Introduction
Glucocorticoids are widely used for the treatment of diseases such as autoimmune disease and chronic kidney disease [
1,
2]. However, such treatment predisposes to diabetes, with odds ratios for new-onset diabetes mellitus (DM) in patients treated with glucocorticoids having been shown to be 1.5–2.5 [
1,
2]. Steroid-induced DM is associated with marked postprandial hyperglycemia due to peripheral insulin resistance and islet cell dysfunction [
1]. Insulin sensitizers, such as thiazolidinediones and metformin, are often used as first-line therapies. However, insulin secretory capacity is also reduced; therefore, insulin therapy and oral hypoglycemic drugs may also be used [
3]. Following these steps, if glycemic control remains insufficient, intensive insulin therapy may also be required after steroid therapy [
3]. Early detection of steroid-induced DM is needed to prevent insulin therapy [
3].
Several indices are now used to evaluate glycemic control, but glycated hemoglobin A1c (A1c) is the most frequently used. However, in specific conditions, such as hemolytic anemia and hemoglobinopathies, there are discrepancies between actual glycemic control and A1c concentration [
4,
5]. In such instances, measurement of glycated albumin (GA) is recommended [
4]. Because albumin (Alb) has a shorter half-life than hemoglobin, GA reflects the efficacy of glycemic control over a shorter period of time than A1c [
6], and more accurately reflects postprandial than fasting hyperglycemia [
7]. Because early stage steroid-induced DM exhibits postprandial hyperglycemia with normal fasting glucose levels [
1], GA can be an appropriate indicator of glycemic status in patients with steroid-induced DM. However, in some previous studies, glucocorticoid administration has been shown to lower plasma GA more effectively than glycemia [
8]. Nevertheless, it remains unclear whether glucocorticoid treatment reduces plasma GA concentration.
In this study, we determined whether high dose prednisolone (PSL) affects plasma GA concentration in patients with connective tissue diseases (CTDs) using multivariate analysis. The identification of factors affecting GA concentration may define contraindications for the use of GA in subjects undergoing steroid treatment.
Discussion
In this study, we investigated whether steroid administration affects GA. Multiple linear regression analysis showed that PSL dose, age, BMI, and A1c significantly correlated with plasma GA. After adjustment of GA for age, sex, BMI, Cre, and A1c, it was higher in patients taking 5 mg PSL than in those taking < 5 mg PSL. Therefore, in subjects undergoing high-dose (≥ 5 mg) PSL therapy, it is possible that the use of GA may be associated with a underestimation of the severity of hyperglycemia.
This study is the first to reveal that high-dose PSL lowers GA, although it was a small retrospective study. A previous study reported that GA in patients with Cushing’s syndrome is lower than in patients with type 2 DM [
9], and a patient treated with 20 mg prednisolone has also been described who exhibited GA-to-A1c ratios that were persistently lower (1.49–1.80) than the ratio normally present in type 2 DM patients (2.5) [
8]. It is known that alterations in albumin concentration can affect GA, and glucocorticoids upregulate both protein synthesis and degradation, thereby increasing protein turnover [
10]. In fact, plasma albumin in patients taking ≥ 5 mg PSL was significantly lower than that in those taking < 5 mg PSL. When it is also considered that plasma GA in patients with nephrotic syndrome and hyperthyroidism is lower than would be expected according to the degree of glycemic control [
11,
12], it is likely that high-dose PSL causes a reduction in GA as a result of altered albumin turnover.
The use of glucocorticoids can been associated with the development of osteoporosis, osteonecrosis, cataracts, hyperglycemia, coronary heart disease, and cognitive impairment, but the minimum dose required to induce these adverse effects has been shown to be about 5 mg PSL per day [
13,
14]. Therefore, high-dose PSL is often defined as ≥ 5 mg PSL [
13,
14]. Moreover, the incidence of DM in patients taking ≥ 5 mg PSL was five times higher than in patients taking < 5 mg PSL [
15]. Therefore, we divided the subjects in this study into those taking < 5 mg PSL and those taking ≥ 5 mg PSL. Our data show that the use of GA as an indicator of glycemic status in patients taking high doses of steroids may be associated with an underestimation of the severity of hyperglycemia.
It has previously been reported that A1c, age, and BMI significantly affect plasma GA levels [
16‐
19]. Because A1c also indicates the severity of recent glycemia, it is closely correlated with GA [
17,
18], and the relationship has been described by HbA1c = 0.216 × GA + 2.978 [
R2 = 0.5882,
p < 0.001] [
18]. GA increases with age from infancy to adulthood and therefore age-adjusted GA can more accurately reflect glycemic status [
19,
20]. Most obese individuals are insulin resistant, which can be associated with postprandial hyperglycemia, which tends to increase GA rather than A1c [
7,
21,
22], such that, for example, the GA-to-A1c ratio is often higher in patients with type 1 DM [
7,
21]. Moreover, the risk of steroid-induced DM is greater in individuals with a higher BMI [
23]. However, our data show that GA is negatively correlated with BMI, which is consistent with many previous reports [
24‐
26]. Finally, other authors have speculated that greater protein turnover and inflammation may contribute to the observed GA levels in obese subjects [
26]. Although the mechanism has not been elucidated in this study, A1c, age, and BMI have been shown to affect GA concentration.
This study had a number of limitations. Firstly, it was not a randomized study, it was small, and conducted only in one hospital; therefore, we are mindful that there is a risk of selection bias. To further investigate the effects of PSL dose on GA, a prospective study (such as a cohort study) is required. Secondly, the range of A1c concentrations was limited to 5.0–7.5%; therefore, conclusions regarding GA can only be drawn for patients with A1c values within this range. Thirdly, we used A1c as a marker of glycemic control, rather than multiple or continuous peripheral blood glucose measurements, which can provide a more accurate picture of glycemic control, but would not be covered by health insurance in Japan. Finally, we only studied subjects with connective tissue diseases and not healthy individuals, for which we would not have had the opportunity to measure A1c and GA; therefore, we could not compare data obtained from diseased subjects with healthy subjects.
Acknowledgements
We thank all the patients included in this study.