Clinica Chimica Acta 440 (2015) 93–96

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Effects of growth hormone excess on glycated albumin concentrations: Analysis in acromegalic patients Daisuke Tamada a, Michio Otsuki a, Tetsuhiro Kitamura a, Satoru Oshino b, Youichi Saitoh b, Iichiro Shimomura a, Masafumi Koga c,⁎ a b c

Departments of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan Departments of Neurosurgery, Osaka University Graduate School of Medicine, Osaka, Japan Department of Internal Medicine, Kawanishi City Hospital, Hyogo, Japan

a r t i c l e

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Article history: Received 12 May 2014 Received in revised form 29 October 2014 Accepted 10 November 2014 Available online 15 November 2014 Keywords: Glycated albumin HbA1c Albumin Acromegaly Growth hormone

a b s t r a c t Background: Glycated albumin (GA) does not reflect glycemic control in patients with disorders of albumin metabolism. In the present study, we examined GA concentrations in acromegalic patients with growth hormone (GH) excess. Methods: We studied the hormonal status of 29 acromegalic patients (10 patients had diabetes mellitus and the remaining 19 patients were non-diabetic), 20 patients with type 2 diabetes mellitus and 38 non-diabetic subjects matched for age, sex and body mass index. Results: Serum GA concentrations, but not those of fasting plasma glucose, 2-h post-load plasma glucose and HbA1c, were significantly higher in non-diabetic acromegalic patients compared with non-diabetic control subjects. Serum GA concentrations, but not those of fasting plasma glucose and HbA1c, were significantly higher in diabetic acromegalic patients compared with patients with type 2 diabetes mellitus. Conclusions: This is the first report describing higher GA concentrations in acromegalic patients relative to plasma glucose concentrations. Special care should be taken when evaluating glycemic control using GA because acromegaly is frequently complicated with diabetes mellitus. © 2014 Elsevier B.V. All rights reserved.

1. Introduction It is known that nonenzymatic glycation of protein increases in diabetic patients compared with non-diabetic subjects, and it is suggested that certain types of these glycated proteins may contribute to the onset and progression of diabetic complications [1]. Among these glycated proteins, HbA1c and glycated albumin (GA) are used as clinical indicators of glycemic control [2,3]. However, in diseases affecting the life span of erythrocytes and albumin metabolism, HbA1c and GA are not suitable markers since they do not accurately reflect the state of glycemic control [4,5]. Since some hormones affect erythrocyte life span and albumin metabolism, they may also affect the markers of glycemic control. For example, testosterone indirectly reduces HbA1c by stimulating erythropoiesis [6], similar to the effects of thyroid hormone and glucocorticoid on GA [7,8]. Acromegaly is caused by hypersecretion of growth hormone (GH) from pituitary adenoma. In acromegalic patients, the prevalence of diabetes mellitus ranges from 19% to 56% [9], and these complications are associated with the prognosis of acromegalic patients [10]. Therefore, glucose intolerance should be managed appropriately in these patients. ⁎ Corresponding author. Tel.: +81 72 794 2321; fax: +81 72 794 6321. E-mail address: [email protected] (M. Koga).

http://dx.doi.org/10.1016/j.cca.2014.11.009 0009-8981/© 2014 Elsevier B.V. All rights reserved.

GH is a strong anabolic hormone, which is essential for maintenance of muscle mass not only in childhood but also in adulthood [11]. Therefore, GH regulates the metabolism of various proteins, including albumin, a major serum protein. Accordingly, GH excess may affect GA concentrations. 2. Patients and methods 2.1. Study patients The study subjects were 29 patients with active acromegaly diagnosed at Osaka University Hospital between April 2010 and March 2013 (Table 1). The diagnosis of acromegaly was based on the following criteria: (1) clinical features (acral enlargement, acromegalic features and macroglossia); (2) lack of suppression of serum GH concentrations below 1 μg/l after 75 g oral glucose tolerance test (OGTT), with serum insulin-like growth factor-I (IGF-I) concentrations above the upper limit of the normal range; and (3) identification of a pituitary mass on magnetic resonance imaging. Among the study subjects, we excluded patients with chronic liver diseases, chronic renal disease including overt proteinuria, anemia, thyroid dysfunction or adrenal dysfunction, which are known to influence the measurements of HbA1c and/or GA. Thus, data were collected from 20 patients with type 2 diabetes mellitus

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Table 1 Clinical characteristics of subjects of the 4 study groups. Control

Acromegaly

Without DM With DM

Without DM

With DM

n Male (%) Age (years) Body mass index (kg/m2) Serum GH (μg/l) Serum IGF-1 (μg/l)

38 19 (50.0) 49.4 ± 5.9 23.2 ± 3.0

20 10 (50.0) 57.8 ± 6.8 24.2 ± 2.8

19 9 (47.4) 49.4 ± 10.8 23.0 ± 2.7

10 5 (50.0) 58.1 ± 10.0 24.1 ± 2.7

n.d. n.d.

n.d. n.d.

Serum albumin (g/l) Hemoglobin (g/l) Serum creatinine (μmol/l) Serum uric acid (μmol/l) Serum albumin/ creatinine ratio

42.0 ± 6.0

43.0 ± 4.0

8.9 (3.9–13.8) 695 (487–1140) 39.0 ± 3.0

11.7 (5.3–19.8) 913 (564–1220) 39.0 ± 3.0##

137 ± 16 140 ± 13 133 ± 11 65.4 ± 10.6 67.2 ± 16.8 49.5 ± 11.5**

132 ± 12 49.5 ± 15.9#

339 ± 95

256 ± 48#

321 ± 77

286 ± 54*

0.97 ± 0.24 1.01 ± 0.25 1.24 ± 0.29**

1.29 ± 0.44#

Data are mean ± SD, or median (interquartile range). The two groups were compared using the unpaired t-test. *P b 0.05, **P b 0.001 vs. non-diabetic control subjects, #P b 0.05, ##P b 0.01 vs. diabetic control subjects. DM, diabetes mellitus; n.d., not done.

and 38 control non-diabetic subjects matched for age, gender and body mass index (BMI). Diabetes mellitus was diagnosed based on the diagnostic criteria of the American Diabetes Association [12]. The study was performed was approved by the Ethics Committee of Osaka University School of Medicine (approval number: 13080) and conducted according to the Helsinki Declaration 2.2. Laboratory tests Blood samples were taken in the early morning after overnight fast. The 75-g OGTT was performed in all acromegalic patients and control subjects, and plasma glucose concentrations were measured before and 2 h after the glucose tolerance test. HbA1c was measured by high-performance liquid chromatography (HPLC) with an HLC-723G8 (Tosoh Co.). The HbA1c values were converted to National Glycohemoglobin Standardization Program (NGSP) equivalent values using the official equation [13]. GA was measured by the enzymatic method with a Hitachi 7600 autoanalyzer (Hitachi Instruments Service Co.) using albumin-specific proteinase, ketoamine oxidase and albumin assay reagent (Lucica GA-L; Asahi Kasei Pharma Co.) [14]. The standard range was 4.6–6.2% for HbA1c and 11.7–16.0% for GA. Serum GH was measured using a chemiluminescent enzyme immunoassay kit (Beckman Coulter Inc.), and IGF-1 was determined by immunoradiometric assay (Daiichi Radioisotope Laboratories) [15]. 2.3. Statistical analysis Data were expressed as mean ± SD for parameters with normal distribution and as medians and interquartile range for those with skewed distribution (GH and IGF-1). The unpaired t-test and the χ2 test were used for intergroup comparisons, and Pearson's correlation coefficient was used for testing the correlation between fasting plasma glucose and HbA1c and GA. The concentration of statistical significance was established as less than 5%. Statistical analysis was performed using JMP 9.0.2 (SAS Institute Inc.). 3. Results The acromegalic patients consisted of 14 males (48.3%) and 15 females, aged 52.4 ± 11.3 years with BMI of 23.4 ± 2.7 kg/m2. Ten of these patients (34.5%) were diagnosed with diabetes mellitus while

the remaining 19 patients were non-diabetic (Table 1). Serum GH and serum IGF-1 were high at 10.4 μg/l (4.6–14.1) and 834 μg/l (535– 1155), respectively. Fasting plasma glucose (5.42 ± 0.51 vs. 5.46 ± 0.49 mmol/l, P = 0.577) and 2-h post-load plasma glucose after OGTT (7.60 ± 1.67 vs. 7.60 ± 1.17 mmol/l, P = 0.905) in the non-diabetic acromegalic patients were not significantly different from those in the non-diabetic control subjects (Fig. 1A, B). HbA1c also showed no significant difference between these two groups (5.7 ± 0.4% vs. 5.5 ± 0.4%, P = 0.150) (Fig. 1C). On the other hand, GA in the non-diabetic acromegalic patients was significantly higher than that in the non-diabetic control subjects (16.7 ± 2.2% vs. 14.0 ± 1.1%, P b 0.0001) (Fig. 1D). Similar results were obtained even after adjustment of GA concentrations for age, gender, BMI and HbA1c (16.4 ± 1.7% vs. 14.2 ± 1.2%, P b 0.0001). HbA1c was higher than the standard value by the same proportion in 2 nondiabetic acromegalic patients (10.5%) and 4 non-diabetic control subjects (10.5%). On the other hand, GA was higher than the standard value in 12 non-diabetic acromegalic patients (63.2%) and only one non-diabetic control subject (2.6%), and the proportion of non-diabetic acromegalic patients was significantly higher compared with non-diabetic control subjects (P b 0.0001). Fasting plasma glucose (7.88 ± 1.72 mmol/l) and HbA1c (7.4 ± 1.1%) in the diabetic acromegalic patients were not significantly different from those of patients with type 2 diabetes mellitus (7.94 ± 1.22 mmol/l, P = 0.943, 7.6 ± 1.0%, P = 0.503, respectively) (Fig. 2A, B). On the other hand, GA was significantly higher in the diabetic acromegalic patients (24.2 ± 4.7%) than those with type 2 diabetes mellitus (19.8 ± 3.0%, P = 0.004) (Fig. 2C). When GA concentrations in both groups were adjusted for age, gender, BMI and HbA1c, the mean values of the 2 groups were still statistically different (24.8 ± 2.9% vs. 19.6 ± 1.5%, P b 0.0001). In the diabetic acromegalic patients and the patients with type 2 diabetes mellitus, fasting plasma glucose correlated significantly with HbA1c (y = 0.031x + 2.96, R = 0.856, P = 0.002 vs. y =0.030x + 3.37, R = 0.645, P = 0.002, respectively), and the regression formulae of the two groups were almost identical (Fig. 3A). Furthermore, GA significantly correlated with fasting plasma glucose (y =0.101x + 9.93, R = 0.655, P = 0.040 vs. y = 0.082x + 8.18, R = 0.615, P = 0.004) (Fig. 3B) and also with HbA1c (y = 3.64x + 2.48, R = 0.854, P = 0.002 vs. y = 2.41x + 1.38, R = 0.845, P b 0.0001) (Fig. 3C) in both groups, but the regression line of the diabetic acromegalic patients was shifted upward compared with that of patients with type 2 diabetes mellitus. Serum albumin was significantly lower in the acromegalic patients (39.0 ± 3.0 g/l) compared with the control (43.0 ± 6.0 g/l, P = 0.006). Furthermore, serum creatinine (49.5 ± 13.3 μmol/l) and serum uric acid (274 ± 54 μmol/l) were significantly lower in acromegalic patients than the control (66.3 ± 13.3 μmol/l, P b 0.0001, 333 ± 89 μmol/l, P = 0.003, respectively). The serum albumin/creatinine ratio was significantly higher in acromegalic patients (1.26 ± 0.34) than the control (0.99 ± 0.24, P b 0.0001). A comparison of the non-diabetic acromegalic patients and non-diabetic control subjects showed a significant correlation between the serum albumin/creatinine ratio and GA (R = 0.340, P = 0.010), but not between serum albumin and GA (R = -0.078, P = 0.564). Stepwise multivariate analysis showed a significant correlation between the serum albumin/creatinine ratio, but not serum albumin, and GA (data not shown). 4. Discussion The main findings of the present study were high GA concentrations in acromegalic patients relative to plasma glucose concentrations and no significant difference in fasting plasma glucose and HbA1c between acromegalic patients and control subjects. The change in GA was observed in both acromegalic patients with and without diabetes mellitus. Patients with diseases known to be associated with abnormal albumin metabolism have abnormal GA values [5]. Patients with nephrotic

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Fig. 1. (A) Fasting plasma glucose (FPG), (B) 2-h post-load plasma glucose (2 h-PG) after OGTT, (C) HbA1c, and (D) GA levels in the non-diabetic subjects and the non-diabetic acromegalic patients. Data are mean ± SD.

syndrome, hyperthyroidism, on treatment with glucocorticoids, and Cushing's syndrome are known to have high albumin metabolism and low GA concentrations [5,7,8]. On the other hand, patients with liver cirrhosis and hypothyroidism have low albumin metabolism and high GA concentrations [5,7]. In the present study, GA was higher in acromegalic patients than glycemic control, although thyroid hormone, cortisol, liver function and renal function were within the normal ranges. These findings suggest that the state of GH excess might influence albumin metabolism. GH is an important anabolic hormone in the body; muscle mass is reduced in adults and children with GH deficiency [11], and GH supplementation increases muscle mass [16]. However, the exact mechanisms of the anabolic effects of GH remain to be elucidated. Zachwieja et al. [17] reported that administration of GH for 2–4 weeks did not affect albumin synthesis, while Barle et al. [18] reported that administration of GH for 5 days resulted in the upregulation of hepatic albumin mRNA concentrations and increased albumin synthesis. Another study reported that administration of GH to patients with burn injury and those who underwent surgery for esophageal cancer increased protein synthesis [19,20]. With regard to protein catabolism, administration of GH alone had no obvious effect on catabolism of proteins, but it suppressed the enhanced effect of glucocorticoid on protein catabolism [21]. Other studies reported that short-term GH administration had no effect on protein catabolism in healthy volunteers [22–24]. Considered together, these studies suggest that GH seems to increase protein synthesis and inhibit protein catabolism under critical condition although further

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studies are needed to determine the net effect of short-term administration of GH on albumin synthesis. In acromegalic patients who show persistently high concentrations of GH and IGF-1, the exact effects of GH excess on protein metabolism have not been elucidated since most of the above studies were conducted over a relatively short period of several hours to several months. Using intravenous 131I-labeled human serum albumin, Hamamoto [25] reported a relatively long half-life of albumin (18.1 days) in an acromegalic patient compared with healthy subjects (12.5 ± 1.0 days). Unfortunately, only one patient with acromegaly was examined in that study. The present study showed significantly lower serum albumin concentrations in acromegalic patients than in the controls. Furthermore, there was no significant correlation between GA and serum albumin in non-diabetic acromegalic patients and non-diabetic control subjects. The presence of low serum albumin concentrations in patients with active acromegaly compared to those with controlled acromegaly has already been reported [26]. In acromegaly, the epithelial sodium channel in the kidneys is activated by GH excess, with resultant increase in renal sodium reabsorption, body fluid expansion and hemodilution [27,28]. In our study, serum creatinine and serum uric acid concentrations were significantly lower in acromegalic patients than in the controls, which was consistent with hemodilution. GH does not directly reduce serum creatinine concentrations because based on the large muscle mass in acromegaly [29]. Consequently, serum albumin concentrations were lower in the acromegaly group than in the control group, whereas the serum albumin/creatinine ratio was significantly higher.

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Fig. 2. (A) Fasting plasma glucose (FPG), (B) HbA1c, and (C) GA levels in the patients with type 2 diabetes mellitus and the diabetic acromegalic patients. Data are mean ± SD.

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Fig. 3. Correlation analyses of the relations between fasting plasma glucose (FPG) and HbA1c (A), FPG and GA (B), and (C) HbA1c and GA, in the control patients with type 2 diabetes mellitus and the diabetic acromegalic patients.

Our results also showed a significant correlation between GA and the serum albumin/creatinine ratio in non-diabetic acromegalic patients. These results suggest that the serum albumin/creatinine ratio, rather than serum albumin, seem to better reflect GH-induced prolongation of serum albumin half-life in consideration of hemodilution. Further research is necessary to verify the physiopathological role of protein (albumin) metabolism in acromegaly. The prevalence of diabetes mellitus is high in acromegalic patients [9], and diabetic complications are associated with prognosis [10]. Diagnosis and treatment of diabetes mellitus are therefore important in acromegaly. It is known that GA reflects short-term glycemic control compared with HbA1c and is a better marker of glycemic control that reflects more closely postprandial plasma glucose and plasma glucose fluctuations [5]. Since GA concentrations are increased in acromegaly, special care should be taken when evaluating glycemic control using GA in acromegalic patients. Conflict of interest The authors declare no conflict of interest. References [1] Cohen MP. Nonenzymatic glycation: a central mechanism in diabetic microvasculopathy? J Diabet Complicat 1988;2:214–7. [2] Koenig RJ, Peterson CM, Jones RL, Saudek C, Lehrman M, Cerami A. Correlation of glucose regulation and hemoglobin AIc in diabetes mellitus. N Engl J Med 1976; 295:417–20. [3] Bunn HF, Gabbay KH, Gallop PM. The glycosylation of hemoglobin: relevance to diabetes mellitus. Science 1978;200:21–7. [4] Jeffcoate SL. Diabetes control and complications: the role of glycated haemoglobin, 25 years on. Diabet Med 2004;21:657–65. [5] Koga M, Kasayama S. Clinical impact of glycated albumin as another glycemic control marker. Endocr J 2010;57:751–62. [6] Fukui M, Tanaka M, Hasegawa G, Yoshikawa T, Nakamura N. Association between serum bioavailable testosterone concentration and the ratio of glycated albumin to glycated hemoglobin in men with type 2 diabetes. Diabetes Care 2008;31:397–401. [7] Koga M, Murai J, Saito H, Matsumoto S, Kasayama S. Effect of thyroid hormone on serum glycated albumin levels: study on non-diabetic subjects. Diabetes Res Clin Pract 2009;84:163–7. [8] Kitamura T, Otsuki M, Tamada D, et al. Glycated albumin is set lower in relation to plasma glucose levels in patients with Cushing's syndrome. Clin Chim Acta 2013; 424:164–7. [9] Colao A, Ferone D, Marzullo P, Lombardi G. Systemic complications of acromegaly: epidemiology, pathogenesis, and management. Endocr Rev 2004;25:102–52. [10] Rajasoorya C, Holdaway IM, Wrightson P, Scott DJ, Ibbertson HK. Determinants of clinical outcome and survival in acromegaly. Clin Endocrinol 1994;41:95–102.

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Effects of growth hormone excess on glycated albumin concentrations: Analysis in acromegalic patients.

Glycated albumin (GA) does not reflect glycemic control in patients with disorders of albumin metabolism. In the present study, we examined GA concent...
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