Characteristics of individuals who developed type 2 diabetes from prediabetes despite undergoing interventions, and evaluation of the performance of urinary myo-inositol as a risk factor for developing diabetes.

AIMS/INTRODUCTION: The aim of this study was to clarify the characteristics of individuals with prediabetes who developed type 2 diabetes despite undergoing interventions, and to evaluate the performance of urinary myo-inositol (UMI) as a noninvasive indicator for the risk of developing diabetes. MATERIALS AND METHODS: A total of 51 individuals with prediabetes who underwent a 75-g oral glucose tolerance test, ΔUMI (the difference in the UMI : creatinine ratio between before and 120 min after 75-g glucose loading), fasting plasma glucose, insulin, hemoglobin A1c, noninvasive testing (age, body mass index, blood pressure) and general blood tests were measured at baseline, and underwent dietary/exercise guidance for 8 years were studied. RESULTS: A total of 31 participants developed diabetes in 8 years. At baseline, the group that developed diabetes was characterized by high ΔUMI, hemoglobin A1c, fasting plasma glucose and low high-density lipoprotein cholesterol, and insulinogenic index (I.I.). I.I and ΔUMI showed a higher correlation than fasting plasma glucose and hemoglobin A1c. Regarding diabetes onset within 8 years, Cox regression analysis of diabetes onset showed the baseline ΔUMI is an independent predictor, adjusted for the result of not only noninvasive markers, but also that of noninvasive and general blood markers. The log-rank test showed that all glycemic indicators were significantly associated with diabetes onset. CONCLUSION: Participants who developed type 2 diabetes from prediabetes despite undergoing interventions were characterized by high glycemic control markers and low I.I. As noninvasive measurement of ΔUMI is associated with I.I. and diabetes onset, it could be a useful indicator for identifying individuals with a high risk of diabetes onset.

Relationship between the cholesterol and triglyceride content of lipoprotein subclasses and carotid intima-media thickness: A cross-sectional population-based study.

BACKGROUND: The association between lipoprotein subclasses and carotid intima-media thickness (cIMT) progression has yet to be fully evaluated. We assessed which lipoprotein subclasses were associated with maximum cIMT levels in the general population. METHODS: In this study, cholesterol and triglyceride content of 20 lipoprotein subclasses were analyzed using gel permeation high-performance liquid chromatography (GP-HPLC) in 864 Japanese women and men (mean age 57 y, free of chronic liver or kidney diseases and off lipid-lowering, hormone replacement, or adrenocorticosteroid medications). Univariate and multivariate regression analyses and univariate and partial correlation analyses were performed to examine the relationships between lipoprotein subclasses and maximum cIMT levels. RESULTS: After adjusting for age, sex, systolic blood pressure, smoking, diabetes, and anti-hypertensive agents, elevated low-density lipoprotein (LDL)-2 and -3 cholesterol (particle diameter 25.5 nm and 23.0 nm, respectively; medium and small LDL) were associated with higher maximum cIMT levels in both women and men (all p for trend < 0.05). These associations were significant even after participants taking anti-diabetic or anti-hypertensive agents were excluded. No significant associations were found between any triglyceride subclasses and maximum cIMT levels. CONCLUSIONS: Smaller LDL particle cholesterol values are the most atherogenic lipoprotein parameter.

Glycated Albumin Correlates With Time-in-Range Better Than HbA1c or Fructosamine.

CONTEXT: Intermediate-term glycemic control metrics may represent a viable alternative to continuous glucose monitoring (CGM) in patients without access to CGM. OBJECTIVE: This work aimed to compare the relationship between CGM parameters and glycated albumin (GA), glycated hemoglobin A1c (HbA1c), and fructosamine for 24 weeks. METHODS: We conducted exploratory comparative analyses of CGM subgroup data from a previously published 24-week prospective study of assay performance in 8 US clinics. Participants included 34 individuals with type 1 (n = 18) and type 2 diabetes (n = 16) undergoing changes to improve glycemic control (n = 22; group 1) or with stable diabetes therapy (n = 12; group 2). Main outcome measures included Pearson correlations between CGM and glycemic indices and receiver operating characteristic (ROC) analysis of glycemic index values predictive of time in range (TIR) greater than 70%. RESULTS: At weeks 4 and 8, GA correlations with TIR were higher than HbA1c correlations in group 1. In group 2, GA correlations with TIR were statistically significant, whereas HbA1c correlations were not. In both groups over the first 12 weeks, GA correlations with TIR were higher than fructosamine-TIR correlations. In the ROC analysis, GA predicted a TIR greater than 70% during weeks 2 to 24 (area under the curve >0.80); HbA1c was predictive during weeks 12 to 24. Cutoff values for TIR greater than 70% were 17.5% (sensitivity and specificity, 0.88) for GA and 7.3% (0.86) for HbA1c. CONCLUSION: GA is the most accurate predictor of TIR over 8 weeks compared with other glycemic indices, which may assist in clinical evaluation of changes in treatment where CGM is not possible and it is too early to use HbA1c (NCT02489773).

Analytical performances of a glycated albumin assay that is traceable to standard reference materials and reference range determination.

BACKGROUND: Glycated albumin (GA) is an intermediate-term marker for monitoring glycemic control (preceding 2-3 weeks) in patients with diabetes mellitus. We evaluated the performance of Lucica Glycated Albumin-L, a new GA assay that is traceable to standard reference materials and determined the reference range in healthy subjects without diabetes. METHODS: The performance and reference range studies were conducted in accordance with Clinical and Laboratory Standards Institute (CLSI) Guidelines. The traceability was established using reference material recommended by the Japan Society of Clinical Chemistry (JSCC). RESULTS: The coefficient of variation (CV) of overall repeatability, within-laboratory precision, and overall reproducibility values of GA values were not more than 2.6%, 3.3%, and 1.6%, respectively, among laboratories. The GA values showed good linearity from 173 to 979 mmol/mol (9.4%-54.9%) across the assay range. The GA reference range in 262 healthy subjects was between 183 and 259 mmol/mol (9.9%-14.2%) while that of subjects with diabetes was 217-585 mmol/mol (11.8-32.6%). The reagent was stable for 2 months on the bench at room temperature. The limits of blank, detection, and qualification were 6.9, 7.9, and 9.7 µmol/L for GA concentration, and 3.8, 7.0, and 21.8 µmol/L for albumin concentration, respectively. Hemoglobin slightly affected the assay, while other classical interfering substances had no significant impact. CONCLUSIONS: The present GA assay shows comparable performance to current clinical assays and could be used for intermediate-term monitoring of glycemic control in diabetes patients.

Glycated albumin as biomarker: Evidence and its outcomes.

Glycemic control markers are important for the diagnosis and treatment of diabetes. Hemoglobin A1c (A1C) is an important marker that is mandatory in routine medical examinations; however, it is well known that it has some limitations. In this review, we focus on the limitation of A1C and introduce a relatively new marker, glycated albumin (GA), which can be used to complement A1C. First, for a better understanding of the characteristics of each marker, we sort the similarities and differences of glycemic control markers as well as the characteristics of each marker. Second, we point out the limitation of A1C, introduce GA as an alternative indicator, and discuss the limitations of GA. Finally, we summarize important evidence regarding the utility of GA. We hope that this review provides useful information that permits more effective usage of GA as well as other glycemic control markers.

Results of a Study Comparing Glycated Albumin to Other Glycemic Indices.

CONTEXT: Intermediate-term glycemic control metrics fulfill a need for measures beyond hemoglobin A1C. OBJECTIVE: Compare glycated albumin (GA), a 14-day blood glucose measure, with other glycemic indices. DESIGN: 24-week prospective study of assay performance. SETTING: 8 US clinics. PARTICIPANTS: Subjects with type 1 (n = 73) and type 2 diabetes (n = 77) undergoing changes to improve glycemic control (n = 98) or with stable diabetes therapy (n = 52). INTERVENTIONS: GA, fructosamine, and A1C measured at prespecified intervals. Mean blood glucose (MBG) calculated using weekly self-monitored blood glucose profiles. MAIN OUTCOME MEASURES: Primary: Pearson correlation between GA and fructosamine. Secondary: magnitude (Spearman correlation) and direction (Kendall correlation) of change of glycemic indices in the first 3 months after a change in diabetes management. RESULTS: GA was more concordant (60.8%) with changes in MBG than fructosamine (55.5%) or A1C (45.5%). Across all subjects and visits, the GA Pearson correlation with fructosamine was 0.920. Pearson correlations with A1C were 0.655 for GA and 0.515 for fructosamine (P < .001) and with MBG were 0.590 and 0.454, respectively (P < .001). At the individual subject level, Pearson correlations with both A1C and MBG were higher for GA than for fructosamine in 56% of subjects; only 4% of subjects had higher fructosamine correlations with A1C and MBG. GA had a higher Pearson correlation with A1C and MBG in 82% and 70% of subjects, respectively. CONCLUSIONS: Compared with fructosamine, GA correlates significantly better with both short-term MBG and long-term A1C and may be more useful than fructosamine in clinical situations requiring monitoring of intermediate-term glycemic control (NCT02489773).

Changes in the albumin glycation site, plasma pentosidine and esRAGE concentrations before and after intensive diabetic treatment in patients with abnormally high glycated albumin levels.

Background We have reported that the blood glucose normalization treatment reduced the albumin glycation sites and the intensity of albumin AGE fluorescence in patients with abnormally high glycated albumin levels. To clarify the relationship between glycaemic control status and levels of glycated proteins and related markers, we studied the change of the markers of the DM patients with and without fatty liver, liver cirrhosis and dialysis before and after the intensive diabetic treatment. Methods Eight diabetic patients with abnormally high glycated albumin levels (no complications: 2, fatty liver: 3, liver cirrhosis: 2, dialysis: 1) were recruited. In the hypoglycaemic treatment for these patients, the HbA1c, glycated albumin, albumin AGE fluorescence, pentosidine, endogenous secretory receptors for AGE (esRAGE) and glycation sites of albumin were determined. Results Glycated albumin and HbA1c levels dropped after the treatment. Albumin glycation sites decreased in almost the same pattern, irrespective of the type of complications. The fluorescence intensity and pentosidine concentrations decreased significantly. However, post-treatment pentosidine concentrations were higher than the reference interval in all cases. Average esRAGE concentrations did not change and were lower than the reference interval. Conclusions Hypoglycaemic treatment reduced the glycated albumin levels, glycation sites of albumin and AGE concentrations but not esRAGE concentrations in diabetic patients with or without fatty liver, liver cirrhosis, and dialysis. Checking and maintaining low glycated albumin levels would prevent the formation of AGE and may be useful to prevent the onset or progression of diabetes complications.

Committee on Diabetes Mellitus Indices of the Japan Society of Clinical Chemistry-recommended reference measurement procedure and reference materials for glycated albumin determination.

BACKGROUND: Glycated albumin is an intermediate glycaemic control marker for which there are several measurement procedures with entirely different reference intervals. We have developed a reference measurement procedure for the purpose of standardizing glycated albumin measurements. METHODS: The isotope dilution liquid chromatography/tandem mass spectrometry method was developed as a reference measurement procedure for glycated albumin. The stable isotopes of lysine and fructosyl-lysine, which serve as an internal standard, were added to albumin isolated from serum, followed by hydrogenation. After hydrolysis of albumin with hot hydrochloric acid, the liberated lysine and fructosyl-lysine were measured by liquid chromatography/tandem mass spectrometry, and their concentrations were determined from each isotope ratio. The reference materials (JCCRM611) for determining of glycated albumin were prepared from pooled patient blood samples. RESULTS: The isotope dilution-tandem mass spectrometry calibration curve of fructosyl-lysine and lysine showed good linearity (r = 0.999). The inter-assay and intra-assay coefficient of variation values of glycated albumin measurement were 1.2 and 1.4%, respectively. The glycated albumin values of serum in patients with diabetes assessed through the use of this method showed a good relationship with routine measurement procedures (r = 0.997). The relationship of glycated albumin values of the reference material (JCCRM611) between these two methods was the same as the relationship with the patient serum samples. CONCLUSION: The Committee on Diabetes Mellitus Indices of the Japan Society of Clinical Chemistry recommends the isotope dilution liquid chromatography/tandem mass spectrometry method as a reference measurement procedure, and JCCRM611 as a certified reference material for glycated albumin measurement. In addition, we recommend the traceability system for glycated albumin measurement.

A comparison of glycated albumin and glycosylated hemoglobin for the screening of diabetes mellitus in Taiwan.

OBJECTIVE: Glycated albumin (GA) values reflect an average plasma glucose level over approximately 2-4 weeks, and the assay is stable and can be run on serum or plasma. The aim of this study was to determine the universality and the clinical utility of GA in screening for diabetes mellitus. METHODS: Subjects consisted of 2192 male and female residents in Yi-lan County, Northern Taiwan (mean age 60.1 years), of whom 54.2% (n = 1188) had previously been diagnosed and treated for diabetes. Fasting blood samples were obtained to measure HbA1c, plasma glucose, serum GA, insulin, and measures of kidney and liver function. The reference values for these parameters were determined. Data from patients with diabetes and non-diabetic controls were also compared. RESULTS: Mean GA values were 13.8% in controls and 18.1% in diabetic subjects (31.2% higher, p < 0.0001), while mean HbA1c values were 5.6% in controls and 7.2% in diabetic subjects (29.2% higher, p < 0.0001). The 95th percentile values for GA and HbA1c in controls were 16.1% and 6.2%, respectively. Our suggested GA and HbA1c cut-points for prediabetes at the 75th percentile of the normal population would be 14.6% and 5.8%, respectively. For both parameters, values greater than these cut-points provided a reasonable degree of specificity and sensitivity for risk of having diabetes, while a GA value of 16.5% corresponds to an HbA1c level of 6.5%, diagnostic of diabetes. CONCLUSION: These data indicate that GA values can be used as a surrogate parameter for HbA1c in screening for prediabetes and diabetes mellitus.

Glycated albumin as a diagnostic tool for diabetes in a general Japanese population.

OBJECTIVE: Diabetes mellitus is a major cause of cardiovascular, kidney, neurologic, and eye diseases, and may be preventable in some cases by lifestyle modification. Screening tests for diabetes mellitus include fasting plasma glucose (FPG) and glycated hemoglobin (HbA1c). Our objective was to evaluate the utility of plasma glycated albumin (GA) in the diagnosis of diabetes mellitus. DESIGN AND METHODS: A cross-sectional, community-based population study of 908 non-diabetic Japanese residents was conducted. Of these subjects, 176 with FPG value between 5.5 and 6.9mmol/l, and an HbA1c level of <6.5% received an oral glucose tolerance test (OGTT). RESULTS: The OGTT results were used for the diagnosis of diabetes mellitus using World Health Organization criteria. Receiver operating characteristic (ROC) analyses demonstrated that optimal threshold values for the diagnosis of diabetes in this population were 15.2% for GA and 5.9% for HbA1c, respectively. Using these cutoff levels, the sensitivity of GA at 62.1% for detecting diabetes was the same as that of HbA1c. However the specificity for GA for detecting diabetes was 61.9%, while for HbA1c it was higher at 66.7%. CONCLUSIONS: Our results indicate that the measurement of glycated albumin may serve as a useful screening test for diabetes in a general Japanese population.

Serum cholesterol and triglyceride reference ranges of twenty lipoprotein subclasses for healthy Japanese men and women.

AIM: This epidemiological study was done to generate normal ranges for the cholesterol and triglyceride levels in serum lipoprotein subclasses isolated from healthy adults based on gender and menopausal status. METHODS: Cholesterol and triglyceride levels in 20 lipoprotein subclasses as separated by high performance liquid chromatography were measured in serum obtained from 825 fasting healthy subjects (267 men, 558 women). RESULTS: For serum cholesterol, 13.7% was found in very low density lipoprotein (VLDL) subclasses, 55.6% in low density lipoprotein (LDL) subclasses, and 30.4% in high density lipoprotein (HDL) subclasses. For serum triglycerides, these values were 52.1%, 27.9%, and 17.4%, respectively. Levels of cholesterol in some VLDL subclasses were inversely correlated with the levels of some HDL subclasses, while for triglycerides, elevated levels in any one subclass were generally strongly associated with elevated levels in all other subclasses. Men had significantly higher large VLDL-cholesterol levels than women (P < 0.05), while women had significantly higher small VLDL-cholesterol levels than men (P < 0.001). Women had significantly higher large LDL- and large and medium HDL-cholesterol levels than men (P < 0.001). Men had significantly higher chylomicron (CM), large and medium VLDL-, and small LDL-triglyceride levels than women (P < 0.001). Women had significantly higher very large and large HDL-triglyceride levels than men (P < 0.01). Postmenopausal women had significantly higher CM, all VLDL, and large, medium and small LDL-cholesterol levels, and significantly higher all VLDL, LDL, and HDL-triglyceride levels than premenopausal women (P < 0.001). CONCLUSIONS: Our data document important gender and menopausal status differences in cholesterol and triglyceride subclass levels, as well as significant correlations between values in the various serum lipoprotein subclasses.

Plasma glycated albumin level and atherosclerosis: results from the Kyushu and Okinawa Population Study (KOPS).

BACKGROUND: Glycated albumin (GA) is a measure of the mean plasma glucose concentration over approximately 2-3 weeks. This study was done to test the hypothesis that GA can serve as a marker for atherosclerosis, similar to glycosylated hemoglobin A1c (HbA1c). METHODS: HbA1c, plasma GA and serum high-sensitivity C-reactive protein (hs-CRP) levels were measured for 1575 residents (age range 26-78 years) of a suburban town in Japan. Carotid artery intima-media thickness (IMT) was measured by ultrasound for each participant. RESULTS: GA levels had significantly positive correlation coefficients with HbA1c level, hs-CRP level, and max-IMT (all P<0.001). Receiver operating characteristic curve analysis indicated a GA level of ≥ 15.5% to be optimal for predicting diabetes. A GA level of 15.5% corresponded to an HbA1c level of 5.8%. The hs-CRP and max-IMT values of participants with GA ≥ 15.5% were significantly higher than the values of those with GA <15.5% (median hs-CRP: 2.4 vs. 2.3mg/L, P=0.048; mean max-IMT 0.852 vs. 0.759 mm, P=0.003, respectively). Among obese participants, the hs-CRP and max-IMT values of those with GA ≥ 15.5% (7.5mg/L and 1.014 mm) were significantly higher than the values of those with GA <15.5% (4.7 mg/dL and 0.823 mm) (P=0.024 and P=0.001, respectively). CONCLUSIONS: Increased IMT and hs-CRP levels were associated with a high GA level, especially for obese participants, suggesting that GA would be as a useful biomarker for assessing the risk of atherosclerosis.

Classification of variant forms of haemoglobin according to the ratio of glycated haemoglobin to glycated albumin.

BACKGROUND: Asymptomatic variant haemoglobin is increasingly being found in the measurement of glycated haemoglobin (HbA(1c)) for the management of diabetes mellitus. We compared the HbA(1c) concentrations measured by high-performance liquid chromatography (HPLC) and immunoassay and glycated albumin (GA) concentrations and calculated the respective ratios in order to classify the variant haemoglobin. METHODS: Twenty different haemoglobin variants from 43 subjects were identified by mass spectrometry and DNA analysis. Since GA accurately reflects glycaemic control in patients with variant haemoglobin, we calculated respective ratios of HbA(1c) and GA. Haemoglobin variants causing a low ratio of HbA(1c) measured by HPLC (HPLC-HbA(1c)) to GA with a normal ratio of HbA(1c) measured by immunoassay (IA-HbA(1c)) to GA were classified as C1. A further classification of α and ß was used with abnormalities of the α chain or ß chain in the haemoglobin gene. Other haemoglobin variants were classified as non-C1. Eight diabetic patients with stable glycaemic control were used as controls. RESULTS: Twenty forms of variant haemoglobins were classified as C1α (2 variants; I-Interlaken and Hb J-Meerut), C1ß (15 variants) and non-C1 (3 variants; Hb Himeji, Hb Woolwich, Hb Peterborough). Positive correlations between GA and HPLC-HbA(1c) or IA-HbA(1c) were seen in the C1ß patients with diabetes mellitus. The regression line between GA and HPLC-HbA(1c), but not that between GA and IA-HbA(1c), showed a downward shift in comparison with the data obtained from the diabetic controls. CONCLUSIONS: Variant haemoglobin could be classified by calculating the ratios of HPLC-HbA(1c), IA-HbA(1c) and GA.

Basic performance of an enzymatic method for glycated albumin and reference range determination.

BACKGROUND: Glycated albumin (GA) is a medium-term glycemic control marker of diabetes and may be more sensitive to changes in plasma glucose than hemoglobin A1c. We studied where and how many fructosyl groups bind to albumin, and which glycation sites are measured by the enzymatic method for GA. We also studied the basic performance of the enzymatic method for GA. METHODS: Glycated albumin was measured using an enzymatic method (Lucica®GA-L, Asahi Kasei Pharma) on a biochemical autoanalyzer. Molecular weights of purified GA and nonglycated albumin were measured by a mass spectrometry system. Two hundred one healthy volunteers with normal results of oral glucose tolerance testing were recruited to determine the reference range in Americans. RESULTS: The present method measured only glycated amino acids from albumin in serum protein. We estimate that the number of glycated amino acids measured by this method was approximately two per molecule of albumin. The general performance (sensitivity, specificity, reproducibility, linearity, interference) of the method was good. The reference range of GA% in Americans with normal glucose tolerance was determined to be 11.9-15.8% (mean ± 2 standard deviations). Significant differences were not observed between the sexes; however, race differences were observed (higher levels in blacks relative to whites). CONCLUSIONS: The method was specific for measuring glycated amino acids in albumin and had good basic performance characteristics. The reference range in Americans was 11.9-15.8%. This method may be a useful indicator for diabetes control.

Lucica GA-L glycated albumin assay kit: a new diagnostic test for diabetes mellitus.

Diabetes mellitus is a worldwide healthcare issue, with the number of diabetic patients continuing to increase. Strict control of plasma glucose levels is critical in order to avoid the potentially severe complications of diabetes, making tests for monitoring of glycemic control essential in the management of the disease. Glycated hemoglobin (HbA(1c)) measurement is currently the most commonly used test to monitor glycemic control in patients with diabetes. Based on the results of the Diabetes Control and Complications Trial (DCCT), an HbA(1c) level of <7% has been recommended to prevent the onset and progression of chronic diabetic complications. However, HbA(1c) may not be suitable for evaluating short-term variations in glycemic control, because of the long lifespan of erythrocytes (120 days). Glycated albumin (GA) is an indicator of diabetes that is more sensitive to change in plasma glucose than HbA(1c). Lucica GA-L is a new diagnostic test for measuring GA. The test is based on an enzymatic method that uses liquid reagents requiring no preparation. Measuring the GA level should provide useful information on glycemic control when monitoring effects of therapy for patients with gestational diabetes, unstable plasma glucose levels, variant hemoglobins or diseases that shorten the lifespan of erythrocytes.