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Background: Glycated albumin (GA), 1,5-anhydroglucitol (1,5-AG), and fructosamine have attracted considerable interest as markers of hyperglycemia. This study aimed to evaluate the optimal cutoff values for GA, 1,5-AG, and fructosamine and to determine their respective diagnostic efficacies in relation to hyperglycemia., Methods: We enrolled 6012 individuals who had undergone fasting blood glucose (FBG) and Hemoglobin A1c (HbA1c) tests along with at least one alternative glycemic marker. Receiver operating characteristic (ROC) curves and the upper or lower limit of the reference range (97.5 or 2.5 percentiles) were used to ascertain the optimal cutoff values. Follow-up data from healthy individuals were used to identify patients who developed diabetes mellitus (DM)., Results: The ROC cutoff values for GA, 1,5-AG, and fructosamine were 13.9%, 13.3 μg/mL, and 278 μmol/L, respectively, with corresponding area under the curve (AUC) values of 0.860, 0.879, and 0.834. The upper limits of the reference intervals for GA and fructosamine were 15.1% and 279 μmol/L, respectively, and the lower limit for 1,5-AG was 5.3 μg/mL. Among the GA cutoff values, the ROC cutoff had the highest sensitivity. Analyzing the follow-up data showed that lowering the GA cutoff from 16.0% to 13.9% identified an additional 40 people with DM progression., Conclusions: Lowering the GA cutoff values significantly increased the sensitivity of DM diagnosis and enhanced its potential as a screening marker by identifying more individuals with diabetes progression. Conversely, modifications to the cutoff values for 1,5-AG and fructosamine did not confer any discernible diagnostic or predictive advantages., (© 2024 The Author(s). Journal of Clinical Laboratory Analysis published by Wiley Periodicals LLC.)

Background: Dicarbonyls are highly reactive compounds and major precursors of advanced glycation end products (AGEs). Both dicarbonyls and AGEs are associated with development of age-related diseases. Dicarbonyls are formed endogenously but also during food processing. To what extent dicarbonyls from the diet contribute to circulating dicarbonyls and AGEs in tissues is unknown., Objectives: To examine cross-sectional associations of dietary dicarbonyl intake with plasma dicarbonyl concentrations and skin AGEs., Methods: In 2566 individuals of the population-based Maastricht Study (age: 60 ± 8 y, 50% males, 26% with type 2 diabetes), we estimated habitual intake of the dicarbonyls methylglyoxal (MGO), glyoxal (GO), and 3-deoxyglucosone (3-DG) by combining FFQs with our dietary dicarbonyl database of MGO, GO, and 3-DG concentrations in > 200 commonly consumed food products. Fasting plasma concentrations of MGO, GO, and 3-DG were measured by ultra-performance liquid chromatography-tandem mass spectrometry. Skin AGEs were measured as skin autofluorescence (SAF), using the AGE Reader. Associations of dietary dicarbonyl intake with their respective plasma concentrations and SAF (all standardized) were examined using linear regression models, adjusted for age, sex, potential confounders related to cardiometabolic risk factors, and lifestyle., Results: Median intake of MGO, GO, and 3-DG was 3.6, 3.5, and 17 mg/d, respectively. Coffee was the main dietary source of MGO, whereas this was bread for GO and 3-DG. In the fully adjusted models, dietary MGO was associated with plasma MGO (β: 0.08; 95% CI: 0.02, 0.13) and SAF (β: 0.12; 95% CI: 0.07, 0.17). Dietary GO was associated with plasma GO (β: 0.10; 95% CI: 0.04, 0.16) but not with SAF. 3-DG was not significantly associated with either plasma 3-DG or SAF., Conclusions: Higher habitual intake of dietary MGO and GO, but not 3-DG, was associated with higher corresponding plasma concentrations. Higher intake of MGO was also associated with higher SAF. These results suggest dietary absorption of MGO and GO. Biological implications of dietary absorption of MGO and GO need to be determined. The study has been approved by the institutional medical ethical committee (NL31329.068.10) and the Minister of Health, Welfare and Sports of the Netherlands (Permit 131088-105234-PG)., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Increasing evidence indicates that enhanced peripheral carbonyl stress markers exist in subtype of schizophrenia, although it may not be the primary cause. This study aimed to investigate whether plasma concentrations of methylglyoxal, 3-deoxy-glucosone, and glyoxal, which are reactive intermediates of protein metabolism in carbonyl stress, are changed in patients with schizophrenia and can function as potential biomarkers for schizophrenia with enhanced carbonyl stress. Plasma concentrations of these di-carbonyls were simultaneously estimated in 40 patients with schizophrenia and 40 healthy controls. As a result, no statistically significant differences were observed in mean plasma concentrations of three di-carbonyls between patients and controls. However, a remarkable increase in methylglyoxal concentrations was observed in four patients but not in controls. This increase was not found with regard to 3-deoxyglucosone and glyoxal both of patients and controls. Our correlation analysis showed that both the plasma methylglyoxal and glyoxal concentrations were significantly correlated with 3-deoxyglucosone concentrations in 40 patients and 40 controls. However, the plasma methylglyoxal concentrations did not show any significant correlation with the glyoxal concentrations in the patients or the controls. In four patients with extremely high methylglyoxal levels, the plasma methylglyoxal and glyoxal concentrations were not correlated to the 3-deoxyglucosone concentrations. Methylglyoxal is a physiological substrate of the glyoxalase system, and the accelerated accumulation of this compound lowers the glyoxalase I activity. These results suggested that this increase in four patients with high methylglyoxal levels may indicate the presence of a subtype of chronic schizophrenia that is associated with enhanced carbonyl stress., Competing Interests: The authors declared that there is no conflict of interests. This study was not funded by anywhere.

Objective: The aim of this study was to explore the association of 1,5-anhydroglucitol with acute C peptide response (ACPR) to arginine among patients with type 2 diabetes., Methods: Patients with type 2 diabetes were enrolled from the Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital. ACPR was assessed using arginine stimulation test. Decreased β -cell function was defined as ACPR < 2.1. Multivariable logistic regression models were used to demonstrate the association between 1,5-anhydroglucitol and decreased β -cell function., Results: Finally, 623 patients with type 2 diabetes were enrolled into the analysis. Multivariable-adjusted odds ratios for decreased β -cell function across quartiles of 1,5-anhydroglucitol were 1.00, 0.47 (95% confidence interval (CI) 0.23-0.99), 0.41 (95% CI 0.20-0.84), and 0.27 (95% CI 0.13-0.57) ( P trend = 0.042), respectively. When 1,5-anhydroglucitol was considered as a continuous variable after logarithm, the corresponding odds ratio was 0.40 (95% CI 0.23-0.71)., Conclusions: We demonstrated a dose-response linear association between 1,5-anhydroglucitol and ACPR. 1,5-Anhydroglucitol was likely to be associated with β -cell function. Further analysis with large sample size and prospective study design is warranted to validate our findings., Competing Interests: The authors declare that they have no conflicts of interest., (Copyright © 2020 Yun Shen et al.)

Background: Postprandial hyperglycemia was reported to play a key role in established risk factors of coronary artery diseases (CAD) and cardiovascular events. Serum 1,5-anhydroglucitol (1,5-AG) levels are known to be a clinical marker of short-term postprandial glucose (PPG) excursions. Low serum 1,5-AG levels have been associated with occurrence of CAD. However, the relationship between 1,5-AG levels and coronary plaque rupture has not been fully elucidated. The aim of this study was to evaluate 1,5-AG as a predictor of coronary plaque rupture in diabetic patients with acute coronary syndrome (ACS)., Methods: A total of 144 diabetic patients with ACS were included in this study. All patients underwent intravascular ultrasound examination, which revealed 49 patients with plaque rupture and 95 patients without plaque rupture in the culprit lesion. Fasting blood glucose (FBG), hemoglobin A 1c (HbA 1c ) and 1,5-AG levels were measured before coronary angiography. Fasting urinary 8-iso-prostaglandin F 2α (8-iso-PGF 2α ) level was measured and corrected by creatinine clearance., Results: Patients with ruptured plaque had significantly lower serum 1,5-AG levels, longer duration of diabetes, higher HbA 1c and FBG levels than patients without ruptured plaque in our study population. In multivariate analysis, low 1,5-AG levels were an independent predictor of plaque rupture (odds ratio 3.421; P = 0.005) in diabetic patients with ACS. The area under the receiver-operating characteristic curve for 1,5-AG (0.658, P = 0.002) to predict plaque rupture was superior to that for HbA 1c (0.587, P = 0.087). Levels of 1,5-AG were significantly correlated with urinary 8-iso-prostaglandin F 2α levels (r = - 0.234, P = 0.005)., Conclusions: Serum 1,5-AG may identify high risk for coronary plaque rupture in diabetic patients with ACS, which suggests PPG excursions are related to the pathogenesis of plaque rupture in diabetes.

To investigate substances related to insulin secretion, we reported a convenient experimental method to reproduce insulin secretion from isolated rat pancreas preparations using an organ bath. While the method has experimental utility for investigating insulin secretion, optimization of the experimental design is still needed. The level of insulin outflow in the control decreased over time in our previous study. Decreasing serum 1,5-anhydroglucitol (1,5-AG) levels is also known to be shown in patients with worsening glycemic control. There is one in vitro report demonstrated that 1,5-AG induced insulin release. It appears that discussion needs to be deepened further on it. In this study, we investigated the effect of 1,5-AG on insulin secretion through to optimize the condition of endocrine function using the ex vivo organ bath technique. The level of insulin outflow in the control and 1,5-AG groups decreased over time in the organ bath experiment. To analyze the effect of trypsin on reduced insulin secretion, pancreas preparation was treated with soybean trypsin inhibitor (TI). Insulin outflow levels of the TI group were significantly higher than the control group. An enzyme indicator of tissue damage tended to be lower in the TI group. There was no significant enhancement of insulin secretion by 1,5-AG. The present study demonstrated the utility of TI application for the organ bath technique. This finding supported the development of an organ bath technique for the assessment of the effects of novel therapeutics on insulin secretion.

Background: Fulminant type 1 diabetes mellitus (FT1DM) onsets abruptly and usually occurs within 1 week after the onset of hyperglycemic symptoms. Glycated albumin (GA) and 1,5-anhydroglucitol (1,5-AG) are indicators that reflect short-term glucose levels. This study was aimed at investigating whether the 1,5-AG/GA index (AGI) is a suitable indicator for early FT1DM identification., Methods: A total of 226 subjects were enrolled, all with glycated hemoglobin A 1c  (HbA 1c ) < 8.7%. FT1DM was diagnosed based on the 2012 Japan Diabetes Society criteria., Results: The AGI level was 0.54 (0.17-1.36) in the whole group. It was lower in FT1DM patients (0.16 [0.10-0.25]). Among the participants whose HbA 1c did not exceed 7.0%, the AGI of FT1DM decreased significantly compared to type 1A diabetes (T1ADM) and latent autoimmune diabetes in adults (LADA) patients (0.16 [0.12-0.26] vs . 0.46 [0.24-0.72] vs . 0.46 [0.24-0.72] P < 0.05). The receiver operating characteristic (ROC) curve showed that AGI can be used to distinguish FT1DM and T1ADM patients with HbA 1c < 8.7%. Diagnosing FT1DM based on AGI ≤ 0.3 only can help narrow down suspected FT1DM by up to 26.87%. If we diagnosed FT1DM when AGI was ≤0.3 and HbA 1c was ≤7.0%, the success rate further increased to 86.57%, among which 85.00% of FT1DM and 87.23% of T1ADM patients were successfully identified. Therefore, using the combination criteria of AGI and HbA 1c would improve the differential diagnosis efficacy by 61.11% compared with the AGI criterion only., Conclusion: AGI can help facilitate the early differential diagnosis of FT1DM and T1ADM when HbA 1c < 8.7%, with an optimal cut-off point of 0.3., Competing Interests: No potential conflicts of interest relevant to this article were reported., (Copyright © 2020 Lingwen Ying et al.)

The unique metabolic demand of cancer cells suggests a new therapeutic strategy targeting the metabolism in cancers. V9302 is a recently reported inhibitor of ASCT2 amino acid transporter which shows promising antitumor activity by blocking glutamine uptake. However, its poor solubility in aqueous solutions and tumor cells' compensatory metabolic shift to glucose metabolism may limit the antitumor efficacy of V9302. 2-Deoxyglucose (2-DG), a derivative of glucose, has been developed as a potential antitumor agent through inhibiting glycolysis in tumor cells. In order to achieve enhanced antitumor effect by inhibiting both metabolic pathways, a 2-DG prodrug-based micellar carrier poly-(oligo ethylene glycol)-co-poly(4-((4-oxo-4-((4-vinylbenzyl)oxy)butyl)disulfaneyl)butanoic acid)-(2-deoxyglucose) (POEG-p-2DG) was developed. POEG-p-2DG well retained the pharmacological activity of 2-DG in vitro and in vivo, More importantly, POEG-p-2DG could self-assemble to form micelles that were capable of loading V9302 to achieve co-delivery of 2-DG and V9302. V9302-loaded POEG-p2DG micelles were small in sizes (~10 nm), showed a slow kinetics of drug release and demonstrated targeted delivery to tumor. In addition, V9302 loaded POEG-p-2DG micelles exhibited improved anti-tumor efficacy both in vitro and in vivo. Interestingly, 2-DG treatment further decreased the glutamine uptake when combined with V9302, likely due to inhibition of ASCT2 glycosylation. These results suggest that POEG-p2DG prodrug micelles may serve as a dual functional carrier for V9302 to achieve synergistic targeting of metabolism in cancers. STATEMENT OF SIGNIFICANCE: Unique cancer cell's metabolism profile denotes a new therapeutic strategy. V9302 is a recently reported glutamine metabolism inhibitor that shows promising antitumor activity. However, its poor waster solubility and tumor cell's compensatory metabolic network may limit its potential clinical application. 2-Deoxyglucose(2-DG) is a widely used glycolysis inhibitor. However, its clinical application is hindered by low efficacy as monotherapy. Thus, in this study, we developed a redox-sensitive, 2-DG-based prodrug polymer, as a dual-functional carrier for co-delivery of V9302 and 2-DG as a combination strategy. V9302 loaded POEG-p-2DG micelle showed significantly improved antitumor activity through synergistic targeting of both glutamine and glycolysis metabolism pathway. More interestingly, POEG-p-2DG itself further facilitates inhibition of glutamine metabolism, likely through inhibition of ASCT2 glycosylation., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interests., (Copyright © 2020 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.)

Background: Cardiovascular disease (CVD) related mortality and morbidity are high in end-stage renal disease (ESRD). The pathophysiology of CVD in ESRD may involve non-traditional CVD risk factors, such as accumulation of advanced glycation endproducts (AGEs), dicarbonyls, endothelial dysfunction (ED) and low-grade inflammation (LGI). However, detailed data on the relation of AGEs and dicarbonyls with ED and LGI in ESRD are limited., Methods: We examined cross-sectional Spearman's rank correlations of AGEs and dicarbonyls with serum biomarkers of ED and LGI in 43 individuals with chronic kidney disease (CKD) stage 5 not on dialysis (CKD5-ND). Free and protein-bound serum AGEs (N∈-(carboxymethyl)lysine (CML), N∈-(carboxyethyl)lysine (CEL), Nδ-(5-hydro-5-methyl-4-imidazolon-2-yl)ornithine (MG-H1)) and serum dicarbonyls (glyoxal, methylglyoxal, 3-deoxyglucosone) were analyzed with tandem mass spectrometry, and tissue AGE accumulation was estimated by skin autofluorescence (SAF). Further, serum biomarkers of ED and LGI included sVCAM-1, sE-selectin, sP-selectin, sThrombomodulin, sICAM-1, sICAM-3, hs-CRP, SAA, IL-6, IL-8 and TNF-α., Results: After adjustment for age, sex and diabetes status, protein-bound CML was positively correlated with sVCAM-1; free CEL with sVCAM-1 and sThrombomodulin; glyoxal with sThrombomodulin; and methylglyoxal with sVCAM-1 (correlation coefficients ranged from 0.36 to 0.44). In addition, free CML was positively correlated with SAA; protein-bound CML with IL-6; free CEL with hs-CRP, SAA and IL-6; free MG-H1 with SAA; protein-bound MG-H1 with IL-6; and MGO with hs-CRP and IL-6 (correlation coefficients ranged from 0.33 to 0.38). Additional adjustment for eGFR attenuated partial correlations of serum AGEs and serum dicarbonyls with biomarkers of ED and LGI., Conclusions: In individuals with CKD5-ND, higher levels of serum AGEs and serum dicarbonyls were related to biomarkers of ED and LGI after adjustment for age, sex and diabetes mellitus. Correlations were attenuated by eGFR, suggesting that eGFR confounds and/or mediates the relation of serum AGEs and dicarbonyls with ED and LGI., Competing Interests: The studies included in this article were supported by an unrestricted grant from Fresenius Medical Care Deutschland GmbH to JPK (study NL33129.068.10 and NL43381.068.13), a Baxter International extramural grant (study NL35039.068.10; grant reference number 11CECHHDEU1004 to TC) and the Dutch Kidney Foundation (study NL35039.068.10; grant reference number SB166 to TC). BC and AG, who are employees of Fresenius Medical Care, reviewed the manuscript. However, the funding sources had no role in the preparation or analysis of data, and the decision to publish. In addition, RJHM, NJHB and JPK are supported by an (un)restricted grant from Fresenius Medical Care. RJHM and NJHB received lectures fees from Fresenius Medical Care. MHLC reports Astellas Travel support grants to visit the international conferences ESOT 2017 and TTS 2018. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: A low 1,5-anhydro-D-glucitol (AG) blood level is considered a clinical marker of postprandial hyperglycemia. Previous studies reported that 1,5-AG levels were associated with vascular endothelial dysfunction and coronary artery disease (CAD). However, the association between 1,5-AG levels and coronary artery plaque in patients with CAD is unclear., Methods: This study included 161 patients who underwent percutaneous coronary intervention for CAD. The culprit plaque characteristics and the extent of coronary calcification, which was measured by the angle of its arc, were assessed by preintervention intravascular ultrasound (IVUS). Patients with chronic kidney disease or glycosylated hemoglobin ≥ 7.0 were excluded. Patients were divided into 2 groups according to serum 1,5-AG levels (< 14.0 μg/mL vs. ≥ 14 μg/mL)., Results: The total atheroma volume and the presence of IVUS-attenuated plaque in the culprit lesions were similar between groups. Calcified plaques were frequently observed in the low 1,5-AG group (p = 0.06). Compared with the high 1,5-AG group, the low 1,5-AG group had significantly higher median maximum calcification (144° vs. 107°, p = 0.03) and more frequent calcified plaques with a maximum calcification angle of ≥ 180° (34.0% vs. 13.2%, p = 0.003). Multivariate logistic regression analysis showed that a low 1,5-AG level was a significant predictor of a greater calcification angle (> 180°) (OR 2.64, 95% CI 1.10-6.29, p = 0.03)., Conclusions: Low 1,5-AG level, which indicated postprandial hyperglycemia, was associated with the severity of coronary artery calcification. Further studies are needed to clarify the effects of postprandial hyperglycemia on coronary artery calcification.

Serum 1,5-anhydroglucitol (1,5-AG) is an emerging biomarker used to monitor glycemic control in persons with diabetes. We performed whole-exome sequencing, examining the association between rare, coding genetic variants and 1,5-AG among European ancestry (N = 6,589) and African ancestry (N = 2,309) participants without diagnosed diabetes in the Atherosclerosis Risk in Communities (ARIC) Study. Five variants representing 3 independent signals on chromosome 17 in SLC5A10, a glucose transporter not previously known to transport 1,5-AG, were associated with 1,5-AG levels up to 10.38 µg/mL lower per allele (1,5-AG range 3.4-32.8 µg/mL) in the European ancestry sample and validated in the African ancestry sample. Together these variants explained 6% of the variance in 1,5-AG. Two of these variants (rs61741107, p = 8.85E-56; rs148178887, p = 1.13E-36) were rare, nonsynonymous, and predicted to be damaging or deleterious by multiple algorithms. Gene-based SKAT-O analysis supported these results (SLC5A10 p = 5.13E-64 in European ancestry, validated in African ancestry, p = 0.006). Interestingly, these novel variants are not associated with other biomarkers of hyperglycemia or diabetes (p > 0.2). The large effect sizes and protein-altering, multiple independent signals suggest SLC5A10 may code for an important transporter of 1,5-AG in the kidney, with a potential nonglucose-related effect on 1,5-AG, impacting its clinical utility as a diabetes biomarker in this subpopulation.

Because of the lack of characteristic morphological findings post mortem diagnosis of diabetes mellitus and identification of diabetic coma can be complicated. 1,5-Anhydroglucitol (1,5-AG), the 1-deoxy form of glucose, competes with glucose for renal reabsorption. Therefore low serum concentrations of 1,5-AG, reflect hyperglycemic excursions over the prior 1-2 weeks in diabetic patients. Next to clinical applications determination of 1,5-AG can also be used in forensic analysis. To investigate the elimination of 1,5-AG, a liquid chromatographic-mass spectrometric method for the determination of 1,5-AG and creatinine in urine was developed and validated according to international guidelines. To evaluate ante mortem concentrations of 1,5-AG spot urine samples of 30 healthy subjects, 46 type 1 and 46 type 2 diabetic patients were analyzed. 1,5-AG urine concentrations of diabetic patients were significantly (p<0.001) lower (mean: 1.54μg/ml, n=92) compared to concentrations of healthy subjects (mean: 4.76μg/ml, n=30) which led to the idea that 1,5-AG urine concentrations post mortem might help in the interpretation of a diabetic coma post mortem. Urine of 47 deceased non-diabetics, 37 deceased diabetic and 9 cases of diabetic coma were measured. Comparison of blood and urine 1,5-AG concentrations in clinic samples (linear, R 2 =0.13) and forensic samples (linear, R 2 =0.02) showed no correlation. Urinary levels of 1,5-AG in deceased diabetic (mean 6.9μg/ml) and in non-diabetic patients (mean 6.3μg/ml) did not show a significant difference (p=0.752). However, urinary 1,5-AG concentrations in deceased due to diabetic coma (mean: 1.7μg/ml) were significantly lower than in non-diabetic (mean: 6.3μg/ml, p=0.039) and lower than in diabetic cases (mean: 4.7μg/ml, p=0.058). The determination of a reliable cut-off for the differentiation of diabetic to diabetic coma cases was not possible. Normalization of urinary 1,5-AG concentrations with the respective creatinine concentrations did not show any gain of information. In clinical (serum) and forensic blood samples a significant difference between all groups could be detected (p<0.05). Comparison of blood and urine 1,5-AG concentrations in clinical samples (linear, R 2 =0.13) and forensic samples (linear, R 2 =0.02) showed no correlation., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Background: There is growing interest in fructosamine, glycated albumin, and 1,5-anhydroglucitol (1,5-AG) as alternative measures of hyperglycemia, particularly for use in settings where traditional measures (glucose and HbA1c) are problematic or where intermediate (2-4 weeks) glycemic control is of interest. However, reference intervals for these alternative biomarkers are not established., Methods: We measured fructosamine, glycated albumin, and 1,5-AG in a community-based sample of US black and white adults who participated in the Atherosclerosis Risk in Communities (ARIC) Study. We calculated reference intervals, evaluated demographic differences, and derived cutoffs aligned with current diagnostic cutpoints for HbA1c and fasting glucose., Results: In a healthy reference population of 1799 individuals (mean age, 55 years; 51% women; 15% black), the 2.5 and 97.5 percentiles, respectively, were 194.8 and 258.0 μmol/L for fructosamine, 10.7% and 15.1% for glycated albumin, and 8.4 and 28.7 μg/mL for 1,5-AG. Distributions differed by race, sex, and body mass index. Equivalent concentrations of fructosamine and glycated albumin corresponding to an HbA1c of 6.5% (96.5 percentile) were 270.2 μmol/L and 15.6%, respectively. Equivalent concentrations of fructosamine and glycated albumin corresponding to a fasting glucose of 126 mg/dL (93.9 percentile) were 261.7 μmol/L and 15.0%, respectively., Conclusions: The reference intervals for these biomarkers should inform their clinical use. Diagnostic cutpoint equivalents for fructosamine and glycated albumin could be useful to identify persons with hyperglycemia in settings where fasting glucose or HbA1c are not available or where the interpretation of these traditional measures is problematic., (© 2018 American Association for Clinical Chemistry.)

Objective: The goal of this study was to determine whether plasma levels of advanced glycation end products (AGE) and oxidation products (OP) predict the incidence of cardiovascular disease (CVD) in type 2 diabetes., Research Design and Methods: Five specific AGE (methylglyoxal hydroimidazolone, carboxymethyl lysine, carboxyethyl lysine, 3-deoxyglucosone hydroimidazolone, and glyoxal hydroimidazolone) and two OP (2-aminoadipic acid and methionine sulfoxide [MetSO]) were measured at baseline in two intensive glucose-lowering studies: 1 ) a subcohort of the Veterans Affairs Diabetes Trial (VADT) ( n = 445) and 2 ) a nested case-control subgroup from the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study ( n = 271)., Results: Increased levels of several AGE and OP were associated with older age, decreased kidney function, previous CVD, and longer diabetes duration, but not with hemoglobin A 1c . In the VADT, increased risk of incident CVD events ( n = 107) was associated with lower MetSO after adjusting for age, race/ethnicity, sex, prior CVD event, kidney function, treatment assignment, and diabetes duration (hazard ratio [HR] 0.53; 95% CI 0.28-0.99; P = 0.047). Individuals with both low MetSO and high 3-deoxyglucosone hydroimidazolone concentrations were at highest risk for CVD (HR 1.70; P = 0.01). In the ACCORD study, those with incident CVD events ( n = 136) had lower MetSO (by 14%; P = 0.007) and higher glyoxal hydroimidazolone and carboxymethyl lysine (by 18% and 15%, respectively; P = 0.04 for both); however, only the difference in MetSO remained significant after adjustment for prior CVD event ( P = 0.002)., Conclusions: Lower levels of MetSO and higher levels of select AGE are associated with increased incident CVD and may help account for the limited benefit of intensive glucose lowering in type 2 diabetes., (© 2017 by the American Diabetes Association.)

Background: Diabetes mellitus is considered an important risk factor for cardiovascular diseases. High hemoglobin A1c (HbA1c) levels, which indicate poor glycemic control, have been associated with occurrence of cardiovascular diseases. There are few parameters which can predict cardiovascular risk in patients with well-controlled diabetes. Low 1,5-anhydroglucitol (1,5-AG) levels are considered a clinical marker of postprandial hyperglycemia. We hypothesized that low 1,5-AG levels could predict long-term mortality in acute coronary syndrome (ACS) patients with relatively low HbA1c levels., Methods: The present study followed a retrospective observational study design. We enrolled 388 consecutive patients with ACS admitted to the cardiac intensive care unit at the Juntendo University Hospital from January 2011 to December 2013. Levels of 1,5-AG were measured immediately before emergency coronary angiography. Patients with early stent thrombosis, no significant coronary artery stenosis, malignancy, liver cirrhosis, a history of gastrectomy, current steroid treatment, moderately to severely reduced kidney function (estimated glomerular filtration rate < 45 ml/min/1.73 m 2 ; chronic kidney disease stage 3B, 4, and 5), HbA1c levels ≥ 7.0%, and those who received sodium glucose co-transporter 2 inhibitor therapy were excluded., Results: During the 46.9-month mean follow-up period, nine patients (4.5%) died of cardiovascular disease. The 1,5-AG level was significantly lower in the cardiac death group compared with that in the survivor group (12.3 ± 5.3 vs. 19.2 ± 7.7 µg/ml, p < 0.01). Kaplan-Meier survival analysis showed that low 1,5-AG levels were associated with cardiac mortality (p = 0.02). Multivariable Cox regression analysis showed that 1,5-AG levels were an independent predictor of cardiac mortality (hazard ratio 0.76; 95% confidence interval 0.41-0.98; p = 0.03)., Conclusion: Low 1,5-AG levels, which indicate postprandial hyperglycemia, predict long-term cardiac mortality even in ACS patients with HbA1c levels < 7.0%.

Background and Objectives: Causes of CKD differ in prognosis and treatment. Metabolomic indicators of CKD cause may provide clues regarding the different physiologic processes underlying CKD development and progression., Design, Setting, Participants & Measurements: Metabolites were quantified from serum samples of participants in the Modification of Diet in Renal Disease (MDRD) Study, a randomized controlled trial of dietary protein restriction and BP control, using untargeted reverse phase ultraperformance liquid chromatography tandem mass spectrometry quantification. Known, nondrug metabolites ( n =687) were log-transformed and analyzed to discover associations with CKD cause (polycystic kidney disease, glomerular disease, and other cause). Discovery was performed in Study B, a substudy of MDRD with low GFR ( n =166), and replication was performed in Study A, a substudy of MDRD with higher GFR ( n =423)., Results: Overall in MDRD, average participant age was 51 years and 61% were men. In the discovery study (Study B), 29% of participants had polycystic kidney disease, 28% had glomerular disease, and 43% had CKD of another cause; in the replication study (Study A), the percentages were 28%, 24%, and 48%, respectively. In the discovery analysis, adjusted for demographics, randomization group, body mass index, hypertensive medications, measured GFR, log-transformed proteinuria, and estimated protein intake, seven metabolites (16-hydroxypalmitate, kynurenate, homovanillate sulfate, N2,N2-dimethylguanosine, hippurate, homocitrulline, and 1,5-anhydroglucitol) were associated with CKD cause after correction for multiple comparisons ( P <0.0008). Five of these metabolite associations (16-hydroxypalmitate, kynurenate, homovanillate sulfate, N2,N2-dimethylguanosine, and hippurate) were replicated in Study A ( P <0.007), with all replicated metabolites exhibiting higher levels in polycystic kidney disease and lower levels in glomerular disease compared with CKD of other causes., Conclusions: Metabolomic profiling identified several metabolites strongly associated with cause of CKD., (Copyright © 2017 by the American Society of Nephrology.)

Glycemic excursions, independent of average glucose, have been implicated in the development of diabetic complications. It is unknown whether low levels of 1,5-anhydroglucitol (1,5-AG) are associated with advanced stages of kidney disease independent of kidney function and glycemia. In the Atherosclerosis Risk in Communities Study (n = 13,277 from 4 US communities), we used structural equation modeling to estimate the association between serum 1,5-AG levels and end-stage renal disease (ESRD) from baseline (1990-1992) through 2013 with adjustment for demographics, risk factors, a latent variable for glycemia (diabetes status, fasting glucose, glycated hemoglobin (HbA1c), fructosamine, glycated albumin), and a latent variable for kidney function (creatinine, cystatin C, β2-microglobulin). After adjusting for demographics, risk factors, and the latent variable for kidney function, the linear spline terms representing 1,5-AG levels <6.0 μg/mL (incidence rate ratio (IRR) = 0.79, 95% confidence interval (CI): 0.70, 0.88) and 6.0-9.9 μg/mL (IRR = 0.80, 95% CI: 0.70, 0.92) were significantly associated with ESRD. After additionally adjusting for the latent variable for glycemia, low 1,5-AG levels (<6.0 μg/mL) were no longer significantly associated with ESRD (IRR = 0.92, 95% CI: 0.81, 1.05). In conclusion, low 1,5-AG levels are associated with higher risk of incident ESRD independent of baseline kidney function but not independent of glycemia., (© The Author(s) 2017. Published by Oxford University Press on behalf of the Johns Hopkins Bloomberg School of Public Health. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Serum 1,5-anhydroglucitol (1,5-AG) levels can not only accurately reflect the mean blood glucose over the previous 1-2 weeks in diabetic patients but also offers the advantage of representing postprandial glucose. To evaluate the clinical significance of 1,5-AG in diabetes detection, especially when used in combination with fasting plasma glucose (FPG), a total of 3098 participants at high risk for diabetes (1467 men, 1631 women) were enrolled. A total of 1471 (47.5%) participants were diagnosed with diabetes, and the mean 1,5-AG level in the diabetic group was significantly lower than that in non-diabetic group [12.5 (7.8-17.5) μg/mL vs. 20.5 (15.3-26.4) μg/mL, P < 0.001]. The optimal cut-off point was 15.9 μg/mL, for which the sensitivity, specificity, and area under the curve (AUC) were 69.2%, 72.3%, and 0.781, respectively. For the combination of FPG and 1,5-AG, the sensitivity, specificity, and AUC improved to 82.5%, 83.5%, and 0.912, respectively. This method helped 75.8% of the participants avoid an oral glucose tolerance test (OGTT), reducing the need to carry out the OGTT by 43.9% compared to the use of the FPG criterion only. In conclusion, the addition of FPG to serum 1,5-AG improves the efficiency of diabetes screening in the Chinese population.

Background: We established the reference intervals for glycated albumin (GA), fructosamine (FA), and 1,5-anhydroglucitol (1,5-AG) in a Chinese healthy population., Methods: This study enrolled a total of 458 eligible reference individuals, consisted of 226 men and 232 women, aged from 20~79 years (median age 43 years), who attending routine healthy checks. We stratified the subjects according to gender (males and females) and age (20-39, 40-59, and 60-79 years), and combined statistical methods with Lahti algorithm, as well as appropriate clinical consideration, to judge whether partitioning for data was needed., Results: Glycated albumin levels between males and females were statistically different (P<.001), but the absolute difference between the upper reference limits was only 0.31%, which was too small to be clinically relevant. GA levels across the three age groups were statistically different (P<.001), and Lahti algorithm suggested partitioning for 20-59 and 60-79 years, which reference intervals were 10.38%-13.89% and 10.23%-14.79%, respectively. 1,5-AG levels in males were significant higher than females (P<.001), and absolute difference was 51 μmol/L (8.5 μg/mL) in mean level. Thus, partitioning for gender was needed. Reference intervals for 1,5-AG were 107-367 μmol/L for males and 79-306 μmol/L for females. The absolute difference of the lower reference limits for FA was only 7 μmol/L between males and females. FA levels across the three age groups were not statistically different (P>.05). The reference interval for FA was 220-298 μmol/L., Conclusion: New reference intervals for nontraditional glycemic markers were established based on a Chinese population., (© 2016 Wiley Periodicals, Inc.)

The importance of 1,5-anhydroglucitol (1,5-AG) as an intermediate biomarker for diabetic pregnancy is multi-fold: (1) it serves as a reliable indicator of moderate-level glycemic control, especially during early gestation; (2) it has been associated with increased risk of diabetes, independent of HbA1c and fasting glucose; and (3) it is an independent risk factor for the development of eclampsia during pregnancy. However, the clinical use of this biomarker during pregnancy has been underutilized due to physiological changes in glomerular filtration rate, plasma volume, and other hemodynamic parameters which have been hypothesized to bias gestational serum 1,5-AG concentrations. Here, we develop an in-silico model of gestational 1,5-AG by combining pre-existing physiological data in the literature with a two-compartment mathematical model, building off of a previous kinetic model described by Stickle and Turk (1997) Am. J. Physiol., 273, E821. Our model quantitatively characterizes how renal and hemodynamic factors impact measured 1,5-AG during normal pregnancy and during pregnancy with gestational diabetes and diabetes mellitus. During both normal and diabetic pregnancy, we find that a simple two-compartment model of 1,5-AG kinetics, with all parameters but reabsorption fraction adjusted for time in pregnancy, efficiently models 1,5-AG kinetics throughout the first two trimesters. Allowing reabsorption fraction to decrease after 25 weeks permits parameters closer to expected physiological values during the last trimester. Our quantitative model of 1,5-AG confirms the involvement of hypothesized renal and hemodynamic mechanisms during pregnancy, clarifying the expected trends in 1,5-AG to aid clinical interpretation. Further research and data may elucidate biological changes during the third trimester that account for the drop in 1,5-AG concentrations, and clarify physiological differences between diabetes subtypes during pregnancy., (© 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.)

Objective: To determine whether plasma levels of advanced glycation end products and oxidation products play a role in the development of atherosclerosis in patients with type 2 diabetes (T2D) over nearly 10 years of the VA Diabetes Trial and Follow-up Study., Research Design and Methods: Baseline plasma levels of methylglyoxal hydroimidazolone, Nε-carboxymethyl lysine, Nε-carboxyethyl lysine (CEL), 3-deoxyglucosone hydroimidazolone and glyoxal hydroimidazolone (G-H1), 2-aminoadipic acid (2-AAA), and methionine sulfoxide were measured in a total of 411 participants, who underwent ultrasound assessment of carotid intima-media thickness (CIMT), and computed tomography scanning of coronary artery calcification (CAC) and abdominal aortic artery calcification (AAC) after an average of 10 years of follow-up., Results: In risk factor-adjusted multivariable regression models, G-H1 was associated with the extent of CIMT and CAC. In addition, 2-AAA was strongly associated with the extent of CAC, and CEL was strongly associated with the extent of AAC. The combination of specific advanced glycation end products and oxidation products (G-H1 and 2-AAA) was strongly associated with all measures of subclinical atherosclerosis., Conclusions: Specific advanced glycation end products and metabolic oxidation products are associated with the severity of subclinical atherosclerosis over the long term and may play an important role in the "negative metabolic memory" of macrovascular complications in people with long-standing T2D., (© 2017 by the American Diabetes Association.)

1,5-anhydroglucitol (1,5-AG), uric acid and urinary proteins are excreted into the urine with increasing glucosuria. In the present retrospective study we analyzed whether these factors could be used as indicators for type 2 diabetes mellitus (T2DM) glucose control in 6,766 (T2DM) patients. There were 3,988 cases (58.9%) with HbA1c ≤ 6.5%, 853 cases (12.61%) with HbA1c levels ranging from 6.5% to 7% and 1,925 cases (28.5%) with HbA1c > 7%. HbA1c percentages were correlated with age, MA and 1,5-AG serum concentrations (P < 0.001). The serum uric acid concentration (P < 0.001) was significantly lower in elevated MA (P < 0.001) and 24-hour urinary protein (P = 0.024) patients. Hb1Ac percentages (P < 0.001) were significantly enhanced in patients with 1,5-AG serum concentrations ≤10 mg/L compared to >10 mg/L. With a derived receiver operating characteristic (ROC) curve, a 1,5-AG cut-off value of 11.55 mg/L for hyperglycemia could be diagnosed with a specificity of 71.2 (69.7-72.6) and a sensitivity of 75.3 (73.6-76.9). The serum 1,5-AG concentration is a marker for hyperglycemia and may be particularly useful as an indicator for short-term glycemic excursions in order to improve treatments in T2DM patients.

Background: Postprandial hyperglycemia plays an important role in the pathogenesis of coronary artery disease and cardiovascular events. Serum 1,5-anhydroglucitol (1,5-AG) levels are known to be a clinical marker of postprandial hyperglycemia. However, the impact of 1,5-AG level on cardiovascular events has not been fully investigated., Methods: We enrolled 240 consecutive patients who had undergone first-time elective percutaneous coronary intervention (PCI) with follow-up angiography within 1 year. We excluded patients with a history of acute coronary syndrome, advanced chronic kidney disease (estimated glomerular filtration rate <30 mL/min/1.73 m 2 ), or uncontrolled diabetes mellitus (HbA1c ≥7.0 %). Fasting blood glucose (FBS), HbA1c, and 1,5-AG levels were measured prior to PCI and at the time of follow-up angiography. Clinical events, including target lesion revascularization, target vessel revascularization, and revascularization of new lesions, were evaluated., Results: Subjects were divided into two groups according to clinical outcomes: the Event (+) group (n = 40) and the Event (-) group (n = 200). No significant differences were observed, except for the number of diseased vessels and the prevalence of statin use, in baseline clinical characteristics between the two groups. Serum levels of 1,5-AG at follow-up were significantly lower in the Event (+) group than in the Event (-) group (P = 0.02). A significant reduction in 1,5-AG level from baseline to follow-up was observed in the Event (+) group compared with the Event (-) group (P = 0.04). The association between 1,5-AG levels at follow-up and clinical events remained significant after adjustment for independent variables, including FBS and HbA1c levels (P = 0.04)., Conclusions: Low and exacerbated levels of 1,5-AG were associated with cardiovascular events in the present study, indicating that postprandial hyperglycemia is an important risk factor for adverse clinical events even in patients with HbA1c < 7.0 %, following first-time elective PCI.

Objective: 1,5-Anhydroglucitol (1,5-AG) is a biomarker of glucose peaks and has been associated with clinical cardiovascular disease. However, the association between 1,5-AG and subclinical cardiovascular disease is unknown. We investigated the association of 1,5-AG with subclinical myocardial damage (assessed by high-sensitivity cardiac troponin T [hs-cTnT]) and atherosclerosis (assessed by carotid intima-media thickness [CIMT] and carotid plaque)., Research Design and Methods: We measured 1,5-AG, hs-cTnT, CIMT, and carotid plaque among 10,072 people without diabetes and 681 with diabetes who attended the second examination of the Atherosclerosis Risk in Communities (ARIC) Study (baseline, 1990-1992). We used Poisson regression to characterize the associations between 1,5-AG and prevalent elevated hs-cTnT, thick CIMT, or carotid plaque. Among 9,145 people with a second hs-cTnT measurement 6 years later, we used multinomial logistic regression to assess associations with incident elevation in hs-cTnT., Results: We found that in people with diabetes, lower 1,5-AG (<6 μg/mL) was cross-sectionally associated with elevated hs-cTnT (prevalence ratio 2.06, 95% CI 1.23-3.46) compared with higher 1,5-AG (≥10 μg/mL). Associations in people without diabetes and with thick CIMT or the presence of carotid plaque were less robust. Low 1,5-AG was prospectively associated with the 6-year incident elevation in hs-cTnT (relative risk 2.90, 95% CI 1.23-6.85) in people with diabetes. All associations were strongly attenuated with further adjustment for HbA1c., Conclusions: In people with diabetes, 1,5-AG was associated with subclinical cardiovascular disease, particularly chronic subclinical myocardial damage. Nonetheless, whether observed associations are truly independent of average glycemia is unclear., (© 2016 by the American Diabetes Association.)

Background: Despite the centrality of nutrition in the management of type 1 diabetes, the association of diet quality and macronutrient distribution with glycemic control is ambiguous., Objective: This study examined longitudinally the association of dietary intake with multiple indicators of glycemic control in youth with type 1 diabetes participating in a behavioral nutrition intervention study., Design: Participants in a randomized clinical trial of a behavioral nutrition intervention [n = 136; mean ± SD age: 12.8 ± 2.6 y; glycated hemoglobin (HbA1c): 8.1% ± 1.0%; 69.1% using an insulin pump] completed 3-d diet records at baseline and months 3, 6, 9, 12, and 18; masked continuous glucose monitoring (CGM) data were obtained concurrently with the use of the Medtronic iPro CGM system. HbA1c was obtained every 3 mo; 1,5-anhydroglucitol was obtained every 6 mo. Linear mixed-effects regression models estimated associations of time-varying dietary intake variables with time-varying glycemic control indicators, controlling for age, height, weight, sex, Tanner stage, diabetes duration, regimen, frequency of blood glucose monitoring, physical activity, and treatment assignment., Results: HbA1c was associated inversely with carbohydrate and natural sugar, and positively with protein and unsaturated fat. 1,5-Anhydroglucitol was associated positively with fiber intake and natural sugar. Greater glycemic control as indicated by ≥1 CGM variable was associated with higher Healthy Eating Index-2005, whole plant food density, fiber, carbohydrate, and natural sugar and lower glycemic index and unsaturated fat., Conclusions: Both overall diet quality and macronutrient distribution were associated with more optimal glycemic control. Associations were more consistent for CGM variables obtained concurrently with dietary intake than for biomarkers of longer-term glycemic control. These findings suggest that glycemic control may be improved by increasing intake of high-fiber, low glycemic-index, carbohydrate-containing foods. This trial was registered at clinicaltrials.gov as NCT00999375., (© 2016 American Society for Nutrition.)

Background: Diabetes testing using saliva, rather than blood and urine, could facilitate diabetes screening in public spaces. We previously identified 1,5-anhydro-D-glucitol (1,5-AG) in saliva as a diabetes biomarker. The Glycomark™ assay kit is FDA approved for 1,5-AG measurement in blood. Here we evaluated its applicability for 1,5-AG quantification in saliva., Methods: Using pooled saliva samples, we validated Glycomark™ assay use with a RX Daytona(+) clinical chemistry analyser. We then used this set-up to analyse 82 paired blood and saliva samples from a diabetes case-control study, for which broad mass spectrometry-based characterization of the blood and saliva metabolome was also available. Osmolality was measured to account for potential variability in saliva samples., Results: The technical variability of the read-outs for the pooled saliva samples (CV = 2.05 %) was comparable to that obtained with manufacturer-provided blood surrogate quality controls (CV = 1.38-1.8 %). We found a high correlation between Glycomark assay and mass spectrometry measurements of serum 1,5-AG (r(2) = 0.902), showing reproducibility of the non-targeted metabolomics results. The significant correlation between the osmolality measurements performed at two independent platforms with the time interval of 2 years (r(2) = 0.887), also indicates the sample integrity. The assay read-out for saliva was not correlated with the mass spectrometry-based 1,5-AG saliva measurements. Comparison with the full saliva metabolome revealed a high correlation of the saliva assay read-outs with galactose., Conclusions: Glycomark™ assay read-outs for saliva were stable and replicable. However, the signal was dominated by galactose, which is biochemically similar to 1,5-AG and absent in blood. Adapting the 1,5-AG kit for saliva analysis will require enzymatic depletion of galactose. This should be feasible, since the assay already includes a similar step for glucose depletion from blood samples.

In diabetes, low concentrations of the biomarker 1,5-anhydroglucitol (1,5-AG) reflect hyperglycemic excursions over the prior 1-2 weeks. To the extent that hyperglycemic excursions are important in atherogenesis, 1,5-AG may provide independent information regarding cardiovascular risk. Nonetheless, few studies have evaluated associations of 1,5-AG with long-term cardiovascular outcomes in a population-based setting. We measured 1,5-AG in 11,106 participants in the Atherosclerosis Risk in Communities (ARIC) study without cardiovascular disease at baseline (1990-1992) and examined prospective associations with coronary heart disease (n = 1,159 events), ischemic stroke (n = 637), heart failure (n = 1,553), and death (n = 3,120) over 20 years of follow-up. Cox proportional hazards models were adjusted for demographic and cardiovascular risk factors. Compared with persons with 1,5-AG ≥6 μg/mL and no history of diabetes, persons with diabetes and 1,5-AG <6.0 μg/mL had an increased risk of coronary heart disease (HR 3.85, 95% CI 3.11-4.78), stroke (HR 3.48, 95% CI 2.66-4.55), heart failure (HR 3.50, 95% CI 2.93-4.17), and death (HR 2.44, 95% CI 2.11-2.83). There was a threshold effect, with little evidence for associations at "nondiabetic" concentrations of 1,5-AG (e.g., >10 μg/mL). Associations remained but were attenuated with additional adjustment for fasting glucose or HbA1c. These data add to the growing evidence for the prognostic value of 1,5-AG for long-term complications in the setting of diabetes., (© 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)

Background: This study investigated whether postprandial hyperglycaemia has an adverse effect on coronary microvascular function and left ventricular diastolic function., Methods: In all, 28 patients with type 2 diabetes mellitus with no significant stenosis in left anterior descending artery were enrolled. In all subjects, plasma 1,5-anhydroglucitol was measured, and coronary flow reserve in the left anterior descending artery was evaluated using a Doppler wire. Membrane type-1 matrix metalloproteinase expression on circulating peripheral blood mononuclear cells was measured by flow cytometry. Correlation analyses were performed for coronary flow reserve and 1,5-anhydroglucitol, other coronary risk factors, membrane type-1 matrix metalloproteinase and E/e'., Results: Strong correlations were found only between 1,5-anhydroglucitol and coronary flow reserve and membrane type-1 matrix metalloproteinase. On multiple regression analysis, 1,5-anhydroglucitol remained an independent predictor of coronary flow reserve (β = 0.38, p = 0.048)., Conclusion: Postprandial hyperglycaemia appears to have an adverse effect on coronary microvascular function, suggesting that improvement of postprandial hyperglycaemia may contribute to the improvement of coronary microvascular dysfunction., (© The Author(s) 2015.)

Background: Dietary energy restriction (DER) has been well established as a potent anticancer strategy. Non-adoption of restricted diet for an extended period has limited its practical implementation in humans with a compelling need to develop agents that mimic effects similar to DER, without reduction in actual dietary intake. Glycolytic inhibitor, 2-deoxy-D-glucose (2-DG), has recently been shown to possess potential as an energy restriction mimetic agent (ERMA). In the present study we evaluated the effect of dietary 2-DG administration on a mouse tumor model, with a focus on several potential mechanisms that may account for the inhibition of tumorigenesis., Methodology/principal Findings: Swiss albino strain 'A' mice were administered with 0.2% and 0.4% w/v 2-DG in drinking water for 3 months prior to tumor implantation (Ehrlich's ascites carcinoma; EAC) and continued till the termination of the study with no adverse effects on general physiology and animal growth. Dietary 2-DG significantly reduced the tumor incidence, delayed the onset, and compromised the tumor growth along with enhanced survival. We observed reduced blood glucose and serum insulin levels along with decreased proliferating cell nuclear antigen (PCNA) and bromodeoxyuridine positive (BrdU+) tumor cells in 2-DG fed mice. Also, reduced levels of certain key players of metabolic pathways such as phosphatidylinositol 3-kinase (PI3K), phosphorylated-Akt and hypoxia inducible factor-1 alpha (HIF-1α) were also noted in tumors of 2-DG fed mice. Further, decrease in CD4+/CD8+ ratio and T-regulatory cells observed in 2-DG fed mice suggested enhanced antitumor immunity and T cell effector function., Conclusion/significance: These results strongly suggest that dietary 2-DG administration in mice, at doses easily achievable in humans, suitably modulates several pleotrophic factors mimicking DER and inhibits tumorigenesis, emphasizing the use of ERMAs as a promising cancer preventive strategy.

Advanced glycation end products (AGEs) may contribute to the development of type 2 diabetes and related complications, whereas their role in the early deterioration of glycaemia is unknown. While previous studies used antibody-based methods to quantify AGEs, data from tandem mass spectrometry coupled liquid chromatography (LC-MS/MS)-based measurements are limited to patients with known diabetes. Here, we used the LC-MS/MS method to test the hypothesis that plasma AGE levels are higher in individuals with impaired fasting glucose (IFG) than in those with normal fasting glucose (NFG). Secondary aims were to assess correlations of plasma AGEs with quantitative markers of glucose metabolism and biomarkers of subclinical inflammation. This study included on 60 women with NFG or IFG (n = 30 each, mean age 74 years) from the German SALIA cohort. Plasma levels of free metabolites (3-deoxyfructose, 3-deoxypentosone, 3-deoxypentulose), two hydroimidazolones, oxidised adducts (carboxymethyllysine, carboxyethyllysine, methionine sulfoxide) and Nε-fructosyllysine were measured using LC-MS/MS. Plasma concentrations of all tested AGEs did not differ between the NFG and IFG groups (all p>0.05). Associations between plasma levels of AGEs and fasting glucose, insulin and HOMA-IR as a measure of insulin resistance were weak (r between -0.2 and 0.2, all p>0.05). The association between 3-deoxyglucosone-derived hydroimidazolone with several proinflammatory biomarkers disappeared upon adjustment for multiple testing. In conclusion, plasma AGEs assessed by LC-MS/MS were neither increased in IFG nor associated with parameters of glucose metabolism and subclinical inflammation in our study. Thus, these data argue against strong effects of AGEs in the early stages of deterioration of glucose metabolism.

Background: The aim of this study was to investigate the associations of two nontraditional glycemic markers, glycated albumin (GA) and 1,5-anhydroglucitol (1,5-AG), as well as glycated hemoglobin A1c (HbA1c) with coronary artery disease (CAD)., Methods: In total, 272 subjects (178 men and 94 postmenopausal women) were enrolled in this study. All of them underwent coronary angiography which was used to diagnose CAD. The severity of coronary artery stenosis was assessed by the coronary stenosis index (CSI). GA and 1,5-AG were assayed using the enzymatic method, and HbA1c was detected by high-pressure liquid chromatography., Results: The HbA1c and GA levels were significantly higher in CAD group than those in non-CAD group (both P < 0.01). While the 1,5-AG level was significantly lower in CAD group than that in non-CAD group (P < 0.05). After adjustment for traditional risk factors of CAD, HbA1c, 1,5-AG, and GA, multivariate logistic regression analysis showed that GA was an independent risk factor for CAD (odds ratio = 1.143, 95% confidence interval: 1.048-1.247, P = 0.002). With CSI as a dependent variable, multiple stepwise regression analysis demonstrated an independent positive correlation between GA and CSI (standardized β = 0.184, P = 0.003), beyond gender, age, and lipid-lowering therapy, after adjustment for traditional risk factors of CAD, HbA1c, 1,5-AG, and GA., Conclusions: GA was more closely correlated with CAD than HbA1c and 1,5-AG in a Chinese population with high risk of CAD.

Background: Several studies have reported that insulin resistance was a major risk factor for the onset of type 2 diabetes mellitus in individuals without diabetes or obesity. We aimed to clarify the association between insulin resistance and glycemic control in Japanese subjects without diabetes or obesity., Methods: We conducted a community-based cross-sectional study including 1083 healthy subjects (323 men and 760 women) in an urban area. We performed multivariate regression analyses to estimate the association between the homeostasis model assessment of insulin resistance (HOMA-IR) values and markers of glycemic control, including glycated haemoglobin (HbA1c), 1,5-anhydroglucitol (1,5-AG), and fasting plasma glucose (FPG) levels, after adjustment for potential confounders., Results: Compared with the lowest tertile of HOMA-IR values, the highest tertile was significantly associated with HbA1c and FPG levels after adjustment for potential confounders, both in men (HbA1c: β = 1.83, P = 0.001; FPG: β = 0.49, P < 0.001) and women (HbA1c: β = 0.82, P = 0.008; FPG: β = 0.39, P < 0.001). The highest tertile of HOMA-IR values was inversely associated with 1,5-AG levels compared with the lowest tertile (β = -18.42, P = 0.009) only in men., Conclusions: HOMA-IR values were associated with markers of glycemic control in Japanese subjects without diabetes or obesity. Insulin resistance may influence glycemic control even in a lean, non-diabetic Asian population.

Increasing evidence has indicated that postprandial hyperglycemia affects coronary artery disease (CAD). The serum 1,5-anhydro-d-glucitol (1,5-AG) value is a useful clinical marker to evaluate short-term glycemic status and reflects glycemic excursions with greater sensitivity when compared with hemoglobinA1c (HbA1c), especially for patients in the postprandial state. The aim of this study was to evaluate the predictive value of 1,5-AG for CAD in patients without diabetes mellitus.This study included 729 consecutive patients who had undergone their first coronary angiography. A total of 284 patients (246 diabetic patients and 38 patients with stage 4 or 5 chronic kidney disease) were excluded. The predictive values of 1,5-AG and HbA1c for CAD were evaluated by multivariable logistic regression analysis.Patients with CAD demonstrated significantly lower 1,5-AG values and higher HbA1c values than did patients without CAD (18.6 μg/mL [12.0, 23.3] versus 19.2 μg/mL [14.4, 25.2], P = 0.036, and 5.7% [5.5, 5.9] versus 5.6% [5.4, 5.8], P = 0.016, respectively). In multivariable logistic regression analysis, the HbA1c values did not indicate a predictive value for the prevalence of CAD. In contrast, the 1,5-AG levels were still an independent predictor of CAD (adjusted odds ratio 0.96, 95% confidence interval 0.93-0.99, P = 0.0097).Serum 1,5-AG is superior to HbA1c for predicting CAD prevalence in patients without diabetes mellitus.

Background: 1,5-Anhydroglucitol (1,5-AG) is inversely related to hyperglycemia and may be a useful indicator of short-term (1-2 weeks) hyperglycemia and glycemic excursions, but its prognostic value is unclear. We sought to evaluate the associations of 1,5-AG with risk of diabetes and microvascular disease., Methods: We measured 1,5-AG in blood samples from over 10 000 participants in the ARIC (Atherosclerosis Risk in Communities) Study (baseline, 1990-1992) and characterized the independent associations with prevalent retinopathy and with incident chronic kidney disease and incident diabetes during approximately 20 years of follow-up., Results: We found that 1,5-AG was associated with prevalent retinopathy, driven primarily by the strong association in persons with diagnosed diabetes: adjusted odds ratio (OR) 11.26 (95% CI, 6.17-20.53) for <6 μg/mL compared to 1,5-AG ≥10 μg/mL. This result remained significant after further adjustment for hemoglobin A(1c) (Hb A(1c)) (OR, 4.85; 95% CI, 2.42-9.74). In persons with diagnosed diabetes, low 1,5-AG (<6 μg/mL vs ≥10 μg/mL) was also associated with a >2-fold increased risk of incident chronic kidney disease [adjusted hazard ratio (HR), 2.83; 95% CI, 2.15-3.74] and remained significant after adjustment for Hb A(1c) (HR, 1.43; 95% CI, 1.02-2.00). Nondiabetic participants with high 1,5-AG (≥10 μg/mL) had the lowest prevalence of retinopathy and lowest risk of kidney disease. In persons without diagnosed diabetes at baseline, 1,5-AG <10 μg/mL was also associated with incident diabetes (adjusted HR, 2.29; 95% CI, 2.03-2.58)., Conclusions: 1,5-AG was associated with long-term risk of important microvascular outcomes, particularly in persons with diagnosed diabetes and even after adjustment for Hb A(1c). Our results suggest 1,5-AG may capture risk information associated with hyperglycemic excursions., (© 2014 American Association for Clinical Chemistry.)

Background: The relationship between hemoglobin A1c (HbA1c) levels and coronary artery disease (CAD) has previously been confirmed. Serum 1,5-anhydro-D-glucitol (1,5-AG) levels are a useful clinical marker for short-term glycemic status that reflect glycemic excursions with greater sensitivity compared with HbA1c, specifically in the postprandial state. Postprandial hyperglycemia is an important CAD risk factor. Thus, the aim of this study was to compare HbA1c with 1,5-AG as a CAD predictor., Methods: The subjects consisted of 336 consecutive patients who underwent their first coronary angiography between July 2011 and March 2013. The relationship between CAD prevalence and HbA1c as well as CAD prevalence and 1,5-AG levels was evaluated. The correlation between CAD complexity and HbA1c or 1,5-AG was also assessed. CAD complexity was evaluated by the SYNTAX score., Results: CAD patients presented with significantly lower 1,5-AG and higher HbA1c values than patients without CAD (11.6 μg/ml [6.1, 19.1] vs. 17.6 μg/ml [11.9, 25.0], p<0.001, and 6.0% [5.6, 7.1] vs. 5.7% [5.4, 6.2], p<0.001, respectively) (median [25th, 75th percentiles]). According to logistic regression analysis, 1,5-AG was a predictor of CAD prevalence (odds ratio 0.94, 95% confidence interval 0.90-0.97). However, HbA1c levels did not present a predictive value for CAD. Levels of 1,5-AG and HbA1c were significantly correlated with SYNTAX scores (ρ=-0.27, p<0.001; and ρ=0.23, p<0.001, respectively)., Conclusions: The use of 1,5-AG, may be superior to HbA1c in predicting CAD prevalence. Both 1,5-AG and HbA1c correlate with CAD complexity., (Copyright © 2014 Japanese College of Cardiology. Published by Elsevier Ltd. All rights reserved.)

Background and Objectives: Novel biomarkers that more accurately reflect kidney function and predict future CKD are needed. The human metabolome is the product of multiple physiologic or pathophysiologic processes and may provide novel insight into disease etiology and progression. This study investigated whether estimated kidney function would be associated with multiple metabolites and whether selected metabolomic factors would be independent risk factors for incident CKD., Design, Setting, Participants, & Measurements: In total, 1921 African Americans free of CKD with a median of 19.6 years follow-up among the Atherosclerosis Risk in Communities Study were included. A total of 204 serum metabolites quantified by untargeted gas chromatography-mass spectrometry and liquid chromatography-mass spectrometry was analyzed by both linear regression for the cross-sectional associations with eGFR (specified by the Chronic Kidney Disease Epidemiology Collaboration equation) and Cox proportional hazards model for the longitudinal associations with incident CKD., Results: Forty named and 34 unnamed metabolites were found to be associated with eGFR specified by the Chronic Kidney Disease Epidemiology Collaboration equation with creatine and 3-indoxyl sulfate showing the strongest positive (2.8 ml/min per 1.73 m(2) per +1 SD; 95% confidence interval, 2.1 to 3.5) and negative association (-14.2 ml/min per 1.73 m(2) per +1 SD; 95% confidence interval, -17.0 to -11.3), respectively. Two hundred four incident CKD events with a median follow-up time of 19.6 years were included in the survival analyses. Higher levels of 5-oxoproline (hazard ratio, 0.70; 95% confidence interval, 0.60 to 0.82) and 1,5-anhydroglucitol (hazard ratio, 0.68; 95% confidence interval, 0.58 to 0.80) were significantly related to lower risk of incident CKD, and the associations did not appreciably change when mutually adjusted., Conclusions: These data identify a large number of metabolites associated with kidney function as well as two metabolites that are candidate risk factors for CKD and may provide new insights into CKD biomarker identification., (Copyright © 2014 by the American Society of Nephrology.)

Background: Vascular endothelial dysfunction is involved in macrovascular disease progression in type 2 diabetes mellitus (T2DM). We reported previously that blood glucose fluctuations, as evaluated by continuous glucose monitoring (CGM), correlate with vascular endothelial function, serving as a marker of vascular endothelial function. However, the use of CGM is limited, suggesting the need for another marker of vascular endothelial function. Here, we investigated the relationship between vascular endothelial dysfunction and blood levels of 1,5-anhydro-D-glucitol (1,5-AG), a marker of both postprandial hyperglycemia and fluctuations in blood glucose., Methods: In 32 inpatients with T2DM and HbA1c less than 8.0%, the reactive hyperemia index (RHI), an index of vascular endothelial function, was determined by peripheral arterial tonometry. The relationships between RHI and 1,5-AG, blood glucose, lipid metabolism markers, and blood pressure, were examined., Results: There was a strong correlation between 1,5-AG and natural logarithmic-scaled RHI (L&#95;RHI) (r = 0.55; P = 0.001). However, there was no correlation between L&#95;RHI and HbA1c, fasting blood glucose, IRI, LDL-C, HDL-C, TG, systolic blood pressure, or diastolic blood pressure. Multivariate analysis identified blood 1,5-AG levels to be the only significant and independent determinant of L&#95;RHI., Conclusions: In T2DM with HbA1c <8.0%, low 1,5-AG levels were associated with vascular endothelial dysfunction, suggesting it is a potentially useful marker for vascular endothelial dysfunction., Trial Registration: UMIN000015317.

Unlabelled: Patients with nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH) often have metabolic disorders including insulin resistance and type 2 diabetes mellitus (T2DM). We clarified the predictive factors in glucose metabolism for progression of hepatic fibrosis in patients with NAFLD by the 75-g oral glucose tolerance test (75gOGTT) and a continuous glucose monitoring system (CGMS). One hundred sixty-nine patients (68 female and 101 male patients) with biopsy-proven NAFLD with performance with 75gOGTT were enrolled and divided into four groups according to the stage of hepatic fibrosis (F0-3). The proportion of patients with T2DM significantly gradually increased, HbA1c and the homeostasis model assessment of insulin resistance were significantly elevated, and 1,5-anhydroglucitol (1,5-AG) was remarkably decreased with the progression of fibrosis. In the 75gOGTT, both plasma glucose and insulin secretion were remarkably increased with the progression of fibrosis. The only factor significantly associated with advanced fibrosis was 1,5-AG (P = 0.008) as determined by multivariate logistic regression analysis. We next evaluated the changes in blood glucose during 24 hours by monitoring with the CGMS to confirm the relationship between glycemic variability and progression of fibrosis. Variability of median glucose, standard deviation of median glucose (P = 0.0022), maximum blood glucose (P = 0.0019), and ΔMin-max blood glucose (P = 0.0029) were remarkably higher in severe fibrosis than in mild fibrosis., Conclusion: Hyperinsulinemia and hyperglycemia, especially glycemic variability, are important predictive factors in glucose impairment for the progression of hepatic fibrosis in NAFLD.

Background: At the start of their work, the European Bioanalysis Forum dried blood spots microsampling consortium did not form a dedicated team to investigate the spot homogeneity. However, two teams performed experiments that produced results relating to sample homogeneity., Results: The data, which were produced via two different approaches (a radiolabeled and a nonradiolabeled approach), are highly complementary and demonstrate clear effects on sample inhomogeneity due to the substrate type, compound and hematocrit levels., Conclusion: The results demonstrate that sample inhomogeneity is a significant hurdle to the use of dried blood spots for regulated bioanalysis that should be investigated further in the method establishment phase if the whole spot is not sampled.

Aims/hypothesis: Most pregnant women with type 1 diabetes mellitus achieve HbA1c targets; however, macrosomia remains prevalent and better pregnancy glycaemic markers are therefore needed. 1,5-Anhydroglucitol (1,5-AG) is a short-term marker of glycaemia, reflecting a period of 1 to 2 weeks. Its excretion rate depends on the renal glucose threshold and thus it is unclear whether it may be used in pregnant type 1 diabetes women. We evaluated 1,5-AG as a glycaemic marker and birthweight predictor in pregnant women with type 1 diabetes, and compared its performance with HbA1c., Methods: 1,5-AG and HbA1c were measured in 82 pregnant women with type 1 diabetes. In addition, 58 continuous glucose monitoring system (CGMS) records were available. Macrosomia was defined as birthweight >90th centile. The data were analysed with Pearson's correlations, and linear and logistic regression models. Receiver operating characteristic (ROC) analysis was used to evaluate third trimester 1,5-AG as a predictor of macrosomia., Results: Unlike HbA1c, 1,5-AG strongly correlated with CGMS indices: the AUC above 7.8 mmol/l (r = -0.66; p < 0.001), average maximum glucose (r = -0.58; p < 0.001) and mean glucose (r = -0.54; p < 0.001). In the third trimester, 1,5-AG was the strongest predictor of macrosomia, with ROC AUC 0.81 (95% CI 0.70, 0.89). In contrast, HbA1c in the third trimester had a ROC AUC of 0.69 (95% CI 0.58, 0.81). The best discrimination was achieved when both markers were used jointly, yielding a ROC AUC of 0.84 (95% CI 0.76, 0.93)., Conclusions/interpretation: In pregnant women with type 1 diabetes, 1,5-AG is a better glycaemic marker than HbA1c, as assessed by CGMS. A decreased third trimester 1,5-AG level, either singly or with HbA1c, is a strong predictor of macrosomia.

Background: The aim of this study was to evaluate the relationship between postprandial glucose level and atherosclerosis in patients without diabetes and cardiovascular disease by determining carotid ultrasonographic variables and serum levels of 1,5-anhydroglucitol (1,5-AG)., Methods: The subjects were 72 patients without diabetes and cardiovascular disease being treated for hypertension or dyslipidemia. The clinical characteristics of all subjects, including the serum level of 1,5-AG, which appears to be well suited for monitoring postprandial hyperglycemia, were evaluated after an overnight fast. The average intima-media thickness (IMT) and the average pulsatility index (PI) of the right and left common carotid arteries were determined with high-resolution ultrasonography and used as ultrasonographic variables. The subjects were divided into a lower 1,5-AG group (n = 36) and a higher 1,5-AG group (n = 36). We evaluated the relationship between clinical characteristics and ultrasonographic variables of the carotid artery in both groups., Results: The average PI in the Lower 1,5-AG group was significantly higher than that in the Higher 1,5-AG group, but the average IMT did not differ between the groups. Linear regression analysis, with the ultrasonographic variables as the dependent variables, with 1,5-AG as the independent variable, and adjusted for other clinical characteristics, showed significant correlation between 1,5-AG and the PI but not between 1,5-AG and IMT., Conclusion: Our results suggest that postprandial hyperglycemia increases carotid artery stiffness, but not morphological change, in patients without diabetes or cardiovascular disease.

To assess the efficacy and safety of adding sitagliptin, an oral dipeptidyl peptidase-4 inhibitor, in subjects with type 2 diabetes inadequately controlled with multiple daily insulin injections therapy (MDI). HbA1c, 1,5-anhydroglucitol (1,5-AG), body mass index (BMI), insulin doses, six-point self-measured plasma glucose (SMPG) profiles were assessed before, after 12 weeks, and after 24 weeks of MDI with 50 mg/day of sitagliptin in 40 subjects with type 2 diabetes. Safety endpoints included hypoglycemia and any adverse events. HbA1c significantly decreased during the first 12 weeks ( -0.64±0.60%), and was sustained over 24 weeks ( -0.69±0.85%). 1,5-AG increased significantly from 7.5±4.5 μg/mL at baseline to 9.6±5.5 μg/mL after 24 weeks. The bolus insulin dose at 12 weeks was decreased, and the mean plasma glucose, the SD of daily glucose, M-value, and the mean amplitude of glycemic excursions (MAGE) also decreased significantly as compared with baseline values. BMI and frequency of hypoglycemia were not changed significantly. Univariate linear regression analyses revealed that % change in HbA1c was significantly associated with BMI, and % changes in the indexes of glycemic instability (SD of daily glucose and MAGE) were significantly associated with age. In conclusion, adding sitagliptin to MDI significantly improved glycemic control and decreased the daily glucose fluctuation in subjects with type 2 diabetes inadequately controlled with MDI, without weight gain or an increase in the incidence of hypoglycemia. This trial was registered with UMIN (no. UMIN000010157).

Background: 1,5-Anhydroglucitol (1,5-AG), fructosamine, and glycated albumin are of increasing interest as alternative measures of hyperglycemia. We characterize the associations of these nontraditional glycemic markers with hemoglobin A(1c) (Hb A(1c)) and fasting glucose and assess their ability to identify people with diabetes., Methods: We conducted a cross-sectional comparison of 1,5-AG, fructosamine, and glycated albumin with Hb A(1c) and fasting glucose measurements in 1719 participants from the Atherosclerosis Risk in Communities Study. We evaluated nonlinear relationships using R(2) and F-statistics. Performance for identification of cases of diabetes was determined using the area under the curve (AUC). Diabetes was defined by Hb A(1c) ≥6.5%, fasting glucose ≥126 mg/dL (≥6.99 mmol/L), and/or a self-reported history of diagnosed diabetes., Results: Median values of Hb A(1c) and fasting glucose were 5.8% and 109 mg/dL (6.05 mmol/L), respectively; 17.3% of the study population had diagnosed diabetes. Glycated albumin, fructosamine, and 1,5-AG were more strongly correlated with Hb A(1c) compared with fasting glucose (all P values <0.05). Nonlinear models provided the best fit for describing the relationships of the alternative markers to Hb A(1c). When diabetes was defined by an Hb A(1c) ≥6.5%, fructosamine (AUC 0.83; 95% CI, 0.79-0.87) and glycated albumin (AUC 0.87; 95% CI, 0.83-0.90) performed comparably to fasting glucose (AUC 0.83; 95% CI, 0.79-0.87), while 1,5-AG performed worse (AUC 0.74; 95% CI, 0.69-0.78) for identifying cases of undiagnosed diabetes., Conclusions: Fructosamine and glycated albumin may be useful adjuncts to Hb A(1c) and fasting glucose. Future studies should examine these markers in situations in which fasting glucose or Hb A(1c) measurements are invalid or not available., (© 2012 American Association for Clinical Chemistry)

Postmortem diagnosis of diabetes and a diabetic coma can be difficult because of the lack of characteristic morphological findings. 1,5-Anhydroglucitol (1,5-AG), the 1-deoxy form of glucose, competes with glucose for reabsorption in the kidneys. Therefore, diabetics with a permanent hyperglycemia show significantly lower serum concentrations of 1,5-AG than non-diabetics. A liquid chromatography-mass spectrometric method for the determination of 1,5-AG in serum and postmortem blood was developed and validated according to international guidelines. Linearity was given between 1 μg/ml and 50 μg/ml. Recovery rates ranged between 70.8% and 89.8%, the limit of quantification of the procedure was 0.20 μg/ml, limit of quantification was 0.55 μg/ml. Serum of 199 diabetics and 116 non-diabetics and femoral blood of 31 diabetic and 27 non-diabetic deceased was measured. Average concentrations were significantly (p<0.001) higher in non-diabetics compared to diabetics ante and postmortem. Seven of the diabetics may have died because of a hyperglycemic coma indicated by a sum formula of Traub>450 mg/dl. 1,5-AG average concentrations in these deceased were not significantly different to diabetics which did not die because of a diabetic coma. Concentrations of 1,5-AG give a hint for not well controlled diabetes antemortem and postmortem and can be assumed as an additional and alternative information postmortem to the measurement of HbA1c or fructosamine., (Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.)

Background: No previous studies have compared the DPP-4 inhibitors vildagliptin and sitagliptin in terms of blood glucose levels using continuous glucose monitoring (CGM) and cardiovascular parameters., Methods: Twenty patients with type 2 diabetes mellitus were randomly allocated to groups who received vildagliptin then sitagliptin, or vice versa. Patients were hospitalized at 1 month after starting each drug, and CGM was used to determine: 1) mean (± standard deviation) 24-hour blood glucose level, 2) mean amplitude of glycemic excursions (MAGE), 3) fasting blood glucose level, 4) highest postprandial blood glucose level and time, 5) increase in blood glucose level after each meal, 6) area under the curve (AUC) for blood glucose level ≥180 mg/dL within 3 hours after each meal, and 7) area over the curve (AOC) for daily blood glucose level <70 mg/dL. Plasma glycosylated hemoglobin (HbA1c), glycoalbumin (GA), 1,5-anhydroglucitol (1,5AG), immunoreactive insulin (IRI), C-peptide immunoreactivity (CPR), brain natriuretic peptide (BNP), and plasminogen activator inhibitor-1 (PAI-1) levels, and urinary CPR levels, were measured., Results: The mean 24-hour blood glucose level was significantly lower in patients taking vildagliptin than sitagliptin (142.1 ± 35.5 vs. 153.2 ± 37.0 mg/dL; p = 0.012). In patients taking vildagliptin, MAGE was significantly lower (110.5 ± 33.5 vs. 129.4 ± 45.1 mg/dL; p = 0.040), the highest blood glucose level after supper was significantly lower (206.1 ± 40.2 vs. 223.2 ± 43.5 mg/dL; p = 0.015), the AUC (≥180 mg/dL) within 3 h was significantly lower after breakfast (484.3 vs. 897.9 mg/min/dL; p = 0.025), and urinary CPR level was significantly higher (97.0 ± 41.6 vs. 85.2 ± 39.9 μg/day; p = 0.008) than in patients taking sitagliptin. There were no significant differences in plasma HbA1c, GA, 1,5AG, IRI, CPR, BNP, or PAI-1 levels between patients taking vildagliptin and sitagliptin., Conclusions: CGM showed that mean 24-h blood glucose, MAGE, highest blood glucose level after supper, and hyperglycemia after breakfast were significantly lower in patients with type 2 diabetes mellitus taking vildagliptin than those taking sitagliptin. There were no significant differences in BNP and PAI-1 levels between patients taking vildagliptin and sitagliptin., Trial Registration: UMIN000007687.

Objective: To assess the relationship between 1,5-anhydroglucitol (AG) levels, which are a marker of glycemic control, and stages of chronic kidney disease (CKD)., Research Design and Methods: This was a cross-sectional study with 269 subjects with type 2 diabetes who were divided into four groups based on estimated glomerular filtration rate (eGFR) using Modification of Diet in Renal Disease (eGFR(MDRD)) formula: 57 in control, 111 in CKD stages 1-2, 78 in stage 3, and 23 in stages 4-5., Results: The study groups differed significantly with respect to 1,5-AG and fasting plasma glucose (FPG), age, duration of diabetes, blood pressure, HDL, and percentage of antihypertension or antidyslipidemia medication use. Stepwise multivariate regression analyses showed that 1,5-AG levels in the control group, the CKD stages 1-2 group, and the CKD stage 3 group could be explained by HbA(1c), age, duration of diabetes, FPG, and antihypertension medication. However, eGFR(MDRD) was the only independent determinant of 1,5-AG levels in CKD stages 4-5. Logarithmic transformed 1,5-AG values (ln[1,5-AG]) had significant inverse correlations with HbA(1c) and FPG levels for CKD stages 1-2 and CKD stage 3 (all P < 0.001). However, associations between ln(1,5-AG) and HbA(1c) or FPG were insignificant for CKD stages 4-5 (P = 0.274 and P = 0.080, respectively)., Conclusions: This study demonstrated that 1,5-AG levels do not appear to be influenced by mild or moderate renal dysfunction, suggesting it is a reliable glycemic marker in type 2 diabetes with CKD stages 1-3.