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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.)

Objective: To explore the relationship between serum 1, 5-dehydratoglucitol (1, 5-AG) level and insulin resistance, microvascular complications in patients with type 2 diabetes mellitus (T2DM). Methods: The clinical data of 836 patients with T2DM admitted to the Changsha Central Hospital Affiliated to University of South China from May to December 2023 were retrospectively and cross-sectionally analyzed. Serum 1, 5-AG levels were detected by pyranose oxidase method. According to the microvascular complications (diabetic peripheral neuropathy, diabetic nephropathy, diabetic retinopathy), the patients were divided into simple group (no microvascular complications, n =490), complication group 1 (1 microvascular complications, n =217), and complication group 2 (2 or more microvascular complications, n =129). The relationship between serum 1, 5-AG level and the related indicators of insulin resistance in T2DM patients were explored by Spearman correlation analysis, and the influencing factors of microvascular complications in T2DM patients were explored by multiple ordered logistic regression analysis. Results: The levels of FBG(fasting blood glucose) [(7.37±0.56) mmol/L], FINS(fasting insulin) [(11.34±1.86) mU/L] and HOMA-IR(homeostatic model assessment of insulin resistance) (0.96±0.31) in simple group were lower than those in complication group 1 [(8.37±1.02) mmol/L, (16.26±2.32) mU/L, (1.32±0.41)], complication group 2 [(10.25±2.13) mmol/L, (18.53±2.67) mU/L, (1.54±0.44)], and FBG, FINS and HOMA-IR in complication group 1 were lower than those in complication group 2, and the differences were statistically significant ( F =537.470, 791.690, 136.340, P <0.001). Serum 1, 5-AG level in simple group [77.16 (16.30, 128.07) μg/ml] was higher than that in complication group 1 [51.05 (14.67, 63.18) μg/ml] and complication group 2 [30.42 (12.53, 47.26) μg/ml], and the serum level of 1, 5-AG in complication group 1 was higher than that in complication group 2, and the difference was statistically significant ( H =210.020, P <0.001). The results of Spearman correlation analysis showed that serum 1, 5-AG level was negatively correlated with FBG, FINS and HOMA-IR in T2DM patients ( r =-0.431, -0.372, -0.546, P <0.001). The results of multiple ordered logistic regression analysis showed that Longer duration of diabetes ( OR =2.261, 95% CI : 1.564-3.269), increased HbA1c ( OR =2.040, 95% CI : 1.456-2.858), and increased HOMA-IR ( OR =2.158, 95% CI : 1.484-3.137) and decreased 1, 5-AG ( OR =2.512, 95% CI : 1.691-3.732) were independent risk factors for microvascular complications in T2DM patients ( P <0.05). The results of ROC curve analysis showed that the area under the curve of serum 1, 5-AG in the identification of one microvascular complication was 0.763 (95% CI : 0.731-0.795), and the area under the curve of serum 1, 5-AG in the identification of two or more microvascular complications was 0.730 (95% CI : 0.692-0.767). Conclusion: Serum 1, 5-AG level is negatively correlated with insulin resistance in T2DM patients. Low serum 1, 5-AG level may be an independent risk factor for microvascular complications in T2DM patients.

Aims: This study aimed to evaluate the ability of HbA 1c combined with glycated albumin (GA) or 1,5-anhydroglucitol (1,5-AG) to detect diabetes in residents of Jiangsu, China., Methods: The oral glucose tolerance test (OGTT) was performed on 2184 people in Jiangsu. HbA 1c , GA, 1,5-AG and other serum biochemical parameters were measured. Receiver operating characteristic curves were plotted to determine the optimal thresholds of HbA 1c , GA and 1,5-AG according to the Youden index., Results: (1) The optimal thresholds of HbA 1c , GA and 1,5-AG for the screening of diabetes were ≥45 mmol/mol (6.3%), ≥13.0% and ≤23.0 μg/ml, respectively. (2) The sensitivities of HbA 1c combined with GA and 1,5-AG were both 85%, higher than that of HbA 1c (70%, p < 0.001)., Conclusions: This study is suitable for cases where plasma glucose is unavailable. Among the residents of Jiangsu, HbA 1c combined with GA or 1,5-AG can improve the sensitivity of diabetes screening, reduce the miss rate and save the use of OGTT. GA and 1,5-AG are superior in individuals with mild glucose metabolism disorder. GA enhances the detection of diabetes in the nonobese, and 1,5-AG enhances the detection in those with hyperuricaemia., (© 2021 Diabetes UK.)

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.)

In this paper, a novel silicon-based light-addressable potentiometric sensor (LAPS) has been designed for the detection of 1,5-anhydroglucitol (1,5-AG) in human serum. Reduced graphene oxide-chitosan-ferrocene (RGO-CS-Fc)/AuNPs nanohybrids and pyranose oxidase (PROD) enzyme is used to fabricate biological sensitive membrane unit by layer-by-layer assembly technology. When a bias voltage is provided to the LAPS system, the catalytic oxidation reaction between 1,5-AG and PROD to produce H 2 O 2 . The by-product H 2 O 2 can oxidize Fc(Fe 2+ ) ions in RGO-CS-Fc nanohybrids into Fc(Fe 3+ ) ions, which cause the potential of the sensitive membrane surface to change and the potential shift of I-V curve will generate a corresponding offset response. Under the optimal conditions, the potential shift of the LAPS is linearly related to the concentration of 1,5-AG at 10 µg·mL -1 -350 µg·mL -1 with the correlation coefficient of 0.97414. The sensitivity is 0.44273 mV/µg·mL -1 and the lowest detection limit is 10 µg·mL -1 . In addition, the biosensor showed good specificity, acceptable stability and satisfactory recovery rates (91.28%-107.66%), which would be a potential testing methods in actual clinical samples., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Aim: Angiotensin receptor blockers (ARBs) reduce vascular complications in diabetes independently of blood pressure. Experimental studies suggested that ARBs may restore the detoxifying enzyme glyoxalase 1, thereby lowering dicarbonyls such as methylglyoxal. Human data on the effects of ARBs on plasma dicarbonyl levels are lacking. We investigated, in individuals with type 2 diabetes, whether irbesartan lowered plasma levels of the dicarbonyls methylglyoxal, glyoxal, 3-deoxyglucosone and their derived advanced glycation end products (AGEs), and increased d-lactate, reflecting greater methylglyoxal flux., Methods: We analysed a subset of the Irbesartan in Patients with T2D and Microalbuminuria (IRMA2) study. We measured plasma dicarbonyls methylglyoxal, glyoxal and 3-deoxyglucosone, free AGEs and d-lactate using ultra-performance liquid chromatography tandem mass-spectrometry (UPLC-MS/MS) in the treatment arm receiving 300 mg irbesartan (n = 121) and a placebo group (n = 101) at baseline and after 1 and 2 years. Effect of treatment was analysed with repeated measurements ANOVA., Results: There was a slight, but significant difference in baseline median methylglyoxal levels [placebo 1119 (907-1509) nmol/l vs. irbesartan 300 mg 1053 (820-1427) nmol/l], but no significant changes were observed in any of the plasma dicarbonyls over time in either group and there was no effect of irbesartan treatment on plasma free AGEs or d-lactate levels at either 1 or 2 years., Conclusion: Irbesartan treatment does not change plasma levels of the dicarbonyls methylglyoxal, glyoxal and 3-deoxyglucosone, free AGEs or d-lactate in type 2 diabetes. This indicates that increased dicarbonyls in type 2 diabetes are not targetable by ARBs, and other approaches to lower systemic dicarbonyls are needed in type 2 diabetes. (Clinical Trial Registry No: #NCT00317915)., (© 2020 The Authors. Diabetic Medicine published by John Wiley & Sons Ltd on behalf of Diabetes UK.)

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: Serum 1,5-anhydroglucitol (1,5-AG) is a new glycemic marker which can reflect glucose fluctuation over 3 to 7 days and is now increasingly used to monitor glucose control and to screen for diabetes. However, 1,5-AG has not been widely used in China due to lack of epidemiological support. Our study aims to establish the reference intervals for a population with normal glucose tolerance in Jiangsu Province and to explore the determinants of these intervals., Method: The study enrolled 646 healthy adults aged 20 to 70 years in Jiangsu Province in 2018 after oral glucose tolerance test. 1,5-AG, fasting and 2-hour glucose, UA, liver enzyme, serum lipid, creatinine, and glycosylated hemoglobin were measured. We calculated reference intervals using the parametric method and examined the relationship between 1,5-AG and influence factors., Results: The average age of the participants was 50.5 ± 9.0 years, and 69.5% of them were females. The reference intervals were 15.8 to 52.6 μg/mL for males and 14.3 to 48.0 μg/mL for females. Among females, the reference intervals were 13.9 to 45.3 and 14.6 to 49.6 μg/mL for menopausal and postmenopausal females, respectively. Males showed higher 1,5-AG concentrations than females, and postmenopausal females had higher 1,5-AG than menopausal females. There was a positive correlation between uric acid and 1,5-AG in both genders. Positive correlation between 1,5-AG and age was only observed in females., Conclusion: We established reference intervals for 1,5-AG in Jiangsu Province, and the level of 1,5-AG is affected by sex, uric acid, and age., (© 2020 Ruijin Hospital, Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.)

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.

Aims: This study aimed to explore the level of and changes in the 1,5-anhydroglucitol × glycated hemoglobin A 1c /100 (AH index, AHI) associated with different glucose metabolism statuses and to evaluate the islet function and insulin sensitivity of patients with type 2 diabetes (T2DM) with different AHI levels., Methods: Of the 3562 subjects enrolled in this study, 1697 had T2DM. The disposition index (DI) was the product of islet secretion function and insulin sensitivity-related indexes., Results: The mean AHI level was 1.0 (0.7-1.3) in the general population, while the mean AHI level in the T2DM group was 0.8 (0.5-1.2), which was significantly lower than that in the impaired glucose regulation and normal glucose tolerance group (both 1.2 (0.9-1.5), both P < 0.01). We further divided patients with T2DM into four subgroups according to the quartile of AHI. The results showed that with the increase in AHI level, the homeostasis model assessment of insulin resistance (HOMA-IR) decreased, while HOMA-β, insulin generation index, insulin sensitivity index, and DI increased (all P for trend  < 0.01). Multivariate logistic regression showed that the odds ratios for a low DI for increasing levels of AHI were 1.00, 0.22 (0.16-0.29), 0.16 (0.11-0.22), and 0.09 (0.06-0.13), showing a decreasing trend (P for trend  < 0.05)., Conclusion: The AHI could reflect the variation in glycemic disorder and the function of islet β cells. The lower the AHI, the worse the glycemic disorder, as well as the islet β-cell function.

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.)

Objective: Dysglycemia is prevalent in cystic fibrosis (CF) but screening with annual oral glucose tolerance tests (OGTT) can be burdensome. We investigated alternate glycemic markers-hemoglobin A1c (HbA1c), 1,5-anhydroglucitol (1,5AG), fructosamine (FA), and glycated albumin (GA)-as screening tests for CF-related diabetes (CFRD) and pre-diabetes (CFPD) in youth with CF as defined by the gold-standard OGTT 2-hour glucose (2hG)., Methods: Youth 10 to 18 years with CF had a 1,5AG, FA, GA, HbA1c, and 2-hour OGTT collected. Correlations between all glycemic markers and 2hG were evaluated. Area under the receiver operative characteristic (ROC-AUC) curves were generated. Optimal cut points for predicting CFPD (2hG ≥ 140 mg/dL) and CFRD (2hG ≥ 200 mg/dL) were determined., Results: Fifty-eight youth with CF were included (2hG < 140, n = 16; CFPD, n = 33; CFRD, n = 9; 41% male, mean ± SD age 14.2 ± 3.6 years, BMI z-score 0.0 ± 0.8, % predicted forced expiratory volume in 1 second [FEV1] 89.9 ± 15.1, % predicted forced vital capacity [FVC] 103.2 ± 14.6). ROC-AUC's for all alternate markers were low for CFPD (0.52-0.67) and CFRD (0.56-0.61). At a cut point of 5.5%, HbA1c had 78% sensitivity (95% CI: 0.45-0.94) and 41% specificity (95% CI: 0.28-0.55) for identifying CFRD, correlating to a ROC-AUC of 0.61 (95% CI: 0.42-0.8)., Conclusions: All alternate markers tested demonstrate poor diagnostic accuracy for identifying CFRD by 2hG., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Purpose: A glycemic control marker to predict neonatal diabetic complications is unavailable. We aimed to examine if 1,5-anhydroglucitol (1,5-AG) can predict neonatal complications in women with diabetes in pregnancy., Methods: Prospective observational study from December 2011 to August 2013. We recruited 105 women, 70 diabetic (gestational and pregestational) and 35 nondiabetic. 1,5-AG at birth was compared between the two groups. In the diabetic group 1,5-AG, HbA1c, and fructosamine were measured before glycemic control initiation (first visit), after 4-6 weeks (second visit), and at delivery. Women were divided to poor (1,5-AG values below median at birth) and good (1,5-AG values at median and above) glycemic control groups. Mean daily glucose charts were collected. The primary outcome was a composite of neonatal diabetic complications: respiratory distress, hypoglycemia, polycythemia, hyperbilirubinemia, and large for gestational age., Results: Mean 1,5-AG in the nondiabetic group was similar to that of the diabetic group without the composite outcome and was significantly higher than in the diabetic group with the composite outcome. The rate of the composite outcome was higher in the poor glycemic control group compared with the good glycemic control group (adjusted odds ratio (OR) 3.8 95% CI [1.2-12.3]). Only 1,5-AG was inversely associated with the composite outcome at all time points; the second visit was the only independent risk factor in multivariable logistic regression (OR 0.7 95% CI 0.54-0.91). The rest of the glycemic markers were not associated with neonatal composite outcome., Conclusions: 1,5-AG is inversely associated with neonatal diabetic complications and is superior to other glycemic markers in predicting those complications.

Background: Type 1 diabetes (T1D) is an autoimmune disease and the leading form of diabetes among young white people. 1,5-Anhydroglucitol (1,5-AG), a nontraditional biomarker of postprandial glycemic control (after 1 - 3 days to 2 weeks), may be useful in T1D screening. We studied serum 1,5-AG concentration as a potential biomarker for T1D screening and diagnosis in adults and children., Methods: In this case-control study, adults (n = 121; age, 19 - 61 years) and children (n = 19; age, 8 - 14 years) with T1D were matched with healthy subjects (n = 242) according to gender and age. Serum 1,5-AG levels were measured enzymatically (GlycoMark Inc., NY, USA)., Results: Patients showed no symptoms of overt kidney disease, assessed by serum creatinine concentrations. The median (25th - 75th percentile) 1,5-AG concentrations for the control group compared with the T1D group were 155 (128 - 183) vs. 21 (14 - 34) µmol/L in adults and 190 (158 - 237) vs. 20 (12 - 30) µmol/L in children (p < 0.001 for both). Receiver operating characteristic curves showed that 1,5-AG cutoffs of ≤ 113 and ≤ 79 µmol/L for adult men and women, respectively, and ≤ 57 µmol/L for children of both genders had > 95% sensitivity and specificity for both groups., Conclusions: Our results suggest that serum 1,5-AG concentration may be useful as an adjunct measure of hyperglycemia for diagnosing T1D and has the potential to screen for T1D in high-risk subjects.

Aim: Advanced glycation end products and their precursors cause vascular damage through oxidative stress. We investigated the hypothesis that methylglyoxal (MG), 3-deoxyglucosone (3-DG) and pentosidine influence outcomes of chronic kidney disease (CKD) patients., Methods: We conducted a 3 years prospective observational study involving 150 outpatients at CKD stages 3-5. At enrolment, MG, 3-DG and pentosidine plasma concentrations were measured; patients were divided into tertiles according to the concentration of each substance. The primary endpoint was death, a cardiovascular event or end-stage renal disease. Survival analysis was performed using the Cox regression model., Results: The patients' mean age was 62 ± 12 years, 97 were men, and 20 had diabetic nephropathy. The mean estimated glomerular filtration rate was 25.0 ± 12.1 mL/min per 1.73 m 2 , which negatively correlated with MG but not with 3-DG and pentosidine. Forty-eight patients reached the primary endpoint. Compared with the lowest MG tertile, the hazard ratio for the primary endpoint was 7.57 (95% confidence interval (CI): 1.71-33.54) in the middle tertile and 27.00 (CI: 6.46-112.82) in the highest tertile. When adjusted for characteristics at baseline, the corresponding hazard ratio decreased to 2.09 (CI: 0.37-11.96) and 6.13 (CI: 0.97-38.82), but MG tertile remained an independent risk factor for the primary endpoint. However, 3-DG and pentosidine were not related to the primary outcome., Conclusion: Methylglyoxal has a close clinical association with CKD. Higher MG concentrations may contribute renal function deterioration in CKD. In CKD patients, MG concentration might be useful when determining the prognosis., (© 2018 Asian Pacific Society of Nephrology.)

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.

Aims: To evaluate 1,5-anhydroglucitol (1,5-AG) according to clinical outcomes and assess the effects of glucose- and blood pressure-lowering interventions on change in 1,5-AG levels in people with type 2 diabetes., Methods: We measured 1,5-AG in 6826 stored samples at baseline and in a random subsample of 684 participants at the 1-year follow-up visit in the ADVANCE trial. We examined baseline 1,5-AG [< 39.7, 39.7-66.2, ≥ 66.2 μmol/L (<6, 6-10, ≥10 μg/mL)] and microvascular and macrovascular events and mortality using Cox regression models during 5 years of follow-up. Using an intention-to-treat approach, we examined 1-year change in 1,5-AG (mean and percent) in response to the glucose- and blood pressure-lowering interventions in the subsample., Results: Low 1,5-AG level [<39.7 μmol/L vs ≥ 66.2 μmol/L (<6 μg/mL vs ≥10 μg/mL)] was associated with microvascular events (hazard ratio 1.28, 95% confidence interval 1.03-1.60) after adjustment for risk factors and baseline glycated haemoglobin (HbA1c); however, the associations for macrovascular events and mortality were not independent of HbA1c. The glucose-lowering intervention was associated with a significant 1-year increase in 1,5-AG (vs standard control) of 6.69 μmol/L (SE 2.52) [1.01 μg/mL (SE 0.38)], corresponding to an 8.26% (SE 0.10%) increase from baseline. We also observed an increase in 1,5-AG of similar magnitude in response to the blood pressure intervention independent of the glucose-lowering effect., Conclusions: Our results suggest that 1,5-AG is a marker of risk in adults with type 2 diabetes, but only for microvascular events independently of HbA1c. We found that 1,5-AG was improved (increased) in response to an intensive glucose-lowering intervention, although the independent effect of the blood pressure-lowering intervention on 1,5-AG suggests potential non-glycaemic influences., (© 2019 John Wiley & Sons Ltd.)

Background: Serum carotenoids are commonly used as biomarkers of fruit and vegetable (F/V) intake in the general population. Although hyperglycemia induces oxidative stress, it is unknown whether this pathway is associated with lower serum carotenoid concentrations in individuals with type 1 diabetes. Consequently, the utility of serum carotenoids as markers of F/V intake in individuals with type 1 diabetes is unclear., Objective: The study objectives were: 1) to investigate the relationship of glycemic control, oxidative stress, dietary carotenoid and F/V intake with serum carotenoid concentrations in youth with type 1 diabetes and 2) to determine whether glycemic control or oxidative stress moderates the association of carotenoid and F/V intake with serum carotenoids., Design: The study was a secondary analysis of baseline data from youth with type 1 diabetes. Blood samples were drawn from youth with type 1 diabetes to assess carotenoids and markers of glycemic control (glycated hemoglobin and 1,5-anhydroglucitol); urine samples were used to assess oxidative stress (8-iso-prostaglandin F 2α ); and 3-day diet records completed by families were used to determine F/V and carotenoid intake., Participants/setting: The study participants were youth with type 1 diabetes (n=136; age range: 8 to 16.9 years; diabetes duration ≥1 year; glycated hemoglobin: 5.8% to 11.9%) enrolled in a nutrition intervention trial from 2010 to 2013 at a tertiary diabetes center in Boston, MA., Main Outcome Measures: Serum carotenoids (total carotenoids and α-carotene, β-carotene, lycopene, β-cryptoxanthin, and lutein+zeaxanthin)., Statistical Analysis: Regression analyses were used to estimate the association of glycemic control, oxidative stress, F/V and carotenoid intake with serum carotenoids, as well as the role of glycemic control and oxidative stress in moderating diet-serum carotenoid associations., Results: Greater F/V intake (β=0.35, P<0.001) and carotenoid intake (β=0.28, P<0.01) were associated with higher total serum carotenoids, and no moderation by glycemic control or oxidative stress was observed. Greater hyperglycemia, as indicated by lower 1,5-anhydroglucitol (β=0.27, P<0.01), was related to lower serum carotenoids; however, glycated hemoglobin was not associated with serum carotenoids. 8-Iso-prostaglandin F2α was not associated with glycemic control or serum carotenoids., Conclusions: Findings support the validity of serum carotenoids as markers of F/V and carotenoid intake in youth with type 1 diabetes., (Published by Elsevier Inc.)

Serum 1,5-anhydro-d-glucitol (1,5-AG) concentrations are short-term hyperglycemia indicators and were used to estimate the effects of serum vitamin D concentrations on glycemic control in patients with type 2 diabetes mellitus (T2DM). Serum concentrations of 1,5-AG, 25-hydroxyvitamin D 2 (25-OH-D 2 ), and 25-hydroxyvitamin D 3 (25-OH-D 3 ) from 11 026 patients with T2DM, hospitalized in the Department of Endocrinology, Shanghai Central Hospital of Xuhui District, from January 2012 to June 2015, were retrospectively analyzed. Correlation analyses revealed correlations between 1,5-AG and 25-OH-D 3 ( r = 0.05, P < 0.001), age ( r = 0.05, P < 0.001), and 25-OH-D 2 + 25-OH-D 3 (25-OH-D 2 /D 3 ) ( r = 0.05, P < 0.001). Linear regression analyses revealed associations between 1,5-AG and 25-OH-D 2 /D 3 (adjusted R 2 = 0.003) as well as 25-OH-D 3 (adjusted R 2 = 0.002). In males with 1,5-AG levels ≤11.55 mg/L, serum concentrations of 25-OH-D 2 ( P < 0.001) and 25-OH-D 3 ( P = 0.001) were significantly lower than those in diabetic males with 1,5-AG levels >11.55 mg/L. Serum concentrations of 25-OH-D 2 /D 3 in patients with T2DM were associated with 1,5-AG retention, suggesting involvement in glycemic control.

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.

Purpose: To investigate the utility of biomarkers of maturity-onset diabetes of the young (MODY), high-sensitivity C-reactive protein (hsCRP), and 1,5-anhydroglucitol (1,5-AG) in conjunction with other clinical and laboratory features to improve diagnostic accuracy and provide a diagnostic algorithm for HNF1A MODY., Methods: We examined 77 patients with HNF1A MODY, 88 with GCK MODY mutations, 99 with type 1 diabetes, and 92 with type 2 diabetes. In addition to 1,5-AG and hsCRP, we considered body mass index (BMI), fasting glucose, and fasting serum C-peptide as potential biomarkers. Logistic regression and receiver operating characteristic curves were used in marker evaluation., Results: Concentration of hsCRP was lowest in HNF1A MODY (0.51 mg/l) and highest in type 2 diabetes (1.33 mg/l). The level of 1,5-AG was lowest in type 1 diabetes and HNF1A MODY, 3.8 and 4.7 μg/ml, respectively, and highest (11.2 μg/ml) in GCK MODY. In the diagnostic algorithm, we first excluded patients with type 1 diabetes based on low C-peptide (C-statistic 0.98) before using high BMI and C-peptide to identify type 2 diabetes patients (C-statistic 0.92). Finally, 1,5-AG and hsCRP in conjunction yielded a C-statistic of 0.86 in discriminating HNF1A from GCK MODY. We correctly classified 92.9% of patients with type 1 diabetes, 84.8% with type 2 diabetes, 64.9% HNF1A MODY, and 52.3% GCK MODY patients., Conclusions: Plasma 1,5-AG and serum hsCRP do not discriminate sufficiently HNF1A MODY from common diabetes types, but could be potentially useful in prioritizing Sanger sequencing of HNF1A gene.

Purpose: To investigate the reliability of 1,5-anhydroglucitol (1,5-AG) in diabetes with mild or moderate renal dysfunction., Methods: 668 patients diagnosed with diabetes as DM group and 336 healthy controls as non-DM group were enrolled in this study. DM group was divided into four groups according to estimated glomerular filtration rate (eGFR). Serum concentrations of 1,5-AG, fructosamine (FMN) and glycated hemoglobin (HbA1c) were assayed via the enzymatic method, the nitro reduction four nitrogen thiazole blue test,high performance liquid chromatography respectively., Results: In diabetic Patients with eGFR≥30 mL/min, significant negative association still existed between logarithmic transformed 1,5-AG values (ln1,5-AG) and HbA1c (all P<0.001) as well as fasting plasma glucose (FPG) (all P<0.05). Besides, eGFR was not one of the determinants of 1,5-AG levels in both DM group (standard β=-0.049, P=0.383 ) and healthy controls (r=-0.095, P=0.084 ). Stepwise multiple linear regression showed that serum uric acid (UA) is one of the influencing factors of 1,5-AG (standard β=0.119, P=0.015) and among the three glycemic markers, only HbA1c was found to be correlated with the homeostasis model assessment for b-cell function (HOMA-β) (standard β=0.097, P=0.012)., Conclusions: 1,5-AG values remain reliable as a glycemic control marker In diabetes with mild or moderate dysfunction. Serum UA was significantly and positively correlated with 1,5-AG levels. HbA1c may be a good biomarker for insulin resistance compared with 1,5-AG and FMN., Competing Interests: No conflict of interest has been declared by the authors., (© Georg Thieme Verlag KG Stuttgart · New York.)

Objective: 1,5 Anhydroglucitol (1,5 AG) is reported to be a more sensitive marker of glucose variability and short-term glycemic control (1-2 weeks) in patients with type1 and type 2 diabetes. However, the role of 1,5 AG in gestational diabetes mellitus (GDM) is not clear. We estimated the serum levels of 1,5 AG in pregnant women with and without GDM., Methods: We recruited 220 pregnant women, 145 without and 75 with GDM visiting antenatal clinics in Tamil Nadu in South India. Oral glucose tolerance tests (OGTTs) were carried out using 82.5 g oral glucose (equivalent to 75 g of anhydrous glucose) and GDM was diagnosed based on the International Association of Diabetes and Pregnancy Study Group criteria. Serum 1,5 AG levels were measured using an enzymatic, colorimetric assay kit (Glycomark®, New York, NY). Receiver operating characteristic (ROC) curves were used to identify 1,5 AG cut-off points to identify GDM., Results: The mean levels of the 1,5 AG were significantly lower in women with GDM (11.8 ± 5.7 μg/mL, p < 0.001) compared to women without GDM (16.2 ± 6.2 μg/mL). In multiple logistic regression analysis, 1.5 AG showed a significant association with GDM (odds ratio [OR]: 0.876, 95% confidence interval [CI]: 0.812-0.944, p < 0.001) after adjusting for potential confounders. 1,5 AG had a C statistic of 0.693 compared to Fructosamine (0.671) and HbA1c (0.581) for identifying GDM. A 1,5 AG cut-off of 13.21 μg/mL had a C statistic of 0.6936 (95% CI: 0.6107-0.7583, p < 0.001), sensitivity of 67.6%, and specificity of 65.3% to identify GDM., Conclusion: 1,5AG levels are lower in pregnant women with GDM compared to individuals without GDM., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

The presence of α‑dicarbonyl compounds (α-DCs) in vivo has been associated with the development of complications of diabetes mellitus (DM) and also with other chronic diseases. Therefore, quantitative analysis of α-DCs in body fluids is crucial to understand their roles in the formation of these chronic diseases. We established in this study a practical HPLC-UV method to measure 3‑deoxyglucosone (3-DG), glyoxal (GO), methylglyoxal (MGO), diacetyl (DA), and pentane‑2,3‑dione (PD) in blood plasma using 4‑(2,3‑dimethyl‑6‑quinoxalinyl)‑1,2‑benzenediamine (DQB) as a derivatizing reagent. The derivatizing reaction could be carried out quickly under mild conditions and the HPLC determination is simple, sensitive, and easy to operate. The recoveries of the α-DCs are between 85.26% and 110.20% (intra-day) and 87.25% and 103.18% (inter-day); the RSDs are between 1.28% and 5.69% (intra-day) and 2.26% and 6.34% (inter-day). We found the plasma levels of 3-DG, GO, and MGO in the diabetic patients are all significantly higher than those in healthy subjects. The results also show that the contents of GO and MGO in diabetic nephropathy (DN) patients are both significantly higher than those in simple T2DM patients. Moreover, it is found for the first time that the plasma level of GO might be a potential predictor of DN. The developed method would be useful for the measurements of the plasma α-DCs and the data acquired could be informative in the diagnosis of DM complications., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: 1,5-anhydroglucitol (1,5-AG) is a validated marker of short-term glycemic control. We determined the reference intervals of 1,5-AG in different age groups and during pregnancy., Methods: Blood samples were collected from 2303 Euro-Brazilian healthy subjects: 580 children, 496 adolescents, 922 adults matched by age and sex, and 305 pregnant women in four gestational periods. Serum 1,5-AG was measured using an enzymatic reagent in an automated system., Results: The calculated reference intervals (nonparametric, 2.5th-97.5th) for males and females were, respectively: children, 96-302 and 89-277 μmol/l; adolescents, 84-311 and 79-277 μmol/l; and adults, 80-260 and 62-241 μmol/l. Males consistently showed significantly higher concentrations than females. 1,5-AG reference intervals in pregnant women were 56-298 μmol/l at <23 weeks gestation (n = 110), 37-166 μmol/l at 24-28 weeks gestation (n = 106), 34-155 μmol/l at 29-32 weeks gestation (n = 52), and 33-246 μmol/l at >32 weeks gestation (n = 37). No significant differences in 1,5-AG concentration were observed between non-pregnant and pregnant women at <23 weeks of gestation. A negative correlation (r = -0.287; p < .001) between 1,5-AG concentration and age was observed., Conclusions: The reference intervals for 1,5-AG were affected by sex and age., (Copyright © 2018. Published by Elsevier B.V.)

Strict glycaemic management is the cornerstone of metabolic control in gestational diabetes mellitus (GDM). Current monitoring standards involve self-monitoring plasma glucose (SMBG) and haemoglobin A1c (HbA1c). However, both have important limitations. SMBG only reflects instantaneous blood glucose and the inconvenience of self-collecting blood frequently results in poor compliance. HbA1c provides information on blood glucose levels from the previous 2 to 3 months and it is influenced by iron-deficient states, common during pregnancy. There is an urgent need for new shorter-term glycaemic markers, as glycated albumin, fructosamine or 1,5-anhydroglucitol. Glycated albumin seems especially interesting as it provides information on blood glucose levels over the foregoing 2-3 weeks and it is not influenced by iron deficiency or the dilutional anaemia of pregnancy. Fructosamine has a precise and inexpensive measurement and it is not affected by haemoglobin characteristics. This review further discusses the potential value of these non-traditional indicators of glycaemic control in patients with GDM, outlining their possible future applications.

Background and Aims: Traditional glycemic markers, fasting glucose and hemoglobin A1c (HbA1c), predict incident peripheral artery disease (PAD). However, it is unknown whether nontraditional glycemic markers, fructosamine, glycated albumin, and 1,5-anhydroglucitol, are associated with PAD and whether these glycemic markers demonstrate particularly strong associations with severe PAD, critical limb ischemia (CLI)., Methods: We quantified the associations of these five glycemic markers with incident PAD (hospitalizations with PAD diagnosis or leg revascularization) in 11,634 ARIC participants using Cox regression models. Participants were categorized according to diabetes diagnosis and clinical cut-points of glycemic markers (nontraditional glycemic markers were categorized according to percentiles corresponding to the HbA1c cut-points)., Results: Over a median follow-up of 20.7 years, there were 392 cases of PAD (133 were CLI with tissue loss). HbA1c was more strongly associated with incident PAD than fasting glucose, with adjusted hazard ratios (HR) 6.00 (95% CI, 3.73-9.66) for diagnosed diabetes with HbA1c ≥ 7% and 3.53 (2.39-5.22) for no diagnosed diabetes with HbA1c ≥ 6.5% compared to no diagnosed diabetes with HbA1c <5.7%. Three nontraditional glycemic markers demonstrated risk gradients intermediate between HbA1c and fasting glucose and their risk gradients were substantially attenuated after adjusting for HbA1c. All glycemic markers consistently demonstrated stronger associations with CLI than PAD without CLI (p for difference <0.02 for all glycemic markers)., Conclusions: Nontraditional glycemic markers were associated with incident PAD independent of fasting glucose but not necessarily HbA1c. Our results also support the importance of glucose metabolism in the progression to CLI., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Early diagnosis of diabetes yields significant clinical benefits. The serum level of 1,5‑anhydroglucitol (1,5‑AG) has been a new biochemical marker for postprandial hyperglycemia. In this study, a simple colorimetric method for 1,5‑AG detection has been designed based on highly efficient peroxidase mimetic activity of GQDs and enzyme-catalyzed reaction. By the catalytic action of pyranose oxidase (PROD), the 1,5‑AG was oxidized to 1,5‑anhydrofuctose and H 2 O 2 . The GQDs in the presence of H 2 O 2 exhibited highly efficient catalytic activity toward the oxidation of 3, 3', 5, 5'‑tetramethylbenzidine (TMB) to a blue colored product. The influence of relevant experimental variables was optimized. A linear relationship of optical signal with the concentration of 1,5‑AG in the range of 20.0-100.0μg/mL with the regression correlation coefficient of 0.9985 was obtained which could be monitored by colorimetry detection. The limit of detection (LOD) for 1,5‑AG detection was approximately 0.144μg/mL. All in all, the proposed 1,5‑AG detection system based on GQDs and PROD-catalyzed reaction showed better performances with simple operation, low-cost, higher selectivity., (Copyright © 2018 Elsevier B.V. All rights reserved.)

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.)

Objectives: Screening and diagnosis of gestational diabetes (GDM) has been a source of controversy. The prevalence has increased in line with an obesity epidemic and a trend towards delayed child-bearing. Treatment of even modest glycaemic impairment in pregnancy has been shown to be beneficial in preventing its clinical sequalae. However the cumbersome nature and timing of the oral glucose tolerance test coupled with debate around universal versus risk factor based screening have been problematic. This group aimed to investigate a panel of biomarkers which have shown promise in the literature to predict GDM from the first trimester in a group of high risk women., Methods: Serum samples were drawn on 248 women deemed at risk of GDM before 15 weeks' gestation to measure C-reactive protein, sex hormone binding globulin, adiponectin and 1,5 anhydroglucitol. Patients underwent an oral glucose tolerance test as per IADPSG criteria at 28 weeks' gestation. Multiple logistic regression was used to examine the link between incidence of GDM and early pregnancy serum biomarkers., Results: Adiponectin levels in the first trimester are independently linked to the risk of GDM. Serum adiponectin <8.9 μg/ml gives an odds ratio of 3.3 for GDM.Mean 1,5 AG levels are significantly lower in those that go on to develop GDM. SHBG levels measured in the first trimester were linked to the risk of GDM. However, this was no longer statistically significant once BMI, ethnicity and family history were taken into consideration. First trimester measurement of CRP is not a useful indicator of GDM risk., Conclusions: First trimester measurement of Adiponectin and 1,5 Anhydroglucitol are potential early biomarkers for the later onset of GDM. Risk stratification using these biomarkers may facilitate early diagnosis and management of GDM to mitigate against its complications., (Copyright © 2018 Elsevier B.V. All rights reserved.)

Aim: This study aimed to investigate alterations in HbA 1c , glycated albumin (GA) and 1,5-anhydroglucitol (1,5-AG) in Chinese first-degree relatives of individuals with diabetes (FDR) in pursuit of an index for early screening of glucose metabolism disturbance., Methods: A total of 467 participants (age range: 20-78 years) with normal weight and normal glucose tolerance, as determined by a 75-g oral glucose tolerance test, were enrolled. HbA 1c was measured using high-performance liquid chromatography. Serum GA and 1,5-AG levels were determined by enzymatic methods. Serum insulin levels were measured using an electrochemiluminescence immunoassay., Results: The study population included 208 FDR and 259 non-FDR. Serum 1,5-AG levels were lower in FDR than that in non-FDR (20.4 ± 7.5 vs 23.8 ± 8.3 μg/ml, P < 0.001), but HbA 1c and GA levels did not differ between them (P = 0.835 and 0.469, respectively). Logistic regression analysis revealed an independent relationship between a first-degree family history of diabetes and reduced serum 1,5-AG levels (odds ratio = 0.944, P < 0.001). Multiple regression analysis showed that a first-degree family history of diabetes (β = -3.041, P < 0.001) and insulinogenic index (β = 0.081, P = 0.001) were independently associated with serum 1,5-AG levels., Conclusion: In a Chinese population with normal glucose tolerance, serum 1,5-AG levels were lower among FDR, and serum 1,5-AG levels were independently associated with FDR status. For FDR, serum 1,5-AG levels were more sensitive than HbA 1c or GA levels to early-phase abnormality in glucose metabolism., (© 2017 Diabetes UK.)

Background: We examined the efficacy and safety of saxagliptin as an add-on to insulin in Japanese patients with type 2 diabetes mellitus., Research Design and Methods: We randomized 240 patients with type 2 diabetes mellitus on insulin monotherapy to 5-mg saxagliptin or placebo as add-on therapy for a 16-week, double-blind period. All patients received 5-mg saxagliptin and insulin for an additional 36 weeks (open-label extension). Change in hemoglobin A1c (HbA1c) at Week 16 was the main endpoint., Results: At Week 16, the adjusted change in HbA1c from baseline increased by 0.51% with placebo and decreased by 0.40% with saxagliptin (difference -0.92% [95% confidence interval -1.07%, -0.76%; p < 0.001]). In patients receiving saxagliptin, reductions in HbA1c at Week 16 were maintained to Week 52, while switching from placebo to saxagliptin resulted in a similar reduction in HbA1c. The incidence of hypoglycemia was not markedly increased with saxagliptin versus placebo in the double-blind period and did not increase substantially during the open-label extension period. The efficacy and safety of saxagliptin was similar between the elderly and non-elderly patient groups., Conclusions: Adding saxagliptin to ongoing insulin therapy improved glycemic control and was well tolerated in Japanese patients with type 2 diabetes.

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.)

Objective: To determine whether the alternate glycemic markers, fructosamine (FA), glycated albumin (GA), and 1,5-anhydroglucitol (1,5AG), predict glycemic variability captured by continuous glucose monitoring (CGM) in obese youth with prediabetes and type 2 diabetes (T2D)., Study Design: Youth with BMI ≥85th%ile, 10-18 years, had collection of fasting plasma glucose (FPG), hemoglobin A1c (HbA1c), FA, GA, and 1,5AG and 72 hours of CGM. Participants with HbA1c ≥5.7% were included. Relationships between glycemic markers and CGM variables were determined with Spearman correlation coefficients. Linear models were used to examine the association between alternate markers and CGM measures of glycemic variability-standard deviation (SD) and mean amplitude of glycemic excursions (MAGE)-after controlling for HbA1c., Results: Total n = 56; Median (25th%ile, 75th%ile) age = 14.3 years (12.5, 15.9), 32% male, 64% Hispanic, 20% black, 13% white, HbA1c = 5.9% (5.8, 6.3), FA=211 mmol/L (200, 226), GA= 12% (11%, 12%), and 1,5AG = 22mcg/mL (19, 26). HbA1c correlated with average sensor glucose, AUC, SD, MAGE, and %time > 140 mg/dL. FA and GA correlated with average and peak sensor glucose, %time >140 and >200 mg/dL, and MAGE. GA also correlated with SD and AUC180. 1,5AG correlated with peak glucose, AUC180, SD, and MAGE. After adjusting for HbA1c, all 3 markers independently predicted MAGE; FA and GA independently predicted SD., Conclusions: Alternate glycemic markers predict glycemic variability as measured by CGM in youth with prediabetes and T2D. After adjusting for HbA1c, these alternate markers continued to predict components of glycemic variability detected by CGM., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

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.)

Objectives: Dicarbonyl stress and high concentrations of advanced glycation endproducts (AGEs) relate to an elevated risk for cardiovascular diseases (CVD). Exercise training lowers the risk for future CVD. We tested the hypothesis that lifelong endurance athletes have lower dicarbonyl stress and AGEs compared to sedentary controls and that these differences relate to a better cardiovascular health profile., Design: Cross-sectional study., Methods: We included 18 lifelong endurance athletes (ATH, 61±7years) and 18 sedentary controls (SED, 58±7years) and measured circulating glyoxal (GO), methylglyoxal (MGO) and 3-deoxyglucosone (3DG) as markers of dicarbonyl stress. Furthermore, we measured serum levels of protein-bound AGEs N Ɛ -(carboxymethyl)lysine (CML), N Ɛ -(carboxyethyl)lysine (CEL), methylglyoxal-derived hydroimidazolone-1 (MG-H1), and pentosidine. Additionally, we measured cardiorespiratory fitness (VO 2 peak) and cardiovascular health markers., Results: ATH had lower concentrations of MGO (196 [180-246] vs. 242 [207-292] nmol/mmol lysine, p=0.043) and 3DG (927 [868-972] vs. 1061 [982-1114] nmol/mmol lysine, p<0.01), but no GO compared to SED. ATH demonstrated higher concentrations CML and CEL compared to SED. Pentosidine did not differ across groups and MG-H1 was significantly lower in ATH compared to SED. Concentrations of MGO en 3DG were inversely correlated with cardiovascular health markers, whereas CML and CEL were positively correlated with VO 2 peak and cardiovascular health markers., Conclusion: Lifelong exercise training relates to lower dicarbonyl stress (MGO and 3DG) and the AGE MG-H1. The underlying mechanism and (clinical) relevance of higher CML and CEL concentrations among lifelong athletes warrants future research, since it conflicts with the idea that higher AGE concentrations relate to poor cardiovascular health outcomes., (Copyright © 2017 Sports Medicine Australia. Published by Elsevier Ltd. All rights reserved.)

Aims: To determine the effects of dietary changes in amount and type of carbohydrate on 1,5-anhydroglucitol levels., Methods: We conducted an ancillary study to a completed, randomized clinical trial in overweight and obese adults without diabetes (N=159). Using a crossover design, participants were fed each one of four diets in turn for 5 weeks, with 2-week washout periods inbetween. The four diets were: high glycaemic index (≥65) with high proportion of carbohydrate (58% kcal) (GC); low glycaemic index (GI≤45) with low proportion of carbohydrate (40% kcal) (gc); low glycaemic index with high proportion of carbohydrate (gC); and high glycaemic index with low proportion of carbohydrate (Gc). Plasma 1,5-anhydroglucitol levels were measured at baseline and after each feeding period., Results: At baseline, participants had a mean age of 53 years (53% women, 52% non-Hispanic black, 50% obese). Their mean fasting glucose and 1,5-anhydroglucitol levels were 97 mg/dl (5.4 mmol/l) and 18.6 μg/mL (113.3 μmol/l), respectively. Compared with baseline, each of the four diets reduced 1,5-anhydroglucitol by a range of -2.4 to -3.7 μg/mL (-14.6 to -22.5 μmol/l); all P <0.001). Reducing either glycaemic index or proportion of carbohydrate lowered 1,5-anhydroglucitol levels. These effects were additive, such that reducing both glycaemic index and proportion of carbohydrates decreased 1,5-anhydroglucitol by -1.31 μg/mL [95% CI: -1.63, -0.99; P<0.001 or -8.0 (-9.9, -6.0) μmol/l]. Furthermore, these effects were confirmed in a subgroup of participants with 12-h glucose monitoring and no documented hyperglycaemia (fasting glucose <160 mg/dl or 8.9 mmol/l)., Conclusions: Both type and amount of dietary carbohydrate affect 1,5-anhydroglucitol plasma concentrations in adults without diabetes. This finding contradicts the long-standing notion that 1,5-anhydroglucitol remains at constant concentrations in the blood in the absence of hyperglycaemic excursions. (Clinical trials registry number: NCT00051350)., (© 2017 Diabetes UK.)

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.)

β‑cell dysfunction is the primary cause of type 2 diabetes mellitus (T2DM). 1,2‑dicarbonyl compounds, such as 3‑deoxyglucosone (3DG) have been reported to increase the risk of T2DM. Abnormal elevation of plasma 3DG may impair β‑cell function and thereby, it is linked to T2DM. Previous findings suggest that exogenous 3DG may serve an important role in the development of pre‑diabetes. In the present study, the authors examine whether exogenous 3DG induces impaired glucose regulation in mice by decreasing β‑cell function involving of accumulation of plasma 3DG. At two weeks following administration of 3DG, fasting blood glucose (FBG) levels, oral glucose tolerance (by a glucose meter) and plasma levels of 3DG (by HPLC) and insulin (by radioimmunoassay) were measured. Glucose‑stimulated insulin secretion in cultured pancreas islets and INS‑1 cells was measured by radioimmunoassay. Western blotting was used to examine the expression of the key molecules of the insulin‑PI3K signaling pathway. 3DG treatment increased FBG and fasting blood insulin levels, reduced oral glucose tolerance in conjunction with decreased ∆Ins30‑0/∆G30‑0. In 3DG‑treated mice, an increase in the plasma 3DG level was observed, which was most likely the mechanism for decreased β‑cell function. This idea was further supported by these results that non‑cytotoxic 3DG concentration obviously decreased glucose‑stimulated insulin secretion in cultured pancreas islets and INS‑1 cells exposure to high glucose (25.5 mM). 3DG decreased the expression of GLUT2 and phosphorylation of IRS‑1, PI3K‑p85 and Akt in high glucose‑induced INS‑1 cells. To the best of the authors' knowledge, the present study is the first to demonstrate that exogenous 3DG induced normal mice to develop IGR, resulting from β‑cell dysfunction. Exogenous 3DG administration increased plasma 3DG levels, which participates in inducing β‑cell dysfunction, at least in part, through impairing IRS‑1/PI3K/GLUT2 signaling.

Aims: SGLT2 inhibitors are a new class of oral hypoglycemic agents used in type 2 diabetes (T2DM). Their effectiveness in maturity onset diabetes of the young (MODY) is unknown. We aimed to assess the response to a single dose of 10 mg dapagliflozin in patients with Hepatocyte Nuclear Factor 1 Alpha (HNF1A)-MODY, Glucokinase (GCK)-MODY, and type 2 diabetes., Methods: We examined 14 HNF1A-MODY, 19 GCK-MODY, and 12 type 2 diabetes patients. All studied individuals received a single morning dose of 10 mg of dapagliflozin added to their current therapy of diabetes. To assess the response to dapagliflozin we analyzed change in urinary glucose to creatinine ratio and serum 1,5-Anhydroglucitol (1,5-AG) level., Results: There were only four patients with positive urine glucose before dapagliflozin administration (one with HNF1A-MODY, two with GCK-MODY, and one with T2DM), whereas after SGLT-2 inhibitor use, glycosuria occurred in all studied participants. Considerable changes in mean glucose to creatinine ratio after dapagliflozin administration were observed in all three groups (20.51 ± 12.08, 23.19 ± 8.10, and 9.84 ± 6.68 mmol/mmol for HNF1A-MODY, GCK-MODY, and T2DM, respectively, p < 0.001 for all comparisons). Post-hoc analysis revealed significant differences in mean glucose to creatinine ratio change between type 2 diabetes and each monogenic diabetes in response to dapagliflozin (p = 0.02, p = 0.003 for HNF1-A and GCK MODY, respectively), but not between the two MODY forms (p = 0.7231). Significant change in serum 1,5-AG was noticed only in T2DM and it was -6.57 ± 7.34 mg/ml (p = 0.04)., Conclusions: A single dose of dapagliflozin, an SGLT-2 inhibitor, induces higher glycosuria in GCK- and HNF1A-MODY than in T2DM. Whether flozins are a valid therapeutic option in these forms of MODY requires long-term clinical studies.

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.)