Combination of milk variables and on-farm data as an improved diagnostic tool for metabolic status evaluation in dairy cattle during the transition period.

Milk composition, particularly milk fatty acids, has been extensively studied as an indicator of the metabolic status of dairy cows during early lactation. In addition to milk biomarkers, on-farm sensor data also hold potential in providing insights into the metabolic health status of cows. While numerous studies have explored the collection of a wide range of sensor data from cows, the combination of milk biomarkers and on-farm sensor data remains relatively underexplored. Therefore, this study aims to identify associations between metabolic blood variables, milk variables, and various on-farm sensor data. Second, it seeks to examine the supplementary or substitutive potential of these data sources. Therefore, data from 85 lactations on metabolic status and on-farm data were collected during 3 wk before calving up to 5 wk after calving. Blood samples were taken on d 3, 6, 9, and 21 after calving for determination of ß-hydroxybutyrate (BHB), nonesterified fatty acids (NEFA), glucose, insulin-like growth factor-1 (IGF-1), insulin, and fructosamine. Milk samples were taken during the first 3 wk in lactation and analyzed by mid-infrared for fat, protein, lactose, urea, milk fatty acids, and BHB. Walking activity, feed intake, and body condition score (BCS) were monitored throughout the study. Linear mixed effect models were used to study the association between blood variables and (1) milk variables (i.e., milk models); (2) on-farm data (i.e., on-farm models) consisting of activity and dry matter intake analyzed during the dry period ([D]) and lactation ([L]) and BCS only analyzed during the dry period ([D]); and (3) the combination of both. In addition, to assess whether milk variables can clarify unexplained variation from the on-farm model and vice versa, Pearson marginal residuals from the milk and on-farm models were extracted and related to the on-farm and milk variables, respectively. The milk models had higher coefficient of determination (R2) than the on-farm models, except for IGF-1 and fructosamine. The highest marginal R2 values were found for BHB, glucose, and NEFA (0.508, 0.427, and 0.303 vs. 0.468, 0.358, and 0.225 for the milk models and on-farm models, respectively). Combining milk and on-farm data particularly increased R2 values of models assessing blood BHB, glucose, and NEFA concentrations with the fixed effects of the milk and on-farm variables mutually having marginal R2 values of 0.608, 0.566, and 0.327, respectively. Milk C18:1 was confirmed as an important milk variable in all models, but particularly for blood NEFA prediction. On-farm data were considerably more capable of describing the IGF-1 concentration than milk data (marginal R2 of 0.192 vs. 0.086), mainly due to dry matter intake before calving. The BCS [D] was the most important on-farm variable in relation to blood BHB and NEFA and could explain additional variation in blood BHB concentration compared with models solely based on milk variables. This study has shown that on-farm data combined with milk data can provide additional information concerning the metabolic health status of dairy cows. On-farm data are of interest to be further studied in predictive modeling, particularly because early warning predictions using milk data are highly challenging or even missing.

1-Amino-1-deoxy-d-fructose ("fructosamine") and its derivatives: An update.

1-Amino-1-deoxy-d-fructose (fructosamine, FN) derivatives are omnipresent in all living organisms, as a result of non-enzymatic condensation and Amadori rearrangement reactions between free glucose and biogenic amines such as amino acids, polypeptides, or aminophospholipids. Over decades, steady interest in fructosamine was largely sustained by its role as a key intermediate structure in the Maillard reaction that is responsible for the organoleptic and nutritional value of thermally processed foods, and for pathophysiological effects of hyperglycemia in diabetes. New trends in fructosamine research include the discovery and engineering of FN-processing enzymes, development of advanced tools for hyperglycemia monitoring, and evaluation of the therapeutic potential of both fructosamines and FN-recognizing proteins. This article covers developments in the field of fructosamine and its derivatives since 2010 and attempts to ascertain challenges in future research.

Effects of coconut oil long-term supplementation in Wistar rats during metabolic syndrome - regulation of metabolic conditions involving glucose homeostasis, inflammatory signals, and oxidative stress.

This study was designed to evaluate the long-term effects of Fructose (20%) feeding in rats, simulating metabolic syndrome (MetS), and the effects of coconut oil (C.O.) supplementation when administered in a MetS context. MetS is a cluster of systemic conditions that represent an increased chance of developing cardiovascular diseases and type 2 diabetes in the future. C.O. has been the target of media speculation, and recent studies report inconsistent results. C.O. improved glucose homeostasis and reduced fat accumulation in Fructose-fed rats while decreasing the levels of triglycerides (TGs) in the liver. C.O. supplementation also increased TGs levels and fructosamine in serum during MetS, possibly due to white adipose tissue breakdown and high fructose feeding. Pro-inflammatory cytokines IL-1ß and TNF-α were also increased in rats treated with Fructose and C.O. Oxidative stress marker nitrotyrosine is increased in fructose-fed animals, and C.O. treatment did not prevent this damage. No significant changes were observed in lipoperoxidation marker 4-Hydroxynonenal; however, fructose feeding increased total conjugated dienes and caused conjugated dienes to switch their conformation from cis-trans to trans-trans, which was not prevented by C.O. treatment. Potential benefits of C.O. have been reported with inconsistent results, and indeed we observed some benefits of C.O. supplementation in aiding weight loss, fat accumulation, and improving glucose homeostasis. Nonetheless, we also demonstrated that long-term C.O. supplementation could present some problematic effects with higher risk for individuals suffering MetS, including increased TGs and fructosamine levels and conformational changes in dienes.

Metabolic programming in the offspring after gestational overfeeding in the mother: toward neonatal rescuing with metformin in a swine model.

OBJECTIVES: Maternal overfeeding during gestation may lead to adverse metabolic programming in the offspring mediated by epigenetic alterations. Potential reversal, in early life, of these alterations may help in the prevention of future cardio-metabolic conditions. In this context, our aims were: (1) to study the effects of maternal overfeeding on the metabolic and epigenetic programming of offspring's adipose tissue; and (2) to test the potential of postnatal metformin treatment to reverse these changes. METHODS: We used a swine animal model where commercial production sows were either overfed or kept under standard diet during gestation, and piglets at birth were randomly assigned to metformin (n = 16 per group) or vehicle treatment during lactation (n = 16 per group). RESULTS: Piglets born to overfed sows showed a worse metabolic profile (higher weight, weight gain from birth and abdominal circumference; all p < 0.05) together with altered serological markers (increased HOMA-IR, fructosamine, total cholesterol, C-Reactive Protein and lower HMW adiponectin; all p < 0.05). The visceral adipose tissue also showed altered morphology (increased adipocyte area, perimeter and diameter; all p < 0.05), as well as changes in gene expression (higher CCL2 and INSR, lower DLK1; all p < 0.05), and in DNA methylation (96 hypermethylated and 99 hypomethylated CpG sites; FDR < 0.05). Metformin treatment significantly ameliorated the abnormal metabolic profile, decreasing piglets' weight, weight gain from birth, abdominal circumference and fructosamine (all p < 0.05) and reduced adipocyte area, perimeter, and diameter in visceral adipose tissue (all p < 0.05). In addition, metformin treatment potentiated several associations between gene expression in visceral adipose tissue and the altered metabolic markers. CONCLUSIONS: Maternal overfeeding during gestation leads to metabolic abnormalities in the offspring, including adipose tissue alterations. Early metformin treatment mitigates these effects and could help rescue the offspring's metabolic health.

An Expanded Genome-Wide Association Study of Fructosamine Levels Identifies RCN3 as a Replicating Locus and Implicates FCGRT as the Effector Transcript.

Fructosamine is a measure of short-term glycemic control, which has been suggested as a useful complement to glycated hemoglobin (HbA1c) for the diagnosis and monitoring of diabetes. To date, a single genome-wide association study (GWAS) including 8,951 U.S. White and 2,712 U.S. Black individuals without a diabetes diagnosis has been published. Results in Whites and Blacks yielded different association loci, near RCN3 and CNTN5, respectively. In this study, we performed a GWAS on 20,731 European-ancestry blood donors and meta-analyzed our results with previous data from U.S. White participants from the Atherosclerosis Risk in Communities (ARIC) study (Nmeta = 29,685). We identified a novel association near GCK (rs3757840, ßmeta = 0.0062; minor allele frequency [MAF] = 0.49; Pmeta = 3.66 × 10-8) and confirmed the association near RCN3 (rs113886122, ßmeta = 0.0134; MAF = 0.17; Pmeta = 5.71 × 10-18). Colocalization analysis with whole-blood expression quantitative trait loci data suggested FCGRT as the effector transcript at the RCN3 locus. We further showed that fructosamine has low heritability (h2 = 7.7%), has no significant genetic correlation with HbA1c and other glycemic traits in individuals without a diabetes diagnosis (P > 0.05), but has evidence of shared genetic etiology with some anthropometric traits (Bonferroni-corrected P < 0.0012). Our results broaden knowledge of the genetic architecture of fructosamine and prioritize FCGRT for downstream functional studies at the established RCN3 locus.

Markers of hyperglycemia in the vitreous humor. A systematic review and meta-analysis.

BACKGROUND: Vitreous humor has been extensively used in forensic practice to assess hyperglycemia after death. The results from different articles, for various hyperglycemia markers are highly variable, and a systematic analysis of the results from studies currently used in forensic practice as landmarks has not yet been performed. Therefore, we aimed to evaluate to usefulness and limits of using the values of vitreous glucose, lactic acid, beta-hydroxybutyrate, and 1,5 Anhydro-d-glucitol to detect postmortem hyperglycemia. MATERIALS AND METHODS: For this purpose, we performed a systematic review and a meta-analysis using the random-effects model to identify the threshold values and average differences for the markers mentioned above in the vitreous humor of diabetic versus nondiabetic subjects. RESULTS: We included eleven studies in the meta-analysis and found the following mean differences between the diabetic and nondiabetic groups: for glucose - 91.4 mg/dl, for lactate - 34.17 mg/dl, for the Traub formula - 111 mg/dl, for fructosamine - 0.71 mmol/L, for beta-hydroxybutyrate - 36.55 mg/dl and 1,5 Anhydro-d-glucitol - -15.2 mg/dl. We also gave practical recommendations, based on the range of values and 95% confidence intervals in normal subjects and controls to identify antemortem hyperglycemia and evaluated, whenever possible, threshold values for fatal diabetes. CONCLUSIONS: Glucose, Traub formula, fructosamine, and beta-hydroxy-butyrate can be used to detect postmortem hyperglycemia with some limitations; 1,5 Anhydro-d-glucitol can only be used to suggest the absence of a hyperglycemic status before death.

A Hypothesis: Fructosamine-3-Kinase-Related-Protein (FN3KRP) Catalyzes Deglycation of Maillard Intermediates Directly Downstream from Fructosamines.

Non-enzymatic glycation (a.k.a. Maillard reaction) is a series of random spontaneous reactions between reducing sugars and amines, resulting in the formation of irreversible advanced glycation endproducts (AGE's). In food chemistry, this process is beneficial by contributing to the flavor, aroma, texture, and appearance of cooked foods. In vivo, however, Maillard reaction is deleterious because uncontrolled modification and crosslinking of biological macromolecules impairs their function. Consequently, chronic hyperglycemia of diabetes mellitus, for instance, leads to increased non-enzymatic glycation and diverse, multi-organ pathologies of diabetic complications. Based on the fact that toxic compounds, such as free radicals, are detoxified in vivo by specific defense mechanisms, one would expect to find mechanisms to control glucose toxicity as well. Thus far, only one such enzyme, fructosamine-3-kinase (FN3K), has been characterized. It operates intracellularly by catalyzing ATP-dependent removal of Maillard adducts, D-fructoselysines, from proteins, thereby reducing the Maillard reaction flux from glucose to AGE's. When FN3K was isolated, a closely related but distinct protein copurified with it. Unlike FN3K, however, this enzyme, fructosamine-3-kinase-related protein (FN3KRP), does not phosphorylate D-fructoselysines but it does phosphorylate several other (non-physiological) substrates. Interestingly, the distribution of FN3KRP in nature appears to be nearly universal whereas that of FN3K is limited to endotherms. In this article, it is suggested that the function of FN3KRP is deglycation of Maillard adducts downstream from fructoselysines. Such a mechanism, if proven correct, would be valuable given reports on apparent correlations between FN3KRP and some chronic conditions and/or diseases, such as a recent publication which proposes that the FN3KRP gene may be a longevity gene.

Fructosamine is a valuable marker for glycemic control and predicting adverse outcomes following total hip arthroplasty: a prospective multi-institutional investigation.

Recently, fructosamine has shown promising results in predicting adverse outcomes following total knee arthroplasty. The purpose of this study was to assess the utility of fructosamine to predict adverse outcomes following total hip arthroplasty (THA). A prospective multi-center study involving four institutions was conducted. All primary THA were evaluated for glycemic control using fructosamine levels prior to surgery. Adverse outcomes were assessed at a minimum 1 year from surgery. Primary outcome of interest was periprosthetic joint infection (PJI) based on the International Consensus Meeting (ICM) criteria. Secondary outcomes assessed were superficial infections, readmissions and death. Based on previous studies on the subject, fructosamine levels above 293 µmol/L were used to define inadequate glycemic control. Overall 1212 patients were enrolled in the present study and were available for follow up at a minimum 1 year from surgery. Of those, 54 patients (4.5%) had elevated fructosamine levels (> 293 µmol/L) and these patients were 6.7 times more likely to develop PJI compared to patients with fructosamine levels below 293 µmol/L (p = 0.002). Patients with elevated fructosamine were also associated with more readmissions (16.7% vs. 4.4%, p < 0.007) and a higher mortality rate (3.7% vs. 0.6%, p = 0.057). These associations remained statistically significant in a multi-regression analysis after adjusting for age, comorbidities and length of stay; Adjusted odds ratio were 6.37 (95% confidence interval 1.98-20.49, p = 0.002) for PJI and 2.68 (95% confidence interval 1.14-6.29, p = 0.023) for readmissions. Fructosamine is a good predictor of adverse outcomes in patients undergoing THA and should be used routinely to mitigate morbidity and mortality risk.

Glycaemic markers and all-cause mortality in older adults with and without diabetes: the Atherosclerosis Risk in Communities (ARIC) study.

AIMS/HYPOTHESIS: There is controversy regarding the performance of HbA1c in old age. We evaluated the prognostic value of HbA1c and other glycaemic markers (fructosamine, glycated albumin, fasting glucose) with mortality risk in older adults (66-90 years). METHODS: This was a prospective analysis of 5636 participants (31% with diagnosed diabetes, mean age 76, 58% female, 21% black) in the Atherosclerosis Risk in Communities (ARIC) study, baseline 2011-2013. We used Cox regression to examine associations of glycaemic markers (modelled in categories) with mortality risk, stratified by diagnosed diabetes status. RESULTS: During a median of 6 years of follow-up, 983 deaths occurred. Among older adults with diabetes, 30% had low HbA1c (<42 mmol/mol [<6.0%]) and 10% had high HbA1c (≥64 mmol/mol [≥8.0%]); low (HR 1.32 [95% CI 1.04, 1.68]) and high (HR 1.86 [95% CI 1.32, 2.62]) HbA1c were associated with mortality risk vs HbA1c 42-52 mmol/mol (6.0-6.9%) after demographic adjustment. Low fructosamine and glycated albumin were not associated with mortality risk. Both low and high fasting glucose were associated with mortality risk. After further adjustment for lifestyle and clinical risk factors, high HbA1c (HR 1.81 [95% CI 1.28, 2.56]), fructosamine (HR 1.96 [95% CI 1.43-2.69]), glycated albumin (HR 1.81 [95% CI 1.33-2.47]) and fasting glucose (HR 1.81 [95% CI 1.24, 2.66]) were associated with mortality risk. Low HbA1c and fasting glucose were no longer significantly associated with mortality risk. Among participants without diabetes, associations of glycaemic markers with mortality risk were less robust. CONCLUSIONS/INTERPRETATION: Elevated HbA1c, fructosamine, glycated albumin and fasting glucose were associated with risk of mortality in older adults with diabetes. Low HbA1c and fasting glucose may be markers of poor prognosis but are possibly confounded by health status. Our findings support the clinical use of HbA1c in older adults with diabetes. Graphical abstract.

Effects of hydrogen-rich water prepared by alternating-current-electrolysis on antioxidant activity, DNA oxidative injuries, and diabetes-related markers.

Hydrogen-rich water is conventionally prepared by direct current-electrolysis, but has been not or scarcely prepared by alternating current (AC)-electrolysis. The AC preparations from tap water for 20-30 minutes exhibit a dissolved hydrogen concentration of 1.55 mg/L, which was close to the theoretical maximum value of 1.6 mg/L. These preparations also displayed an oxidation-reduction potential of -270 mV (tap water: +576 mV) and pH of 7.7-7.8, being closer to physiological values of body fluids than general types of direct current-electrolytic hydrogen-rich water. We examined whether AC-electrolytic hydrogen-water is retained for hydrogen-abundance after boiling or for antioxidant abilities, and whether the oral administration of this water is clinically effective for diabetes and prevention against systemic DNA-oxidative injuries. 5,5-Dimethyl-1-pyrroline-N-oxide spin trapping and electron spin resonance revealed that the hydrogen-rich water generated by AC-electrolysis exhibited hydroxyl-radical-scavenging activities. Laser nanoparticle tracking method revealed that nanoparticle suspensions as abundant as 5.4 × 107/mL were efficiently retained (up to 3.5 × 107/mL) even after boiling for 10 minutes, being thermodynamically contrary to Henry's law. Oral intake of hydrogen-rich water, 1500 mL per day, lasted for 8 weeks in nine people with the diabetes-related serum markers beyond the normal ranges. The subjects exhibited significant tendencies for the decreased fasting blood glucose and fructosamine, and for the increased 1,5-anhydro-D-glucitol, concomitantly with significant decreases in urinary 8-hydroxy-2-deoxyguanosine contents and its rate of generation. Hydrogen-rich water prepared by AC-electrolysis may be effective in improving diverse diabetes-related markers and systemic DNA oxidative injuries through the formation of abundant heat-resistant nanobubbles and the increased hydrogen concentrations. The study protocol was officially approved by the Medical Ethics Committee of the Japanese Center for Anti-Aging Medical Sciences (approval No. 01S02) on September 15, 2009.

Curcumin, Alone or in Combination with Aminoguanidine, Increases Antioxidant Defenses and Glycation Product Detoxification in Streptozotocin-Diabetic Rats: A Therapeutic Strategy to Mitigate Glycoxidative Stress.

Both oxidative stress and the exacerbated generation of advanced glycation end products (AGEs) have crucial roles in the onset and progression of diabetic complications. Curcumin has antioxidant and antidiabetic properties; its combination with compounds capable of preventing the advanced glycation events, such as aminoguanidine, is an interesting therapeutic option to counteract diabetic complications. This study is aimed at investigating the effects of treatments with curcumin or aminoguanidine, alone or in combination, on metabolic alterations in streptozotocin-diabetic rats; the focus was mainly on the potential of these bioactive compounds to oppose the glycoxidative stress. Curcumin (90 mg/kg) or aminoguanidine (50 and 100 mg/kg), alone or in combination, slightly decreased glycemia and the biomarkers of early protein glycation, but markedly decreased AGE levels (biomarkers of advanced glycation) and oxidative damage biomarkers in the plasma, liver, and kidney of diabetic rats. Some novel insights about the in vivo effects of these bioactive compounds are centered on the triggering of cytoprotective machinery. The treatments with curcumin and/or aminoguanidine increased the activities of the antioxidant enzymes (paraoxonase 1, superoxide dismutase, and catalase) and the levels of AGE detoxification system components (AGE-R1 receptor and glyoxalase 1). In addition, combination therapy between curcumin and aminoguanidine effectively prevented dyslipidemia in diabetic rats. These findings demonstrate the combination of curcumin (natural antioxidant) and aminoguanidine (prototype therapeutic agent with anti-AGE activity) as a potential complementary therapeutic option for use with antihyperglycemic agents, which may aggregate beneficial effects against diabetic complications.

Mechanistic inhibition of non-enzymatic glycation and aldose reductase activity by naringenin: Binding, enzyme kinetics and molecular docking analysis.

The aldose reductase (AR) enzyme is considered a potential target for the management of diabetic complications. In this study, we describe the binding and enzyme kinetics of AR by naringenin, a bioflavonoid present in many dietary sources. Naringenin showed an inhibitory effect on the activity of AR with an IC50 value of 2.6 µM in an uncompetitive manner. Binding studies confirmed that the naringenin-AR complex has high spontaneous affinity (Ka = 1.94-7.88 × 104) with negative ΔG° value (-5.78 kcal mol-1). The interaction was enthalpy driven and the microenvironment of aromatic residues of AR was also altered. Various stages of protein oxidation and glycation were also measured. Naringenin inhibited fructosamine content by approximately 31.6% at 10 µM, and at the same concentration, >93% inhibition of fluorescent advanced glycation end-products (AGEs) was achieved. There was a significant recovery in free thiol groups and carbonyl content of bovine serum albumin (BSA). Furthermore, molecular docking of naringenin with AR revealed that naringenin formed two hydrogen bonds (Asn160 and Ile260), and three Pi-Pi interactions (two with Trp20 and one with His110). This study provides molecular insight of naringenin-AR interaction and mechanism of antiglycation which may be useful in the development of inhibitors for AGEs formation.

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

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

Xanthine oxidase activity in type 2 diabetic Nigerians.

AIM: This study evaluated the activity of xanthine oxidase in Nigerians with type 2 diabetic mellitus as well as its relationship with lipid peroxidation, inflammatory bio markers and glycemic control indices. METHODS: Two hundred and thirty seven (237) subjects, comprising of one hundred and fifty seven (157) DM subjects and eighty (80) aged matched controls participated in this study. Blood samples were collected from the participants for the estimations of xanthine oxidase activity, uric acid, malon diadehyde (MDA), erythrocyte sedimentation rate (ESR), high sensitive c - reactive protein (hs CRP), glucose, fructosamine and glycosylated hemoglobin by standard methods. RESULTS: The results of this study showed a significantly increased activity of xanthine oxidase in DM (0.044 ±â€¯0.05µ/mg) compared with apparently healthy controls (0.028 ±â€¯0.00 µ/mg). The mean plasma levels of MDA (42.40 ±â€¯2.50µmol/l) and uric acid (7.22 ±â€¯0.20 mg/dl) in DM were significantly higher (p ≤ 0.05) than healthy non DM group. The mean levels of hs CRP in DM (4.09 ±â€¯0.91µg/ml) was significantly higher than controls (1.30 ±â€¯0.50µg/ml, p = 0.009). While no association of xanthine oxidase was observed with glycemic control indices and hs CRP, a negative association of xanthine oxidase was observed with MDA (r = -0.514, p = 0.000). CONCLUSION: Increased activity of xanthine oxidase in DM was associated with increased lipid peroxidation and could be a salient entity towards the onset on complications.

Association between glycated albumin, fructosamine, and HbA1c with neonatal outcomes in a prospective cohort of women with gestational diabetes mellitus.

OBJECTIVE: To investigate whether glycated albumin, fructosamine, and hemoglobin A1c (HbA1c) are associated with neonatal complications in newborns of pregnant women with gestational diabetes mellitus (GDM). METHODS: Between November 2016 and September 2017, women with a singleton pregnancy and GDM were enrolled in a prospective study in an obstetric Portuguese referral center. Glycemic markers were compared between mothers of newborns with and without complications. Multivariable logistic regression models and corresponding areas under the receiver operating characteristic curve (AUC) were used. RESULTS: A total of 85 women participated in the study. Raised levels of glycated albumin and fructosamine were associated with at least one neonatal complication (OR- [odds ratio] estimate: 1.33, P=0.015; OR: 1.24, P=0.027, respectively) and with respiratory disorders at birth (OR 1.41, P=0.004; OR 1.26, P=0.014, respectively). HbA1c was not associated with these outcomes. All biomarkers were associated with large-for-gestational age (LGA) status (OR 1.61, P<0.001; OR 1.45, P<0.001; OR 3.62, P=0.032 for glycated albumin, fructosamine, and HbA1c, respectively). All had similar AUC for at least one neonatal complication (0.82; 0.81; 0.79, respectively). For newborn respiratory disorders, AUCs were 0.83, 0.81, and 0.76, respectively, and for LGA status were 0.81, 0.79, and 0.71, respectively. CONCLUSION: Raised values of glycated albumin and fructosamine were associated with particular perinatal complications in newborns of mothers with GDM, better discriminating mothers of newborns with and without complications than HbA1c.

Diabetic cats have decreased gut microbial diversity and a lack of butyrate producing bacteria.

Obesity and inactivity are major risk factors of feline diabetes mellitus (FDM) and human type II diabetes mellitus (T2DM). In recent years, changes in the gut microbiota have been suggested as a contributing factor to T2DM. Whether the gut microbiota (GM) composition plays a role in FDM remains unknown. The aim of the current study was firstly a cross-sectional comparison of the GM of diabetic cats, to that of lean, and of obese/overweight non-diabetic cats of a similar age. Specifically, fecal samples from 82 privately-owned cats from Denmark and Switzerland were sequenced using 16S rRNA gene amplicon metabarcoding. Secondly dietary intervention data was generated, by obtaining additional samples from a subset of cats after placing them on a high-protein diet for four weeks. The GM diversity of diabetic cats was lower than that of lean cats in the cross-sectional study, and lower compared to lean and to overweight/obese cats after diet intervention. Diabetic cats also exhibited fewer Anaerotruncus, Dialister, and unknown Ruminococcaceae than lean cats. Serum fructosamine levels correlated negatively with Prevotellaceae abundance and positively with Enterobacteriaceae abundance. In summary the intestinal microbiota of diabetic cats was characterized by decreased GM diversity and loss of butyrate producing bacterial genera.

Oxidative Stress in Animal Models of Acute and Chronic Renal Failure.

INTRODUCTION: Kidney disease is a worldwide health and economic burden, with rising prevalence. The search for biomarkers for earlier and more effective disease screening and monitoring is needed. Oxidative stress has been linked to both, acute kidney injury (AKI) and chronic kidney disease (CKD). The aim of our study was to investigate whether the concentrations of systemic markers of oxidative stress and antioxidant status are affected by AKI and CKD, and to identify potential biomarkers. METHODS: In adult male Wistar rats, AKI was induced by bilateral nephrectomy, and CKD was induced by 5/6 nephrectomy. Blood was collected 48 hours after surgery in AKI and 6 months after surgery in CKD. Advanced oxidation protein products (AOPP), thiobarbituric acid reactive substances (TBARS), advanced glycation end products (AGEs), fructosamine, total antioxidant capacity (TAC), and ferric reducing antioxidant power (FRAP) were measured. RESULTS: Impaired renal function was confirmed by high concentrations of plasma creatinine and urea in AKI and CKD animals. AOPP and fructosamine were higher by 100% and 54% in AKI, respectively, and by 100% and 199% in CKD, respectively, when compared to corresponding control groups. Similarly, there was approximately a twofold increase in AGEs (by 92%) and TAC (by 102%) during AKI. In CKD, concentrations of FRAP, as an antioxidative status marker, were doubled (by 107%) when compared to the control group, but concentration of TAC, another marker of antioxidative status, did not differ between the groups. CONCLUSIONS: AKI and CKD led to increased systemic oxidative stress. AOPP and fructosamine could be considered potential biomarkers for both, acute and chronic kidney damage. On the other hand, AGEs, TAC, and FRAP seem to be disease specific, which could help to differentiate between acute and chronic kidney injuries. However, this needs further validation in clinical studies.

Effects of sacubitril/valsartan on neprilysin targets and the metabolism of natriuretic peptides in chronic heart failure: a mechanistic clinical study.

AIM: This study aimed at evaluating the effects of sacubitril/valsartan on neprilysin (NEP), and the metabolism of natriuretic peptides in heart failure (HF) and providing additional mechanistic information on the mode of action of the drug. METHODS AND RESULTS: We enrolled 73 chronic HF patients who were switched from angiotensin-converting enzyme inhibitor or angiotensin receptor blocker to sacubitril/valsartan. In addition to clinical and echocardiographic assessment, plasma biomarkers were measured at baseline, day 30 and day 90 after initiation of treatment. Sacubitril/valsartan led to decrease in New York Heart Association class and improvement of echocardiographic parameters, as well as a dose-dependent decrease in soluble NEP (sNEP) activity, while sNEP concentration remained unchanged. Neprilysin inhibition translated into an increase in its substrates such as atrial natriuretic peptide (ANP), substance P, and glucagon-like peptide 1, the latter translating into a decrease in fructosamine. Cardiac troponin and soluble ST2 levels, biomarkers of HF severity unrelated to NEP metabolism also decreased. While there was a ∼4-fold increase in ANP, we observed no change in plasma brain natriuretic peptide (BNP) and plasma BNP activity, and a mild decrease in N-terminal proBNP (NT-proBNP) concentrations. Finally, we found a progressive increase in the relationship between BNP and NT-proBNP, which strongly correlated with an increase in T71 proBNP glycosylation (R2 = 0.94). CONCLUSION: Sacubitril/valsartan rapidly and strongly reduced sNEP activity, leading to an increase in levels of NEP substrates. These data suggest a pleiotropic favourable impact of sacubitril/valsartan on the metabolism of HF patients with ANP rather than BNP as major effectors amongst natriuretic peptides.

The effect of resveratrol on glycation and oxidation products in plasma and liver of chronic methylglyoxal-treated rats.

BACKGROUND: Methylglyoxal (MG) is a highly reactive dicarbonyl compound. It is produced by processes like glycolysis, glucose autooxidation, lipid peroxidation, and protein glycation. It is a major precursor of advanced glycation end products (AGE). It also exacerbates oxidative stress in the organism. Although there are some in vitro studies investigating the effect of resveratrol (RES) as an antioxidant and antiglycating agent on MG-induced toxicity, in vivo effect of RES is unknown. Therefore, we aimed to investigate the efficiency of RES in chronic MG-treated rats. METHODS: Rats were given incrementally increased doses (100-300 mg/kg) of MG in drinking water for ten weeks. RES (10 mg/kg ip) was administered together with MG. Reactive oxygen species (ROS) formation, thiobarbituric reactive substances (TBARS), protein carbonyl (PC), advanced oxidation protein products (AOPP) and AGE levels as well as ferric reducing antioxidant power (FRAP) values were determined in plasma and liver. RESULTS: Significant increases in plasma TBARS, PC, AOPP and AGE and fructosamine levels were detected in MG-treated rats. However, plasma ROS and FRAP levels remained unchanged. Hepatic ROS, TBARS, PC and AOPP, but not AGE and FRAP levels were also increased in MG-treated rats. RES treatment diminished high levels of plasma PC, AOPP and AGE levels in MG-treated rats. Additionally, significant decreases in hepatic ROS, TBARS, PC and AOPP levels together with histopatological amelioration were detected due to RES treatment in MG-treated rats. CONCLUSIONS: Our results indicate that RES may be considered as a protective agent against glycoxidative stress generated by in vivo MG treatment.

Carbamylation is a competitor of glycation for protein modification in vivo.

AIM: Chronic kidney disease (CKD) and diabetes mellitus are two diseases that accelerate protein molecular ageing through carbamylation and glycation reactions, characterized by the binding of urea-derived isocyanic acid and of sugars on proteins, respectively. These two reactions target the same protein amino groups and, thus, compete with each other. Such competition may arise especially in diabetic patients with nephropathy. This study aimed to evaluate their potential competitive effects in vitro and under conditions reproducing CKD and/or diabetes in vivo. METHODS: Albumin was incubated in vitro with glucose, urea or cyanate. Carbamylation in vivo was enhanced in normal and diabetic (db/db) mice by either subtotal nephrectomy or cyanate consumption. Homocitrulline, carbamylated haemoglobin and furosine were measured by LC-MS/MS, fructosamine by colorimetric assay and HbA1c by immunological assay. RESULTS: Reciprocal inhibition between carbamylation and glycation was observed during albumin incubations in vitro. Besides, 5 weeks after induction of CKD in vivo, plasma homocitrulline concentrations were similar in both diabetic and non-diabetic mice, whereas fructosamine and HbA1c were decreased (-23% and -42%, respectively) in diabetic mice with CKD compared with only diabetic ones. Fructosamine and HbA1c were also decreased in cyanate-spiked water-drinking mice compared with plain water-drinking diabetic mice. CONCLUSION: Carbamylation competes with glycation in vivo, especially under conditions of high glycation. Thus, the classic markers of glycaemic control should be interpreted with caution in diabetic patients with CKD because of this competitive effect.