Higher habitual intake of dietary dicarbonyls is associated with higher corresponding plasma dicarbonyl concentrations and skin autofluorescence: the Maastricht Study.

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 (ß: 0.08; 95% CI: 0.02, 0.13) and SAF (ß: 0.12; 95% CI: 0.07, 0.17). Dietary GO was associated with plasma GO (ß: 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).

HbA1c combined with glycated albumin or 1,5-anhydroglucitol improves the efficiency of diabetes screening in a Chinese population.

AIMS: This study aimed to evaluate the ability of HbA1c 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. HbA1c , GA, 1,5-AG and other serum biochemical parameters were measured. Receiver operating characteristic curves were plotted to determine the optimal thresholds of HbA1c , GA and 1,5-AG according to the Youden index. RESULTS: (1) The optimal thresholds of HbA1c , 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 HbA1c combined with GA and 1,5-AG were both 85%, higher than that of HbA1c (70%, p < 0.001). CONCLUSIONS: This study is suitable for cases where plasma glucose is unavailable. Among the residents of Jiangsu, HbA1c 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.

1,5-anhydroglucitol biosensor based on light-addressable potentiometric sensor with RGO-CS-Fc/Au NPs nanohybrids.

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 H2O2. The by-product H2O2 can oxidize Fc(Fe2+) ions in RGO-CS-Fc nanohybrids into Fc(Fe3+) 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.

Increase in the peripheral blood methylglyoxal levels in 10% of hospitalized chronic schizophrenia patients.

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.

Irbesartan treatment does not influence plasma levels of the dicarbonyls methylglyoxal, glyoxal and 3-deoxyglucosone in participants with type 2 diabetes and microalbuminuria: An IRMA2 sub-study.

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).

Association between 1,5-Anhydroglucitol and Acute C Peptide Response to Arginine among Patients with Type 2 Diabetes.

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 ß-cell function was defined as ACPR < 2.1. Multivariable logistic regression models were used to demonstrate the association between 1,5-anhydroglucitol and decreased ß-cell function. RESULTS: Finally, 623 patients with type 2 diabetes were enrolled into the analysis. Multivariable-adjusted odds ratios for decreased ß-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 ß-cell function. Further analysis with large sample size and prospective study design is warranted to validate our findings.

Effect of 1,5-anhydroglucitol levels on culprit plaque rupture in diabetic patients with acute coronary syndrome.

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 A1c (HbA1c) and 1,5-AG levels were measured before coronary angiography. Fasting urinary 8-iso-prostaglandin F2α (8-iso-PGF2α) 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 HbA1c 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 HbA1c (0.587, P = 0.087). Levels of 1,5-AG were significantly correlated with urinary 8-iso-prostaglandin F2α 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.

Serum 1,5-Anhydroglucitol to Glycated Albumin Ratio Can Help Early Distinguish Fulminant Type 1 Diabetes Mellitus from Newly Onset Type 1A Diabetes Mellitus.

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 A1c (HbA1c) < 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 HbA1c 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 HbA1c < 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 HbA1c 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 HbA1c 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 HbA1c < 8.7%, with an optimal cut-off point of 0.3.

Co-delivery of 2-Deoxyglucose and a glutamine metabolism inhibitor V9302 via a prodrug micellar formulation for synergistic targeting of metabolism in cancer.

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.

Reference intervals for serum 1,5-anhydroglucitol of a population with normal glucose tolerance in Jiangsu Province.

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.

Development of an organ bath technique for isolated rat pancreas preparations to assess the effect of 1,5-AG on insulin secretion.

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.

1,5-Anhydroglucitol × glycated hemoglobin A1c/100 as a potential biomarker for islet ß-cell function among patients with type 2 diabetes.

AIMS: This study aimed to explore the level of and changes in the 1,5-anhydroglucitol × glycated hemoglobin A1c/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-ß, insulin generation index, insulin sensitivity index, and DI increased (all Pfor 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 (Pfor trend < 0.05). CONCLUSION: The AHI could reflect the variation in glycemic disorder and the function of islet ß cells. The lower the AHI, the worse the glycemic disorder, as well as the islet ß-cell function.

Serum 1,5-Anhydroglucitol Concentration as a Biomarker for Type 1 Diabetes in Adults and Children.

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.

Screening for cystic fibrosis-related diabetes and prediabetes: Evaluating 1,5-anhydroglucitol, fructosamine, glycated albumin, and hemoglobin A1c.

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.

Relations of advanced glycation endproducts and dicarbonyls with endothelial dysfunction and low-grade inflammation in individuals with end-stage renal disease in the transition to renal replacement therapy: A cross-sectional observational study.

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.

Inverse association between 1,5-anhydroglucitol and neonatal diabetic complications.

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.

Impact of serum 1,5-anhydro-D-glucitol level on the prediction of severe coronary artery calcification: an intravascular ultrasound study.

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.

Hyperglycemia and Carotenoid Intake Are Associated with Serum Carotenoids in Youth with Type 1 Diabetes.

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 F2α); 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, ß-carotene, lycopene, ß-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 (ß=0.35, P<0.001) and carotenoid intake (ß=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 (ß=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.

Response of 1,5-anhydroglucitol level to intensive glucose- and blood-pressure lowering interventions, and its associations with clinical outcomes in the ADVANCE trial.

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.

Rare variants in SLC5A10 are associated with serum 1,5-anhydroglucitol (1,5-AG) in the Atherosclerosis Risk in Communities (ARIC) Study.

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.