are few and non-specific, conducting GA tests during blood donation can be beneficial for diabetes screening.

The mean GA levels and the percentage of prediabetes among healthy blood donors were shown to have been decreasing during the 10 years from 2009 to 2018. The present study also identified the relationship of GA levels with BMI in healthy individuals and seasonal variations in GA levels, with higher levels noted in the warmer months.

These data obtained from a huge number of samples provide important information for interpreting the glycaemic status of healthy Japanese individuals, including those with prediabetes. Although a bias towards blood donors is included, the data may also be beneficial in the evaluation of diabetes countermeasures by the government and other organisations, as well as in the evaluation of health promotion to the public. Further analyses of the characteristics of GA and its relationship to glucose metabolism are needed.

Supplemental Material

Supplemental Material - Seasonal and decadal changes in glycated albumin levels of Japanese blood donors

Supplemental Material for Seasonal and decadal changes in glycated albumin levels of Japanese blood donors by Takeshi Araki, Tadashi Nagai, Shigeki Miyata, Yoshihiko Tani, and Masahiro Satake in Annals of Clinical Biochemistry

Footnotes

Acknowledgement

The authors would like to thank R. Yamaguchi for his help in drawing the figures.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Ethical approval

The study protocol was approved by the Japanese Red Cross Society Research Ethics Committee (2019-003).

Guarantor

TA.

Contributorship

TA conceived and designed the study. TA analysed all data, performed the research, and wrote the manuscript. TN, SM, YT, and MS supervised the research and reviewed and edited the manuscript.

ORCID iDs

Takeshi Araki

Shigeki Miyata

Yoshihiko Tani

Masahiro Satake

Data Availability Statement

The data regarding the findings of this study are available from the corresponding author upon reasonable request and with permission of the Ethics Review Board. Some of the data are available at and within the supplementary information of this article.

Supplemental material

Supplemental material for this article is available online.

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