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Glycated albumin is low in obese, type 2 diabetic patients
Diabetes Research and Clinical Practice 78 (2007) 51–55 www.elsevier.com/locate/diabres
Glycated albumin is low in obese, type 2 diabetic patients Yumi Miyashita *, Rimei Nishimura, Aya Morimoto, Toru Matsudaira, Hironari Sano, Naoko Tajima Division of Diabetes Metabolism & Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan Received 25 July 2006; received in revised form 29 January 2007; accepted 21 February 2007 Available online 16 April 2007
Abstract This study is to clarify whether obesity status affects glycated albumin (GA) and HbA1c levels in adults with type 2 diabetes. One hundred and seven individuals with type 2 diabetes without advanced complications participated in this study. The relationship between HbA1c, GA, hemoglobin (Hb), albumin (ALB), absolute value of GA (aGA) and Body Mass Index (BMI) were examined using Pearson’s correlation coefficient. The comparison of each parameter was conducted using unpaired t-test between the obese (BMI 25) and the non-obese (BMI < 25) group. Additionally the multiple regression analyses to find factors related with GA (i.e. BMI, HbA1c, age, ALB and the insulin therapy) were performed. HbA1c level and BMI showed very weak correlation (r = 0.04; p = 0.65). However, GA, aGA and BMI showed a significant negative correlation (r = 0.28; p = 0.004, r = 0.22; p = 0.024). The GA and aGA values of the obese group were significant lower than those in the non-obese group. In multiple regression analysis, BMI (b = 0.24; p = 0.001) was negatively, and HbA1c (b = 3.65; p < 0.001) was positively correlated with GA. In conclusion, the current analysis demonstrated a need of careful evaluation of GA values in obese diabetic patients in daily practice. Further researches are required to elucidate the underlying mechanisms. # 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Obesity; Glycated albumin; Type 2 diabetes; BMI
1. Introduction The explosive increasing prevalence of type 2 diabetes is a global problem [1,2]. Up until the present, many large clinical trials were done, which proved that tight glycemic control could keep diabetic patients from developing complications [3–8]. When we examine diabetic patients in Japan, we measure the indices of glucose control (i.e., hemoglobin A1c (HbA1c, %) and/or glycated albumin (GA, %), etc.) in order to monitor chronic glycemic control [9–11]. Previously, we have reported that GA
* Corresponding author at: 3-25-8, Nishishimbashi, Minato-ku, Toyko 105-8461, Japan. Tel.: +81 33433 1111; fax: +81 33578 9753. E-mail address: [email protected] (Y. Miyashita).
levels of non-diabetic obese children were lower than those of non-obese, non-diabetic children [12]. Therefore, this study is to clarify whether obesity status affects GA and HbA1c levels in adults with type 2 diabetes. 2. Methods One hundred and seven individuals with type 2 diabetes without advanced complications, who visited our hospital over 3 consecutive months between April and December 2005, participated in this study. The advanced complications were the underlying disease that had no influence on protein metabolism, e.g. renal failure, liver disfunction, thyroid disease, anemia and so on. Subjects were included if the difference in their HbA1c levels for 3 months was under 0.5% and whose HbA1c were less than 8%.
0168-8227/$ – see front matter # 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2007.02.021
52
Y. Miyashita et al. / Diabetes Research and Clinical Practice 78 (2007) 51–55
First, we investigated the body height and weight of the subjects and measured their HbA1c, GA, plasma glucose (PG, mg/dl), hemoglobin (Hb, mg/dl) and albumin (ALB, g/dl). From 3 consecutive months of data, we adopted the figures from the second month to use in the analysis. We defined ‘‘obese’’ as BMI 3 25 (kg/m2), as classified by the Japan Society for Study of Obesity [13], and divided subjects into an obese group and a non-obese group. We also divided subjects into the insulin therapy group and the non-insulin therapy group. We compared the indices between the obese group and the non-obese group, additionally between the insulin therapy and the non-insulin therapy group by unpaired t-test. Next, the relationship between BMI and the indexes including HbA1c, GA, Hb, ALB, and absolute value of GA (aGA, g/dl), which was calculated from GA (%) and ALB (g/ dl), were analyzed using Pearson’s correlation coefficient. Then, the multiple regression analysis was performed. The dependent variable was the GA, and the explanation variables were age, BMI, HbA1c, insulin therapy, and albumin in the analysis. Linear regression analysis between GA and PG in respective obese or non-obese group was performed to investigate the distribution difference of GA between both groups. Statistical analysis was performed using the SPSS program. The GA was measured using an enzyme assay developed by the Asahi Kasei Corporation of Japan. In the assay, endogenous glycated amino acids are first eliminated by oxidation by ketoamine oxidase. Second, GA is hydrolyzed to glycated amino acids by proteinase digestion, and the glycated amino acids are then oxidized to produce hydrogen peroxide, which is quantitatively measured. Third, albumin is measured by the new BCP method. Finally, the GA value is calculated as the percentage of GA in total albumin, as was reported in the paper by Kouzuma et al. [14]. The HbA1c was determined by an automated high-performance liquid chromatography (HPLC) assay. The study protocol was approved by the Institutional Review Board (IRB) at the Jikei University of Medicine.
3. Results Table 1 shows the clinical characteristics of the 107 subjects. The mean age and BMI were 65.9 12.2 years old, and 23.1 3.9, respectively. Twenty seven (male 16/female 11) of the total number of participants were classified as obese (Table 1). We compared the indices between the obese group and the non-obese group. The obese group was significantly lower for GA, and aGA (GA, p = 0.003; aGA, p = 0.007), but not for HbA1c or ALB (HbA1c, p = 0.32; ALB, p = 0.801) (Table 1). Because of the significant difference of aGA and not ALB, it was demonstrated that the GA of the obese group was lower, independent of ALB. We compared the GA/HbA1c ratio between the obese group and the non-obese group. The ratio of the obese group was significantly lower than that of the non-obese group ( p < 0.001). When we compared the indices between the insulin therapy group and the non-insulin therapy group, the insulin therapy group was significantly higher for HbA1c ( p = 0.008); GA ( p = 0.001); aGA ( p = 0.026); and GA/HbA1c ratio ( p = 0.02). The non-insulin therapy group was significantly higher for BMI ( p = 0.04) and ALB ( p = 0.03) (Table 1). Then, the correlations between the each index were analyzed. The HbA1c level and BMI showed no correlation at all (r = 0.04; p = 0.65), however, GA (%) and BMI showed a significantly negative correlation (r = 0.28; p = 0.004). The correlation between ALB (g/dl) and BMI was very weak (r = 0.11; p = 0.28). On the other hand, the correlation between aGA (g/dl) and BMI was also significantly negative (r = 0.22; p = 0.02) (Fig. 1). In the multiple regression
Table 1 Clinical characteristics of study subjects
n (%) Male (%) Age (year) BMI (kg/m2) HbA1c (%) GA (%) PG (mg/dl) aGA (g/dl) ALB (g/dl) GA (%)/HbA1c ratio
Obese group
Non-obese group
Insulin group
Non-insulin group
Total
27 (25.2) 16 (59.3) 61.5 16.3 28.2 3.0 6.7 0.8 18.4 3.5 151.5 78.2 0.8 0.2 4.5 0.4 2.7 0.3
80 (74.8) 52 (65.0) 67.4 10.1 21.4 2.3 * 6.9 0.7 21.0 2.3 * 145.5 53.0 0.9 0.2 * 4.4 0.3 3.0 0.4 *
58 (54.2) 33 (56.9) 65.2 11.7 22.1 4.0 7.0 0.7 21.5 4.1 155.2 70.0 0.9 0.2 4.4 0.3 3.1 0.4
49 (45.8) 35 (71.4) 66.8 12.7 23.9 3.6 ** 6.6 0.7 ** 18.9 3.6 ** 138 45.5 0.9 0.2 ** 4.5 0.4 ** 2.9 0.4 **
107 (100) 68 (63.6) 65.9 12.2 23.1 3.9 6.8 0.7 20.3 4.0 147.0 60.0 0.9 0.2 4.4 0.3 3.0 0.4
Data are expressed as frequencies (%), or means S.D. The obese group was defined as BMI 3 25 (kg/m2). The sex ratio between the groups were compared using chi-square test. The means of other data were compared using unpaired t-test. BMI, body mass index; GA, glycated albumin; PG, plasma glucose; aGA, absolute value of GA; ALB, albumin. * p < 0.05 obese vs. non-obese by t-test. ** p < 0.05 insulin vs. non-insulin by t-test.
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Fig. 1. The correlations between HbA1c, GA, ALB, aGA and BMI in type 2 diabetes. GA, glycated albumin; ALB, albumin; aGA, absolute glycated albumin; BMI, body mass index; r, the Pearson’ s correlation coefficient; n = 107.
analysis, the correlation between GA and HbA1c was significantly positive (b = 3.65; p < 0.001), however, that between GA and BMI was significantly negative (b = 0.24; p = 0.001). No correlation had been found with other variables (Table 2). The correlation between PG and GA in obese group was similar to that in nonobese group. However, the distribution of GAwas located lower in obese group than in non-obese group (Fig. 2). 4. Discussion HbA1c and GA are glycated proteins used for an index of glycemic control in daily practice. HbA1c is an
index recommended by the American Diabetes Association as a long-term monitor of blood glucose of the previous 2 or 3 months [15]. In addition, we sometimes require an index of glycemic control for a shorter term, in some cases. In that case, GA becomes more useful than HbA1c because it can change during about a 2week period [16]. HbA1c reflects the glycemic control over the previous 120-day average, which is the lifespan of erythrocytes [9]; similarly GA reflects the glycemic control over the previous 20-day average, which is the lifespan of albumin. Therefore, GA measurements may be lower in patients with disorders showing abnormal albumin turnover, such as nephrotic syndrome,
Table 2 The multiple regression analysis of glycated albumin (GA) as the dependent variable b Intercept Age BMI (kg/m2) HbA1c (%) ALB (g/ml) Insulin therapy (yes/no)
0.17 2.1E 0.24 3.65 0.19 0.78
03
95% confidence interval
p
11.5 to 11.2 0.1 to 0.1 0.4 to 0.1 2.9 to 4.4 1.5 to 1.9 0.4 to 2.0
0.98 0.94 0.001 <0.001 0.83 0.19
The correlation between GA and HbA1c was significantly positive (b = 3.65; p < 0.001), however, that between GA and BMI was significantly negative (b = 0.24; p = 0.001). No correlation had been found with other variables.
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Y. Miyashita et al. / Diabetes Research and Clinical Practice 78 (2007) 51–55
that the usage of insulin did not correlate with GA. The fundamental experiment to prove the effect of obesity on albumin metabolism is necessary in type 2 diabetes. Furthermore, nobody has ever proven the mechanism of the relationship between obesity and glycation of albumin. 5. Conclusions
Fig. 2. The correlation between PG and GA in respective obese or non-obese group. The regression line: non-obese group; f(x) = 2.14x + 17.9 ( p = 0.017) obese group; f(x) = 2.32x + 14.9 ( p = 0.05); PG, plasma glucose; GA, glycated albumin.
hyperthyroidism, burns, massive bleeding, etc. Moreover, we reported previously that GA level was lower in non-diabetic obese children [12]. In this study, we aimed to investigate whether an obese state affected GA level in type 2 diabetic patients, as well as non-diabetic obese children, and found the assumption to be applicable. So, we hypothesized that the obese state was able to be one of reasons to increase albumin turnover. We reported previously that one of the reasons why GA level was lower in obese children was that hyperinsulinemia led albumin turnover to increase. However, the previous report in Ref. [17] about protein metabolism and diabetes showed that insulin deficiency (i.e., type 1 diabetes) increased protein breakdown and amino acid oxidation, and that these effects were reversible by insulin treatment. On the other hand, the studies of Bogardus et al. [18] and Staten et al. [19], suggested that protein metabolism was essentially normal in type 2 diabetes, implying a dissociation between the effect of insulin on protein and carbohydrate metabolism in type 2 diabetes. In the abovementioned report, the reason was that small amount of endogenous circulating insulin were sufficient to prevent the protein catabolism associated with insulin deficiency. However, Tessari et al. [20], proved that albumin fractional synthesis rates (FSRs), and absolute synthesis rates (ASRs), increased by 25% after hyperinsulinemia. In some obese type 2 diabetic patients, as they have the both exogenous and endogenous insulin, the effect of both types of insulin on albumin metabolism is questionable. In multiple regression analysis, we found
In conclusions, the obtained data demonstrated that the GA level was lower in obese type 2 diabetic patients than non-obese type 2 diabetic patients. When we examine obese diabetic patients, we need to evaluate GA values carefully. The detailed mechanism of the relationship between obesity and lower GA level is not known yet. The further researches are required to elucidate the mechanism that affects GA. References [1] T. Kitagawa, M. Owada, T. Urakami, K. Yamauchi, Increased incidence of non-insulin dependent diabetes mellitus among Japanese school children correlates with an increased intake of animal protein and fat, Clin. Pediatr. (Phila) 37 (1998) 111–115. [2] S. Wild, G. Roglic, A. Green, R. Sicree, H. King, Global prevalence of diabetes: estimates for the year 2000 and projections for 2030, Diabetes Care 27 (2004) 1047–1053. [3] 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. Engl. J. Med. 329 (1993) 977–986. [4] M. Shichiri, H. Kishikawa, Y. Ohkubo, N. Wake, Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients, Diabetes Care 23 (Suppl. 2) (2000) B21– B29. [5] UK Prospective Diabetes Study (UKPDS) Group, Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33), Lancet 352 (1998) 837–853. [6] UK Prospective Diabetes Study (UKPDS) Group, Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34), Lancet 352 (1998) 854–865. [7] UK Prospective Diabetes Study Group, Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38, BMJ 317 (1998) 703–713. [8] The Diabetes Control and Complications Trial Research Group, The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the diabetes control and complications trial, Diabetes 44 (1995) 968–983. [9] R.J. Koenig, C.M. Peterson, R.L. Jones, C. Saudek, M. Lehrman, A. Cerami, Correlation of glucose regulation and hemoglobin Alc in diabetes mellitus, N. Engl. J. Med. 295 (1976) 417–420. [10] H.F. Bunn, K.H. Gabbay, P.M. Gallop, The glycosylation of hemoglobin: relevance to diabetes mellitus, Science 200 (1978) 21–27. [11] C.E. Guthrow, M.A. Morris, J.F. Day, S.R. Thorpe, J.W. Baynes, Enhanced nonenzymatic glucosylation of human serum albumin
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[12]
[13]
[14]
[15]
in diabetes mellitus, Proc. Natl. Acad. Sci. U.S.A. 76 (1979) 4258–4261. R. Nishimura, A. Kanda, H. Sano, T. Matsudaira, Y. Miyashita, A. Morimoto, et al., Glycated albumin is low in obese, nondiabetic children, Diabetes Res. Clin. Pract. 71 (2006) 334–338. E. Anuurad, K. Shiwaku, A. Nogi, K. Kitajima, B. Enkhmaa, K. Shimono, et al., The new BMI criteria for Asians by the regional office for the western pacific region of WHO are suitable for screening of overweight to prevent metabolic syndrome in elder Japanese workers, J. Occup. Health 45 (2003) 335–343. T. Kouzuma, Y. Uemastu, T. Usami, S. Imamura, Study of glycated amino acid elimination reaction for an improved enzymatic glycated albumin measurement method, Clin. Chim. Acta 346 (2004) 135–143. American Diabetes Association, Standards of medical care in diabetes, Diabetes Care 29 (suppl. 1) (2006) s4–s42.
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[16] T. Matsuyama, Y. Katayama, S. Fujita, Recent progress in evaluation of glycemic control by glycated protein and 1,5AG, Rinsho Byori 43 (1995) 445–448. [17] P. De Feo, M.G. Gaisano, M.W. Haymond, Differential effects of insulin deficiency on albumin and fibrinogen synthesis in humans, J. Clin. Invest. 88 (1991) 833–840. [18] C. Bogardus, M.R. Taskinen, J. Zawadzki, S. Lillioja, D. Mott, B.V. Howard, Increased resting metabolic rates in obese subjects with non-insulin-dependent diabetes mellitus and the effect of sulfonylurea therapy, Diabetes 35 (1986) 1–5. [19] M.A. Staten, D.E. Matthews, D.M. Bier, Leucine metabolism in type II diabetes mellitus, Diabetes 35 (1986) 1249–1253. [20] P. Tessari, E. Kiwanuka, R. Millioni, M. Vettore, L. Puricelli, M. Zanetti, et al., Albumin and fibrinogen synthesis and insulin effect in type 2 diabetic patients with normoalbuminuria, Diabetes Care 29 (2006) 323–328.
Glycated albumin is low in obese, type 2 diabetic patients Yumi Miyashita *, Rimei Nishimura, Aya Morimoto, Toru Matsudaira, Hironari Sano, Naoko Tajima Division of Diabetes Metabolism & Endocrinology, Department of Internal Medicine, Jikei University School of Medicine, Tokyo, Japan Received 25 July 2006; received in revised form 29 January 2007; accepted 21 February 2007 Available online 16 April 2007
Abstract This study is to clarify whether obesity status affects glycated albumin (GA) and HbA1c levels in adults with type 2 diabetes. One hundred and seven individuals with type 2 diabetes without advanced complications participated in this study. The relationship between HbA1c, GA, hemoglobin (Hb), albumin (ALB), absolute value of GA (aGA) and Body Mass Index (BMI) were examined using Pearson’s correlation coefficient. The comparison of each parameter was conducted using unpaired t-test between the obese (BMI 25) and the non-obese (BMI < 25) group. Additionally the multiple regression analyses to find factors related with GA (i.e. BMI, HbA1c, age, ALB and the insulin therapy) were performed. HbA1c level and BMI showed very weak correlation (r = 0.04; p = 0.65). However, GA, aGA and BMI showed a significant negative correlation (r = 0.28; p = 0.004, r = 0.22; p = 0.024). The GA and aGA values of the obese group were significant lower than those in the non-obese group. In multiple regression analysis, BMI (b = 0.24; p = 0.001) was negatively, and HbA1c (b = 3.65; p < 0.001) was positively correlated with GA. In conclusion, the current analysis demonstrated a need of careful evaluation of GA values in obese diabetic patients in daily practice. Further researches are required to elucidate the underlying mechanisms. # 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Obesity; Glycated albumin; Type 2 diabetes; BMI
1. Introduction The explosive increasing prevalence of type 2 diabetes is a global problem [1,2]. Up until the present, many large clinical trials were done, which proved that tight glycemic control could keep diabetic patients from developing complications [3–8]. When we examine diabetic patients in Japan, we measure the indices of glucose control (i.e., hemoglobin A1c (HbA1c, %) and/or glycated albumin (GA, %), etc.) in order to monitor chronic glycemic control [9–11]. Previously, we have reported that GA
* Corresponding author at: 3-25-8, Nishishimbashi, Minato-ku, Toyko 105-8461, Japan. Tel.: +81 33433 1111; fax: +81 33578 9753. E-mail address: [email protected] (Y. Miyashita).
levels of non-diabetic obese children were lower than those of non-obese, non-diabetic children [12]. Therefore, this study is to clarify whether obesity status affects GA and HbA1c levels in adults with type 2 diabetes. 2. Methods One hundred and seven individuals with type 2 diabetes without advanced complications, who visited our hospital over 3 consecutive months between April and December 2005, participated in this study. The advanced complications were the underlying disease that had no influence on protein metabolism, e.g. renal failure, liver disfunction, thyroid disease, anemia and so on. Subjects were included if the difference in their HbA1c levels for 3 months was under 0.5% and whose HbA1c were less than 8%.
0168-8227/$ – see front matter # 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.diabres.2007.02.021
52
Y. Miyashita et al. / Diabetes Research and Clinical Practice 78 (2007) 51–55
First, we investigated the body height and weight of the subjects and measured their HbA1c, GA, plasma glucose (PG, mg/dl), hemoglobin (Hb, mg/dl) and albumin (ALB, g/dl). From 3 consecutive months of data, we adopted the figures from the second month to use in the analysis. We defined ‘‘obese’’ as BMI 3 25 (kg/m2), as classified by the Japan Society for Study of Obesity [13], and divided subjects into an obese group and a non-obese group. We also divided subjects into the insulin therapy group and the non-insulin therapy group. We compared the indices between the obese group and the non-obese group, additionally between the insulin therapy and the non-insulin therapy group by unpaired t-test. Next, the relationship between BMI and the indexes including HbA1c, GA, Hb, ALB, and absolute value of GA (aGA, g/dl), which was calculated from GA (%) and ALB (g/ dl), were analyzed using Pearson’s correlation coefficient. Then, the multiple regression analysis was performed. The dependent variable was the GA, and the explanation variables were age, BMI, HbA1c, insulin therapy, and albumin in the analysis. Linear regression analysis between GA and PG in respective obese or non-obese group was performed to investigate the distribution difference of GA between both groups. Statistical analysis was performed using the SPSS program. The GA was measured using an enzyme assay developed by the Asahi Kasei Corporation of Japan. In the assay, endogenous glycated amino acids are first eliminated by oxidation by ketoamine oxidase. Second, GA is hydrolyzed to glycated amino acids by proteinase digestion, and the glycated amino acids are then oxidized to produce hydrogen peroxide, which is quantitatively measured. Third, albumin is measured by the new BCP method. Finally, the GA value is calculated as the percentage of GA in total albumin, as was reported in the paper by Kouzuma et al. [14]. The HbA1c was determined by an automated high-performance liquid chromatography (HPLC) assay. The study protocol was approved by the Institutional Review Board (IRB) at the Jikei University of Medicine.
3. Results Table 1 shows the clinical characteristics of the 107 subjects. The mean age and BMI were 65.9 12.2 years old, and 23.1 3.9, respectively. Twenty seven (male 16/female 11) of the total number of participants were classified as obese (Table 1). We compared the indices between the obese group and the non-obese group. The obese group was significantly lower for GA, and aGA (GA, p = 0.003; aGA, p = 0.007), but not for HbA1c or ALB (HbA1c, p = 0.32; ALB, p = 0.801) (Table 1). Because of the significant difference of aGA and not ALB, it was demonstrated that the GA of the obese group was lower, independent of ALB. We compared the GA/HbA1c ratio between the obese group and the non-obese group. The ratio of the obese group was significantly lower than that of the non-obese group ( p < 0.001). When we compared the indices between the insulin therapy group and the non-insulin therapy group, the insulin therapy group was significantly higher for HbA1c ( p = 0.008); GA ( p = 0.001); aGA ( p = 0.026); and GA/HbA1c ratio ( p = 0.02). The non-insulin therapy group was significantly higher for BMI ( p = 0.04) and ALB ( p = 0.03) (Table 1). Then, the correlations between the each index were analyzed. The HbA1c level and BMI showed no correlation at all (r = 0.04; p = 0.65), however, GA (%) and BMI showed a significantly negative correlation (r = 0.28; p = 0.004). The correlation between ALB (g/dl) and BMI was very weak (r = 0.11; p = 0.28). On the other hand, the correlation between aGA (g/dl) and BMI was also significantly negative (r = 0.22; p = 0.02) (Fig. 1). In the multiple regression
Table 1 Clinical characteristics of study subjects
n (%) Male (%) Age (year) BMI (kg/m2) HbA1c (%) GA (%) PG (mg/dl) aGA (g/dl) ALB (g/dl) GA (%)/HbA1c ratio
Obese group
Non-obese group
Insulin group
Non-insulin group
Total
27 (25.2) 16 (59.3) 61.5 16.3 28.2 3.0 6.7 0.8 18.4 3.5 151.5 78.2 0.8 0.2 4.5 0.4 2.7 0.3
80 (74.8) 52 (65.0) 67.4 10.1 21.4 2.3 * 6.9 0.7 21.0 2.3 * 145.5 53.0 0.9 0.2 * 4.4 0.3 3.0 0.4 *
58 (54.2) 33 (56.9) 65.2 11.7 22.1 4.0 7.0 0.7 21.5 4.1 155.2 70.0 0.9 0.2 4.4 0.3 3.1 0.4
49 (45.8) 35 (71.4) 66.8 12.7 23.9 3.6 ** 6.6 0.7 ** 18.9 3.6 ** 138 45.5 0.9 0.2 ** 4.5 0.4 ** 2.9 0.4 **
107 (100) 68 (63.6) 65.9 12.2 23.1 3.9 6.8 0.7 20.3 4.0 147.0 60.0 0.9 0.2 4.4 0.3 3.0 0.4
Data are expressed as frequencies (%), or means S.D. The obese group was defined as BMI 3 25 (kg/m2). The sex ratio between the groups were compared using chi-square test. The means of other data were compared using unpaired t-test. BMI, body mass index; GA, glycated albumin; PG, plasma glucose; aGA, absolute value of GA; ALB, albumin. * p < 0.05 obese vs. non-obese by t-test. ** p < 0.05 insulin vs. non-insulin by t-test.
Y. Miyashita et al. / Diabetes Research and Clinical Practice 78 (2007) 51–55
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Fig. 1. The correlations between HbA1c, GA, ALB, aGA and BMI in type 2 diabetes. GA, glycated albumin; ALB, albumin; aGA, absolute glycated albumin; BMI, body mass index; r, the Pearson’ s correlation coefficient; n = 107.
analysis, the correlation between GA and HbA1c was significantly positive (b = 3.65; p < 0.001), however, that between GA and BMI was significantly negative (b = 0.24; p = 0.001). No correlation had been found with other variables (Table 2). The correlation between PG and GA in obese group was similar to that in nonobese group. However, the distribution of GAwas located lower in obese group than in non-obese group (Fig. 2). 4. Discussion HbA1c and GA are glycated proteins used for an index of glycemic control in daily practice. HbA1c is an
index recommended by the American Diabetes Association as a long-term monitor of blood glucose of the previous 2 or 3 months [15]. In addition, we sometimes require an index of glycemic control for a shorter term, in some cases. In that case, GA becomes more useful than HbA1c because it can change during about a 2week period [16]. HbA1c reflects the glycemic control over the previous 120-day average, which is the lifespan of erythrocytes [9]; similarly GA reflects the glycemic control over the previous 20-day average, which is the lifespan of albumin. Therefore, GA measurements may be lower in patients with disorders showing abnormal albumin turnover, such as nephrotic syndrome,
Table 2 The multiple regression analysis of glycated albumin (GA) as the dependent variable b Intercept Age BMI (kg/m2) HbA1c (%) ALB (g/ml) Insulin therapy (yes/no)
0.17 2.1E 0.24 3.65 0.19 0.78
03
95% confidence interval
p
11.5 to 11.2 0.1 to 0.1 0.4 to 0.1 2.9 to 4.4 1.5 to 1.9 0.4 to 2.0
0.98 0.94 0.001 <0.001 0.83 0.19
The correlation between GA and HbA1c was significantly positive (b = 3.65; p < 0.001), however, that between GA and BMI was significantly negative (b = 0.24; p = 0.001). No correlation had been found with other variables.
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Y. Miyashita et al. / Diabetes Research and Clinical Practice 78 (2007) 51–55
that the usage of insulin did not correlate with GA. The fundamental experiment to prove the effect of obesity on albumin metabolism is necessary in type 2 diabetes. Furthermore, nobody has ever proven the mechanism of the relationship between obesity and glycation of albumin. 5. Conclusions
Fig. 2. The correlation between PG and GA in respective obese or non-obese group. The regression line: non-obese group; f(x) = 2.14x + 17.9 ( p = 0.017) obese group; f(x) = 2.32x + 14.9 ( p = 0.05); PG, plasma glucose; GA, glycated albumin.
hyperthyroidism, burns, massive bleeding, etc. Moreover, we reported previously that GA level was lower in non-diabetic obese children [12]. In this study, we aimed to investigate whether an obese state affected GA level in type 2 diabetic patients, as well as non-diabetic obese children, and found the assumption to be applicable. So, we hypothesized that the obese state was able to be one of reasons to increase albumin turnover. We reported previously that one of the reasons why GA level was lower in obese children was that hyperinsulinemia led albumin turnover to increase. However, the previous report in Ref. [17] about protein metabolism and diabetes showed that insulin deficiency (i.e., type 1 diabetes) increased protein breakdown and amino acid oxidation, and that these effects were reversible by insulin treatment. On the other hand, the studies of Bogardus et al. [18] and Staten et al. [19], suggested that protein metabolism was essentially normal in type 2 diabetes, implying a dissociation between the effect of insulin on protein and carbohydrate metabolism in type 2 diabetes. In the abovementioned report, the reason was that small amount of endogenous circulating insulin were sufficient to prevent the protein catabolism associated with insulin deficiency. However, Tessari et al. [20], proved that albumin fractional synthesis rates (FSRs), and absolute synthesis rates (ASRs), increased by 25% after hyperinsulinemia. In some obese type 2 diabetic patients, as they have the both exogenous and endogenous insulin, the effect of both types of insulin on albumin metabolism is questionable. In multiple regression analysis, we found
In conclusions, the obtained data demonstrated that the GA level was lower in obese type 2 diabetic patients than non-obese type 2 diabetic patients. When we examine obese diabetic patients, we need to evaluate GA values carefully. The detailed mechanism of the relationship between obesity and lower GA level is not known yet. The further researches are required to elucidate the mechanism that affects GA. References [1] T. Kitagawa, M. Owada, T. Urakami, K. Yamauchi, Increased incidence of non-insulin dependent diabetes mellitus among Japanese school children correlates with an increased intake of animal protein and fat, Clin. Pediatr. (Phila) 37 (1998) 111–115. [2] S. Wild, G. Roglic, A. Green, R. Sicree, H. King, Global prevalence of diabetes: estimates for the year 2000 and projections for 2030, Diabetes Care 27 (2004) 1047–1053. [3] 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. Engl. J. Med. 329 (1993) 977–986. [4] M. Shichiri, H. Kishikawa, Y. Ohkubo, N. Wake, Long-term results of the Kumamoto Study on optimal diabetes control in type 2 diabetic patients, Diabetes Care 23 (Suppl. 2) (2000) B21– B29. [5] UK Prospective Diabetes Study (UKPDS) Group, Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33), Lancet 352 (1998) 837–853. [6] UK Prospective Diabetes Study (UKPDS) Group, Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34), Lancet 352 (1998) 854–865. [7] UK Prospective Diabetes Study Group, Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38, BMJ 317 (1998) 703–713. [8] The Diabetes Control and Complications Trial Research Group, The relationship of glycemic exposure (HbA1c) to the risk of development and progression of retinopathy in the diabetes control and complications trial, Diabetes 44 (1995) 968–983. [9] R.J. Koenig, C.M. Peterson, R.L. Jones, C. Saudek, M. Lehrman, A. Cerami, Correlation of glucose regulation and hemoglobin Alc in diabetes mellitus, N. Engl. J. Med. 295 (1976) 417–420. [10] H.F. Bunn, K.H. Gabbay, P.M. Gallop, The glycosylation of hemoglobin: relevance to diabetes mellitus, Science 200 (1978) 21–27. [11] C.E. Guthrow, M.A. Morris, J.F. Day, S.R. Thorpe, J.W. Baynes, Enhanced nonenzymatic glucosylation of human serum albumin
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