The clinical usefulness of glycated albumin in patients with diabetes and chronic kidney disease: Progress and challenges

Prolonged hyperglycemia leads to a non-enzymatic glycation of proteins, and produces Amadori products, such as glycated albumin (GA) and glycated hemoglobin (HbA1c). The utility of HbA1c in the setting of chronic kidney disease (CKD) may be problematic since altered lifespan of red blood cells, use of iron and/or erythropoietin therapy, uremia and so on. Therefore, as an alternative marker, GA has been suggested as a more reliable and sensitive glycemic index in patients with CKD. In addition to the mean plasma glucose concentration, GA also reflects postprandial plasma glucose and glycemic excursion. Besides, with a half-life of approximately 2–3?weeks, GA may reflect the status of blood glucose more rapidly than HbA1c. GA is also an early precursor of advanced glycation end products (AGEs), which cause alterations in various cellular proteins and organelles. Thus, high GA levels may correlate with adverse outcomes of patients with CKD. In this review, the clinical usefulness of GA was discussed, including a comparison of GA with HbA1c, the utility and limitations of GA as a glycemic index, its potential role in pathogenesis of diabetic nephropathy and the correlations between GA levels and outcomes, specifically in patients with diabetes and CKD.     

Recent Topics in Chemical and Clinical Research on Glycated Albumin

The measuring method for glycated albumin (GA) has been developed as a new glycemic control marker since the beginning of the 21st century. Since GA has an advantage in reflecting glycemic status over a shorter period than hemoglobin A1c (HbA1c), much research and many reviews have been reported. However, so far there have been few reports on glycation sites based on the tertiary structure of human serum albumin (HSA) and the comparison of glycation rates between GA and HbA1c in detail. The present review discusses how the glycation sites of lysine residues in HSA are modified with glucose, whereas the glycation sites of lysine residues are located inside of HSA as well as the direct comparison of glycation rates between GA and HbA1c using human blood. Moreover, the most recent clinical researches on GA are described.     

Body mass index negatively influences glycated albumin, but not glycated hemoglobin, in diabetic patients

Measurement of serum glycated albumin (GA) is accepted as an alternative method to evaluate chronic glycemic control in diabetic patients in whom measurement of HbA 1c is inadequate for some reason. Although GA levels are known to be influenced by serum albumin turnover besides glycemia, little is known about the physiological and pathological conditions affecting GA levels. This study was aimed to prove the effects of body mass index (BMI) on GA measurement in diabetic patients. We studied 209 patients with type 2 diabetes mellitus whose HbA 1c levels had been stable for at least the past three months. In the study patients HbA 1c and GA levels were found to be correlated to one another. Fasting plasma glucose (FPG) was significantly correlated with HbA 1c and GA. BMI showed a significant negative correlation with GA levels, whereas there was no correlation of BMI with HbA 1c levels. Multivariate regression analyses revealed that only FPG was positively correlated with HbA 1c, while FPG was positively and BMI was negatively correlated with GA. Only BMI was negatively correlated with the ratio of GA to HbA 1c. These results clearly demonstrate that GA levels are negatively influenced by BMI in diabetic patients.     

Glycated albumin is a better indicator for glucose excursion than glycated hemoglobin in type 1 and type 2 diabetes

To determine the impact of blood glucose profile, involving fluctuation and excursion of blood glucose levels, on glycated proteins, we evaluated the association among the daily profile of blood glucose, and glycated albumin (GA) and HbA1c levels in patients with type 1 diabetes (n = 93) and type 2 diabetes (n = 75). GA levels were strongly correlated with HbA1c levels in type 1 (r = 0.85, P<0.0001) and type 2 diabetes (r = 0.61, P<0.0001), respectively. HbA1c levels were similar between patients with type 1 and type 2 diabetes, while GA levels were significantly higher in type 1 diabetes. Thus the ratio of GA levels to HbA1c levels was significantly higher in type 1 diabetes than that in type 2 diabetes (3.32 0.36 vs. 2.89 0.44, p<0.001). The degrees of GA levels and HbA1c levels correlated with maximum and mean blood glucose levels in patients with type 1 and type 2 diabetes. Stepwise multivariate analysis revealed that GA levels independently correlated with maximum blood glucose levels in type 1 diabetes (F = 43.34, P<0.001) and type 2 diabetes (F = 41.57, P<0.001). HbA1c levels also independently correlated with maximum blood glucose levels in type 1 diabetes (F = 34.78, P<0.001), as well as being correlated with mean blood glucose levels in type 2 diabetes (F = 11.28, P<0.001). In summary, GA could be a better marker for glycemic control than glycated hemoglobin in diabetic patients, especially for evaluating glycemic excursion, which is considered to be a major cause of diabetic angiopathy.     

A comparison of home glucose monitoring with determinations of hemoglobin A1c, total glycated hemoglobin, fructosamine, and random serum glucose in diabetic patients

We compared four objective measures of glycemic control (fructosamine, total glycated hemoglobin, hemoglobin A1c, and random serum glucose) with home glucose monitoring records in 17 diabetic patients followed up prospectively for 4 months. There was good overall correlation between all of these objective measures and weekly mean capillary glucose values. However, considerable scatter was seen in the data such that none of the glycated protein measurements was an ideal predictor of home glucose values. For example, all markedly elevated home glucose levels (greater than 11.1 mmol/L) were associated with elevated glycated protein levels, but moderately high blood glucose levels (8.3 to 11.1 mmol/L) were associated with one or more normal glycated protein values in some patients. Similar correlations were obtained whether glycemia was estimated by 1-week or 6-week home averages. Random serum glucose level also correlated with average home glucose level; however, there was wide fluctuation within individual subjects. All three glycated protein measurements (hemoglobin A1c, glycated hemoglobin, and fructosamine) appear equally useful as a supplement to home glucose monitoring in the assessment of glycemic control. Of the three types of glycated protein assays, fructosamine, with its advantage of speed and simplicity, may offer a more cost-effective alternative.     

Clinical Advances in Hemoglobin A1c Measurement: The Clinical Use of Hemoglobin A1c

Hemoglobin A1c (HbA1c) has been accepted as an index of glycemic control since the mid-1970s and is the best marker for diabetic microvascular complications. Clinically, it is now used to assess glycemic control in people with diabetes. Assays are most reliable when certified by the National Hemoglobin Standardization Program but are subject to confounders and effect modifiers, particularly in the setting of hematologic abnormalities. Other measures of chronic glycemic control—fructosamine and 1,5-anhydroglucitol—are far less widely used. The relationship of HbA1c to average blood glucose was intensively studied recently, and it has been proposed that this conversion can be used to report an “estimated average glucose, eAG” in milligrams/deciliter or millimolar units rather than as per cent glycated hemoglobin. Finally, HbA1c has been proposed as a useful method of screening for and diagnosing diabetes.     

Diabetes mellitus in chronic kidney disease: Biomarkers beyond HbA1c to estimate glycemic control and diabetes-dependent morbidity and mortality

Diabetes mellitus (DM) is the leading cause of chronic kidney disease (CKD). Optimal glycemic control contributes to improved outcomes in patients with DM, particularly for microvascular damage, but blood glucose levels are too variable to provide an accurate assessment and instead markers averaging long-term glycemic load are used. The most established glycemic biomarker of long-term glycemic control is HbA1c. Nevertheless, HbA1c has pitfalls that limit its accuracy to estimate glycemic control, including the presence of altered red blood cell survival, hemoglobin glycation and suboptimal performance of HbA1c assays. Alternative methods to evaluate glycemic control in patients with DM include glycated albumin, fructosamine, 1–5 anhydroglucitol, continuous glucose measurement, self-monitoring of blood glucose and random blood glucose concentration measurements. Accordingly, our aim was to review the advantages and pitfalls of these methods in the context of CKD.     

The roles of glycated albumin as intermediate glycation index and pathogenic protein

The conventional glycemic indices used in management of diabetic patients includes A1c, fructosamine, 1,5-anhydroglucitol, and glycated albumin (GA). Among these indices, A1c is currently used as the gold standard. However, A1c cannot reflect the glycemic change over a relatively short period of time, and its accuracy is known to decrease when abnormalities in hemoglobin metabolism, such as anemia, coexist. When considering these weaknesses, there have been needs for finding a novel glycemic index for diagnosing and managing diabetes, as well as for predicting diabetic complications properly. Recently, several studies have suggested the potential of GA as an intermediate-term glycation index in covering the short-term effect of treatment. Furthermore, its role as a pathogenic protein affecting the worsening of diabetes and occurrence of diabetic complications is receiving attention as well. Therefore, in this article, we wanted to review the recent status of GA as a glycemic index and as a pathogenic protein.     

The relative value of glycated albumin, hemoglobin A1c and fructosamine when screening for diabetes mellitus

We compared the usefulness of three glycated serum proteins, glycated albumin (GA), glycated hemoglobin (HBA1c) and fructosamine (FA), for diabetic screening purposes. We measured these indices in 302 adults, most of whom underwent yearly physical examinations. We measured GA and HbA1c with high precision using high-performance liquid chromatography (interassay coefficients of variation 4.9 and 4.0%, respectively) and FA using commercial reagents (interassay coefficient of variation 1.65%). All the individuals underwent a 75-g oral glucose tolerance test, which revealed significant correlations between the values of the three glycated proteins and the four plasma glucose concentrations measured as well as the sum of these glucose concentrations, sigma BS (GA, r = 0.80; HbA1c, r = 0.80; FA, r = 0.65). On the basis of the test, 130 of the subjects were classified as normal (N), 123 as borderline and 49 as having diabetes mellitus (D) according to the criteria of the Japan Diabetes Society. Of the 123 borderline cases, 26 showed impaired glucose tolerance (IGT) according to the WHO criteria. The normal group values of GA, HbA1c and FA were 17.8 +/- 0.17% (mean +/- SEM), 5.02 +/- 0.03%, and 2.55 +/- 0.02 mM/l, respectively. Borderline and IGT subjects had significantly more GA and HbA1c than normal but not more FA (P less than 0.01). We divided the subjects into 10 groups on the basis of their sigma BS values; those with values higher than 671 +/- 4.7 mg/dl had significantly more GA and HbA1c than normal, while those with values higher than 1068 +/- 40.9 mg/dl (the most extreme cases) had significantly more FA.(ABSTRACT TRUNCATED AT 250 WORDS)     

Glycated albumin is a useful glycation index for monitoring fluctuating and poorly controlled type 2 diabetic patients

Glycated albumin (GA) is recognized as a reliable marker for short-term glycemic monitoring in diabetic patients. We investigated the clinical relevance of GA and the ratio of GA to glycated hemoglobin (A1c) in Korean type 2 diabetic patients. In this retrospective study, we compared A1c, GA, and the GA/A1c ratio and analyzed the relationship between glycemic indices and various parameters in 1,038 Korean type 2 diabetic patients. The patients were divided into two groups: a stably maintained A1c group whose A1c levels did not fluctuate by more than 0.5% for at least 6 months and an unstably maintained A1c group whose A1c levels fluctuated by more than 0.5%. Serum GA was strongly correlated with A1c in both groups. Fasting plasma glucose and postprandial glucose were correlated with GA in unstably maintained A1c group, whereas they were correlated with A1c in stably maintained A1c group. The GA/A1c ratio tended to increase as A1c increased. Postprandial glucose and body mass index affected the GA/A1c ratio. Our data show that serum GA may be a more useful glycation index than A1c for monitoring glycemic control in type 2 diabetic patients with fluctuating and poorly controlled glycemic excursions.     

Hemoglobin variants and determination of glycated hemoglobin (HbA1c)

Measurement of glycated hemoglobin in diabetic patients is an established procedure for evaluating long-term control of diabetes. The Diabetes Control and Complications Trial (DCCT), as well as the United Kingdom Prospective Diabetes Study (UKPDS), confirmed the direct relationship between the degree of glycemic control as estimated by glycohemoglobin (GHb) determinations and the development and progression of long-term complications in diabetic patients. Samples with known interferences of HbA(1c) determination as hemoglobinopathies are specifically excluded from certification testing and there are no guidelines or requirements for comparability of samples containing hemoglobin (Hb) variants. This paper reviews the interference of Hb variants on determination methods of glycated hemoglobin as they result in false HbA(1c) results.     

Analytical Evaluation of the Diazyme Glycated Serum Protein Assay on the Siemens ADVIA 1800: Comparison of Results Against HbA1c for Diagnosis and Management of Diabetes

Background:

Hemoglobin A1c (HbA1c) is considered the gold standard for assessment of glycemic control in diabetic patients. HbA1c is inadequate in individuals homozygous or compound heterozygous for hemoglobin variants or in conditions with an altered red blood cell turnover. In these cases glycated albumin (GA) is proposed as an alternative assay. We aimed to evaluate the analytical performance of the Diazyme glycated serum protein (GSP) assay on an automated analyzer, to establish a reference interval (RI), and to compare from a clinical perspective, GSP/GA with glycated Hb (glyHb) results.

Methods:

Validation studies followed the CLSI guidelines and included precision, linearity, interferences, concordance of results with glyHb, and RI calculation. GSP was analyzed on representative samples with previously ordered HbA1c and albumin from the DynaLIFE_DX laboratory. Samples from patients with bisalbuminemia, hemoglobinopathies, and multiple myeloma were also included.

Results:

Within-run and total imprecision was <3.0% at both levels of control, analytical sensitivity was 5.31 μmol/L, and linearity was verified from 10 to 1150 μmol/L (total allowable error of 5%). Clinical concordance between %GA and glyHb was substantial (n = 175, R² = .91, kappa = .78, P = .167). GSP RI was 160 to 340 μmol/L or if expressed as %GA 10.5 to 17.5%.

Conclusion:

Analytical performance of the Diazyme GSP assay on the Siemens ADVIA 1800 is acceptable for clinical use. The RI obtained was higher than that suggested by the manufacturer.     

Glycated albumin in chronic kidney disease: Pathophysiologic connections

Nephropathy in diabetes patients is the most common etiology of end-stage kidney disease (ESKD). Strict glycemic control reduces the development and progression of diabetes-related complications, and there is evidence that improved metabolic control improves outcomes in subjects having diabetes mellitus with advanced chronic kidney disease (CKD). Glycemic control in people with kidney disease is complex. Changes in glucose and insulin homoeostasis may occur as a consequence of loss of kidney function and dialysis. The reliability of measures of long-term glycemic control is affected by CKD and the accuracy of glycated haemoglobin (HbA1c) in the setting of CKD and ESKD is questioned. Despite the altered character of diabetes in CKD, current guidelines for diabetes management are not specifically adjusted for this patient group. The validity of indicators of long-term glycemic control has been the focus of increased recent research. This review discusses the current understanding of commonly used indicators of metabolic control (HbA1c, fructosamine, glycated albumin) in the setting of advanced CKD.     

Glycated Albumin Predicts the Risk of Mortality in Type 2 Diabetic Patients on Hemodialysis: Evaluation of a Target Level for Improving Survival

Glycated albumin (GA) is considered a more reliable marker than glycated hemoglobin (HbA1c) for monitoring glycemic control, particularly in diabetic hemodialysis patients. We investigated the associations of GA, HbA1c, and random serum glucose levels with survival, and evaluated possible targets for improving survival in diabetic hemodialysis patients. In this prospective, longitudinal, observational study, we enrolled 90 diabetic hemodialysis patients across six dialysis centers in Japan. The median duration of follow‐up was 36.0 months (mean follow‐up, 29.8 months; range, 3–36 months). There were 11 deaths during the observation period. GA was a significant predictor for mortality (hazard ratio, 1.143 per 1% increase in GA; 95% confidence interval, 1.011–1.292; P = 0.033), whereas HbA1c and random glucose levels were not predictors for mortality. Receiver operating characteristics curve analysis showed that the cutoff value of GA for predicting the risk of mortality was 25%. In the Kaplan–Meier analysis, the cumulative survival rate was significantly greater in patients with GA ≤25% than in patients with GA >25%. GA predicted the risk of all‐cause and cardiovascular mortality in diabetic hemodialysis patients. Our results suggest that GA ≤25% is an appropriate target for improving survival in diabetic hemodialysis patients.     

The lack of long-range negative correlations in glucose dynamics is associated with worse glucose control in patients with diabetes mellitus

Glucose dynamics measured in ambulatory settings are fluid in nature and exhibit substantial complexity. We recently showed that a long-range negative correlation of glucose dynamics, which is considered to reflect blood glucose controllability over a substantial period, is absent in patients with diabetes mellitus. This was demonstrated using detrended fluctuation analysis (DFA), a modified random-walk analysis method for the detection of long-range correlations. In the present study, we further assessed the relationships between the established clinical indices of glycemic or insulinogenic control of hemoglobin A(1c) (HbA(1c)), glycated albumin (GA), 1,5-anhydroglucitol, and urine C-peptide immunoreactivity and the recently proposed DFA-based indices obtained from continuous glucose monitoring in 104 Japanese diabetic patients. Significant correlations between the following parameters were observed: (1) HbA(1c) and the long-range scaling exponent α(2) (r = 0.236, P < .05), (2) GA and α(2) (r = 0.254, P < .05), (3) GA and the short-range scaling exponent α(1) (r = 0.233, P < .05), and (4) urine C-peptide immunoreactivity and the mean glucose fluctuations (r = -0.294, P < .01). Therefore, we concluded that increases in the long-range DFA scaling exponent, which are indicative of the lack of a long-range negative correlation in glucose dynamics, reflected abnormalities in average glycemic control as clinically determined using HbA(1c) and GA parameters.     

糖化血清白蛋白检测在糖调节受损及新诊断糖尿病人群中的临床意义

目的 评估糖化血清白蛋白(GA)作为反映近期血糖总体水平的指标在糖调节受损(IGR)及新诊断糖尿病人群中的临床意义.方法 选取2007年1月至6月来本院门诊进行口服葡萄糖耐量试验的个体516名共分为3组,其中正常糖调节(NGR)组130名、IGR组154例、糖尿病组232例.测定空腹血糖(FPG)及糖负荷后0.5h血糖(0.5 h PG)、1hPG、2hPG、3hPG,同时测定HbA1c及GA等指标,对GA与各监测指标的相关性进行分析.结果 GA水平在NGR、IGR、糖尿病3组间两两比较差异均有统计学意义(P<0.01),HbA1c水平在NGR与IGR两组差异无统计学意义(P>0.05).GA与HbA1c呈显著正相关(r=0.75,P<0.01),多元逐步回归分析显示,FPG、2hPG及体重指数为GA的独立影响因素.结论 测定血糖的同时检测GA可能更有助于对糖代谢状态的评估.     

Comparison of glycated albumin (GA) and glycated hemoglobin (HbA1c) in type 2 diabetic patients: usefulness of GA for evaluation of short-term changes in glycemic control

We studied the cross-sectional relationship between GA and HbA1c in 142 type 2 diabetic patients who had an HbA1c level < 7.5% for at least one year without fluctuation by more than 0.5%. We also followed the changes of GA and HbA1c in 18 type 2 diabetic patients for 16 weeks as they progressed from untreated severe hyperglycemia (HbA1c > or = 9.0%) to good glycemic control (HbA1c < or = 6.5%) by intensive insulin treatment. The annual mean levels of GA and HbA1c in the stably controlled patients showed a weak, but significant, correlation (r = 0.23, p<0.001) in the 142 diabetic patients. However, the GA/HbA1c ratio ranged widely from 2.0 to 4.0 showing a normal distribution (2.9 +/- 0.34, M +/- SE), although patients with conditions affecting albumin turnover or RBC lifespan were excluded from the study. The GA/HbA1c ratio was significantly higher when patients were in hyperglycemic than when glycemic control was good (3.5 +/- 0.15 vs. 2.9 +/- 0.07, M +/- SE, p<0.01). GA decreased more rapidly than HbA1c during intensive insulin therapy, but the percent reduction of HbA1c eventually corresponded with that of GA by 16 weeks after the start of treatment. These results demonstrate that, although unknown influences on GA or HbA1c may exist, GA may be a useful marker for monitoring short-term variations of glycemic control during treatment of diabetic patients.     

Determination of reference intervals of glycated albumin and hemoglobin A1c in healthy pregnant Japanese women and analysis of their time courses and influencing factors during pregnancy

Glycemic control is an important issue in gestational diabetes mellitus (GDM) and in diabetic pregnant women. We determined the reference intervals of glycated albumin (GA) and hemoglobin A1c (HbA1c) as glycemic control markers in healthy Japanese pregnant women and analyzed their time courses and factors that influence these variables during pregnancy. 676 women were screened for the present study. After the exclusion of non-pregnant and puerperal women, 574 women were studied to determine the reference intervals. HbA1c, GA, casual plasma glucose, urinary glucose, urinary protein, and body mass index (BMI) (non-pregnancy) were measured. HbA1c levels significantly decreased in the second trimester of pregnancy and increased in the third trimester, while GA levels significantly decreased towards the third trimester. Casual plasma glucose levels decreased in the first trimester and subsequently remained constant. The reference intervals of GA and HbA1c in the healthy pregnant women were 11.5-15.7% and 4.5-5.7%, respectively. GA levels were lower (p<0.01) and HbA1c levels were higher (p<0.05) in pregnant women with proteinuria. In the obese group, GA levels were lower (p<0.01) than those of the control group (18.5≤ BMI <25kg/m2), and HbA1c levels were higher (p<0.01) than those of the control group. On the basis of the results of this multicenter study, the reference intervals of GA and HbA1c in healthy Japanese pregnant women were determined. Strict glycemic control is essential to reduce perinatal complications. GA appears to be a useful marker for pregnant women, since it can be measured easily and changes rapidly and markedly.     

A comparative analysis of fructosamine with other risk factors for kidney dysfunction in diabetic patients with or without chronic kidney disease

BackgroundHyperglycemia is the driving force for the development of diabetic nephropathy leading to the end stage renal disease. It is well known that in hyperglycaemic condition, serum proteins become glycated through non-enzymatic glycation. With the other risk factors, serum fructosamine may be an important risk factor for kidney impairment. To assess coexistence of frequently documented risk factors of kidney dysfunction with serum fructosamine in diabetic patients with chronic kidney disease (CKD).MethodsIn this study, total 150 individuals, as control, type2 diabetic patients without complication and with CKD were included. Blood samples were collected from all the samples to estimate blood glucose, HbA1c, serum creatinine, fructosamine levels and lipid profile. Statistical analysis i.e. regression and correlation between serum fructosamine and other documented risk factors for diabetic CKD has been done. P < 0.001 was considered significant.ResultsSerum fructosamine, HbA1c, creatinine levels, cholesterol and LDL were increased significantly (P < 0.001) in diabetic patients with CKD compared to without complications. Systolic and diastolic blood pressure and BMI were also significantly higher in diabetic patients compared to control. Serum creatinine, total cholesterol and LDL showed a significant positive correlation but HDL showed a negative correlation with fructosamine in CKD diabetic patients. No significant correlation was found with any risk factors in diabetic patients without complications expect HbA1c.ConclusionIt is concluded that elevated serum fructosamine level is strongly associated with kidney dysfunction in diabetic patients. As there is a significant link between serum fructosamine and other risk factors for CKD diabetic patients.     

Clinical Advances in Hemoglobin A1c Measurement: Biologic Variability in Plasma Glucose, Hemoglobin A1c, and Advanced Glycation End Products Associated with Diabetes Complications

Plasma glucose plays a key role in the complications of diabetes mellitus. Hemoglobin A1c (HbA1c) and circulating concentrations of advanced glycation end products (AGEs) are central to diabetes clinical care and pathophysiology. However, there is evidence for variation between individuals in the relationship of plasma glucose to both these measures and to specific complications. The glycation gap (GG) and hemoglobin glycation index represent tools for quantitating the variability in the relationship between plasma glucose and HbA1c useful for identification of underlying mechanisms. Recent evidence demonstrates the heritability of HbA1c, the GG, and AGEs, yet not of glycated serum proteins. There has been tremendous effort devoted to identifying the heritable basis of types 1 and 2 diabetes; however, studies on the heritable contributors to these mediators of glucose effect on complications are only beginning. New evidence for normal biologic variation in the distribution of glucose into the red blood cell (RBC) intracellular compartment and RBC lifespan in people with and without diabetes represent candidates for heritable mechanisms and contributors to the rise in HbA1c with age. Taken as a whole, genetic and mechanistic evidence suggests new potential targets for complications prevention and improvement in complications risk estimation. These observations could help tilt the risk–benefit balance in glycemic control toward a more beneficial outcome.