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Aim: To investigate the effects of pyridoxamine (PM), a B6 vitamer and dicarbonyl scavenger, on glycation and a large panel of metabolic and vascular measurements in a randomized double‐blind placebo‐controlled trial in abdominally obese individuals. Materials and methods: Individuals (54% female; mean age 50 years; mean body mass index 32 kg/m2) were randomized to an 8‐week intervention with either placebo (n = 36), 25 mg PM (n = 36) or 200 mg PM (n = 36). We assessed insulin sensitivity, β‐cell function, insulin‐mediated microvascular recruitment, skin microvascular function, flow‐mediated dilation, and plasma inflammation and endothelial function markers. PM metabolites, dicarbonyls and advanced glycation endproducts (AGEs) were measured using ultra‐performance liquid chromatography tandem mass spectrometry. Treatment effects were evaluated by one‐way ANCOVA. Results: In the high PM dose group, we found a reduction of plasma methylglyoxal (MGO) and protein‐bound Nδ‐(5‐hydro‐5‐methyl‐4‐imidazolon‐2‐yl)‐ornithine (MG‐H1), as compared to placebo. We found a reduction of the endothelial dysfunction marker soluble vascular cell adhesion molecule‐1 (sVCAM‐1) in the low and high PM dose group and of soluble intercellular adhesion molecule‐1 (sICAM‐1) in the high PM dose, as compared to placebo. We found no treatment effects on insulin sensitivity, vascular function or other functional outcome measurements. Conclusions: This study shows that PM is metabolically active and reduces MGO, AGEs, sVCAM‐1 and sICAM‐1, but does not affect insulin sensitivity and vascular function in abdominally obese individuals. The reduction in adhesion markers is promising because these are important in the pathogenesis of endothelial damage and atherosclerosis. [ABSTRACT FROM AUTHOR]

Objective: A proinflammatory adipose tissue (AT) microenvironment and systemic low‐grade inflammation may differentially affect tissue‐specific insulin sensitivity. This study investigated the relationships of abdominal subcutaneous AT (aSAT) and circulating immune cells, aSAT gene expression, and circulating inflammatory markers with liver and skeletal muscle insulin sensitivity in people with overweight and obesity. Methods: Individuals with overweight and obesity from the PERSonalized Glucose Optimization Through Nutritional Intervention (PERSON) Study (n = 219) and the Maastricht Study (replication cohort; n = 1256) underwent a seven‐point oral glucose tolerance test to assess liver and muscle insulin sensitivity, and circulating inflammatory markers were determined. In subgroups, flow cytometry was performed to identify circulating and aSAT immune cells, and aSAT gene expression was evaluated. Results: The relative abundances of circulating T cells, nonclassical monocytes, and CD56dim CD16+ natural killer cells were inversely associated with liver, but not muscle, insulin sensitivity in the PERSON Study. The inverse association between circulating (classical) monocytes and liver insulin sensitivity was confirmed in the Maastricht Study. In aSAT, immune cell populations were not related to insulin sensitivity. Furthermore, aSAT gene expression of interleukin 6 and CD14 was positively associated with muscle, but not liver, insulin sensitivity. Conclusions: The present findings demonstrate that circulating immune cell populations and inflammatory gene expression in aSAT show distinct associations with liver and muscle insulin sensitivity. [ABSTRACT FROM AUTHOR]

Aim: To study the effect of metformin on plasma levels of arginine, asymmetric dimethylarginine (ADMA) and symmetric dimethylarginine (SDMA), indicators of the nitric oxide pathway. Materials and Methods: In this post hoc analysis of the HOME trial, we analysed plasma levels of arginine, ADMA and SDMA during the 4.3‐year follow‐up (comparing the effects of metformin versus placebo on top of insulin therapy). Statistical analysis was performed with a mixed model approach, in which simultaneously constant treatment effects were estimated, as well as time‐dependent treatment effects. Results: We found that metformin compared with placebo did not affect ADMA or SDMA plasma levels but rapidly decreased arginine plasma levels and hence the arginine to ADMA ratio. The constant treatment effect on ADMA was 0.99 (95% CI 0.97, 1.00) relative to placebo and the time‐dependent treatment effect was 1.00 (95% CI 1.00, 1.01). By contrast, the constant treatment effect on arginine was 0.86 (95% CI 0.84, 0.88), with only a minimal time‐dependent change of 1.01 (95% CI 1.00, 1.01). Conclusions: The potential benefits of metformin on endothelial function cannot be explained by a decrease in ADMA or by improved global arginine availability. The clinical significance of the decreased arginine plasma levels is not clear and can be harmful or beneficial, depending on the mechanism involved. However, a potential effect of metformin on the nitric oxide pathway is not restricted to the studied metabolites. [ABSTRACT FROM AUTHOR]

Background: Diabetes mellitus (DM) induces cardiac and cerebral microvascular dysfunction via increased glycation, oxidative stress and endothelial activation. Liraglutide, a glucagon‐like peptide‐1 analogue, inhibited NOX2 and adhesion molecules in isolated endothelial cells. Here, we have studied how Liraglutide affects advanced glycation, NOX expression and inflammation of the cardiac, cerebral and renal microvasculature in diabetic rats. Methods: DM was induced in Sprague–Dawley rats (n = 15) via intraperitoneal streptozotocin (STZ) injection (60 mg/kg bodyweight). Ten control rats remained nondiabetic. From day 9 post‐STZ injection, Liraglutide (200 μg/kg bodyweight; n = 7) or vehicle (n = 8) was injected subcutaneously daily until termination on day 29. The advanced glycation endproduct N‐ε‐(carboxymethyl)lysine (CML), NOX2, NOX4, ICAM‐1 and VCAM‐1 were subsequently immunohistochemically analysed and quantified to compare Liraglutide treatment with placebo. Results: In the heart, Liraglutide treatment significantly reduced the DM‐increased scores/cm2 for CML in both ventricles (from 253 ± 53 to 72 ± 12; p =.003) and atria (343 ± 29 to 122 ± 8; p =.0001) and for NOX2, ICAM‐1 and VCAM‐1, but not for NOX4. Also in the cerebrum and cerebellum of the brain, Liraglutide significantly reduced the scores/cm2 for CML (to 60 ± 7 (p =.0005) and 47 ± 13 (p =.02), respectively), and for NOX2 and NOX4. In the kidney, the DM‐induced expression of ICAM‐1 and VCAM‐1 was decreased in the blood vessels and glomeruli by Liraglutide treatment. Liraglutide did not affect blood glucose levels or bodyweight. Conclusions: Our study implies that Liraglutide protects the cardiac, cerebral and renal microvasculature against diabetes‐induced dysfunction, independent of lowering blood glucose in a type 1 diabetes rat model. [ABSTRACT FROM AUTHOR]

Objective: Complement C3 and other components of the alternative pathway are higher in individuals with obesity. Moreover, C3 has been identified as a risk factor for cardiovascular disease. This study investigated whether, and how, a weight-loss intervention reduced plasma C3, activated C3 (C3a), and factor D and explored potential biological effects of such a reduction.Methods: The study measured plasma C3, C3a, and factor D by ELISA and measured visceral adipose tissue, subcutaneous adipose tissue, and intrahepatic lipid by magnetic resonance imaging in lean men (n = 25) and men with abdominal obesity (n = 52). The men with obesity were randomized to habitual diet or an 8-week dietary weight-loss intervention.Results: The intervention significantly reduced C3 (-0.15 g/L [95% CI: -0.23 to -0.07]), but not C3a or factor D. The C3 reduction was mainly explained by reduction in visceral adipose tissue but not subcutaneous adipose tissue or intrahepatic lipid. This reduction in C3 explained a part of the weight-loss-induced improvement of markers of endothelial dysfunction, particularly the reduction in soluble endothelial selectin and soluble intercellular adhesion molecule.Conclusions: Diet-induced weight loss in men with abdominal obesity could be a way to lower plasma C3 and thereby improve endothelial dysfunction. C3 reduction may be part of the mechanism via which diet-induced weight loss could ameliorate the risk of cardiovascular disease in men with abdominal obesity. [ABSTRACT FROM AUTHOR]

Advanced glycation endproducts (AGEs) may contribute to liver carcinogenesis because of their proinflammatory and prooxidative properties. Diet is a major source of AGEs, but there is sparse human evidence on the role of AGEs intake in liver cancer etiology. We examined the association between dietary AGEs and the risk of hepatobiliary cancers in the European Prospective Investigation into Cancer and Nutrition prospective cohort (n = 450 111). Dietary intake of three AGEs, Nε‐[carboxymethyl]lysine (CML), Nε‐[1‐carboxyethyl]lysine (CEL) and Nδ‐[5‐hydro‐5‐methyl‐4‐imidazolon‐2‐yl]‐ornithine (MG‐H1), was estimated using country‐specific dietary questionnaires linked to an AGEs database. Cause‐specific hazard ratios (HR) and their 95% confidence intervals (CI) for associations between dietary AGEs and risk of hepatocellular carcinoma (HCC), gallbladder and biliary tract cancers were estimated using multivariable Cox proportional hazard regression. After a median follow‐up time of 14.9 years, 255 cases of HCC, 100 cases of gallbladder cancer and 173 biliary tract cancers were ascertained. Higher intakes of dietary AGEs were inversely associated with the risk of HCC (per 1 SD increment, HR‐CML = 0.87, 95% CI: 0.76‐0.99, HR‐CEL = 0.84, 95% CI: 0.74‐0.96 and HR‐MH‐G1 = 0.84, 95% CI: 0.74‐0.97). In contrast, positive associations were observed with risk of gallbladder cancer (per 1 SD, HR‐CML = 1.28, 95% CI: 1.05‐1.56, HR‐CEL = 1.17; 95% CI: 0.96‐1.40, HR‐MH‐G1 = 1.27, 95% CI: 1.06‐1.54). No associations were observed for cancers of the intra and extrahepatic bile ducts. Our findings suggest that higher intakes of dietary AGEs are inversely associated with the risk of HCC and positively associated with the risk of gallbladder cancer. What's new? Advanced glycation endproducts (AGEs) are proteins or lipids with sugars added to them, and they can form in foods during cooking. They have pro‐inflammatory and pro‐oxidative properties in the body. These authors investigated whether dietary consumption of AGEs affect risk of liver cancer, using the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Participants filled out food questionnaires to determine AGE consumption. Higher intakes of AGEs were associated with reduced risk of hepatocellular carcinoma (HCC) and increased risk of gallbladder cancer. However, it's still not entirely clear how much AGEs in the diet contribute to circulating AGE levels. [ABSTRACT FROM AUTHOR]

Objective: This study investigated whether arterial stiffening is a determinant of subtle retinal microvascular changes that precede diabetic retinopathy. Research design and methods: This study used cross‐sectional data from the Maastricht Study, a type 2 diabetes‐enriched population‐based cohort study. We used multivariable linear regression analysis to investigate, in individuals without and with type 2 diabetes, the associations of carotid distensibility coefficient and carotid‐femoral pulse wave velocity with retinal microvascular diameters and flicker light‐induced dilation and adjusted for cardiovascular and lifestyle risk factors. Results: The retinal microvascular diameter study population consisted of N = 2434 participants (51.4% men, mean ± SD age 59.8 ± 8.1 years, and 28.1% type 2 diabetes). No measures of arterial stiffness were significantly associated with microvascular diameters. Greater carotid distensibility coefficient (i.e., lower carotid stiffness) was significantly associated with greater retinal arteriolar flicker light‐induced dilation (per standard deviation, standardized beta [95% CI] 0.06 [0.00; 0.12]) and non‐significantly, but directionally similarly, associated with greater retinal venular flicker light‐induced dilation (0.04 [−0.02; 0.10]). Carotid‐femoral pulse wave velocity (i.e., aortic stiffness) was not associated with retinal microvascular flicker light‐induced dilation. The associations between carotid distensibility coefficient and retinal arteriolar and venular flicker light‐induced dilation were two‐ to threefold stronger in individuals with type 2 diabetes than in those without. Conclusion: In this population‐based study greater carotid, but not aortic, stiffness was associated with worse retinal flicker light‐induced dilation and this association was stronger in individuals with type 2 diabetes. Hence, carotid stiffness may be a determinant of retinal microvascular dysfunction. [ABSTRACT FROM AUTHOR]

Objective: Obesity and liver fat are associated with decreased levels of serum sex hormone binding globulin (SHBG). Laboratory studies suggest that hepatic de novo lipogenesis (DNL) is involved in the downregulation of SHBG synthesis. The aim of the present study was to address the role of DNL on serum SHBG in humans. Design: A cross‐sectional study examining the association between DNL, measured by stable isotopes, and serum SHBG, stratified by sex. Participants: Healthy men (n = 34) and women (n = 21) were combined from two cross‐sectional studies. Forty‐two per cent of participants had hepatic steatosis, and the majority were overweight (62%) or obese (27%). Results: DNL was inversely associated with SHBG in women (β: −0.015, 95% CI: −0.030; 0.000), but not in men (β: 0.007, 95% CI: −0.005; 0.019) (p for interaction =.068). Adjustment for study population, age and body mass index did not materially change these results, although statistical significance was lost after adjustment for serum insulin. Conclusions: An inverse association between DNL and SHBG may explain the decreased SHBG levels that are observed in obesity, at least in women. [ABSTRACT FROM AUTHOR]

Background & Aims: Plasma soluble E‐selectin (sE‐selectin) is a frequently used biomarker of systemic endothelial dysfunction. The present study explored the relationship between nonalcoholic fatty liver disease (NAFLD) and plasma sE‐selectin levels. Methods: Expression of E‐selectin in liver, visceral adipose tissue (VAT) and muscle was studied in relation to plasma sE‐selectin in severely obese individuals (n = 74). The course of hepatic E‐selectin expression in relation to hepatic steatosis and inflammation was examined in C57BL/6J LDLR−/− mice on a Western‐type diet. The relationship between biomarkers of NAFLD, that is, plasma aminotransferase (ALT) and NAFLD susceptibility genes (rs738409 [PNPLA3] and rs1260326 [GCKR]), and plasma sE‐selectin was studied in the combined CODAM (n = 571) and Hoorn (n = 694) studies. Results: E‐selectin expression in liver, not VAT or muscle, was associated with plasma sE‐selectin in severely obese individuals (β = 0.26; 95% CI: 0.05‐0.47). NAFLD severity was associated with hepatic E‐selectin expression (P =.02) and plasma sE‐selectin (P =.003). LDLR−/− mice on a Western‐type diet displayed increased hepatic E‐selectin expression that followed the same course as hepatic inflammation, but not steatosis. In the CODAM study, plasma ALT was associated with plasma sE‐selectin, independent of potential confounders (β = 0.25; 95% CI: 0.16‐0.34). Both rs738409 and rs1260326 were associated with higher plasma sE‐selectin in the combined CODAM and Hoorn studies (P =.01 and P =.004 respectively). Conclusions: NAFLD and related markers are associated with higher expression of hepatic E‐selectin and higher levels of plasma sE‐selectin. Further studies are required to investigate the role of E‐selectin in the pathogenesis of NAFLD and the applicability of sE‐selectin as a plasma biomarker of NAFLD/NASH. [ABSTRACT FROM AUTHOR]

Objective: To examine the associations of gestational weight gain (GWG) and diet with low-grade inflammation in pregnancy.Methods: A cross-sectional analysis of 671 pregnant women was performed, and diet was assessed in gestational week 30. GWG was recorded in weeks 30 and ∼37 (difference between the weight recorded at these time points and pre-pregnancy weight). Markers of inflammation, high-sensitivity C-reactive protein (hsCRP), serum amyloid A (SAA), interleukin (IL)-6, IL-8, IL-1β, and tumor necrosis factor-α were quantified in serum from week 30.Results: After adjusting for age, pre-pregnancy BMI, parity, smoking status, and education, each 1 kg increase in GWG was associated with 3% (95% CI: 1-5) higher hsCRP and 3% (95% CI: 1-4) higher SAA concentrations, which corresponded to ∼18% to 25% increase in these biomarkers among those with excessive weight gain. GWG was inversely associated with IL-8 while no associations were found for the other inflammatory markers. With respect to diet, women in the highest compared with lowest quintile of protein intake had 26% (95% CI: 3-54) higher hsCRP concentrations. This increase appeared to be driven by intake of animal protein. A similar pattern was observed for SAA.Conclusions: Excessive GWG, as well as high intake of animal protein, was associated with higher concentrations of inflammatory factors. [ABSTRACT FROM AUTHOR]

Objective N(ε)-(carboxymethyl)lysine ( CML) is one of the major advanced glycation end products in both diabetics and nondiabetics. CML depositions in the microvasculature have recently been linked to the aetiology of acute myocardial infarction and cognitive impairment in Alzheimer's disease, possibly related to local enhancement of inflammation and oxidative processes. We hypothesized that CML deposition in the microvasculature of the heart and brain is age-induced and that it could be inhibited by a diet intervention with docosahexaenoic acid ( DHA), an omega-3 fatty acid known for its anti-inflammatory and antioxidative actions. Materials and methods ApoE−/− mice ( n = 50) were fed a Western diet and were sacrificed after 40, 70 and 90 weeks. Part of these mice ( n = 20) were fed a Western diet enriched with DHA from 40 weeks on. CML in cardiac and cerebral microvessels was quantified using immunohistochemistry. Results Cardiac microvascular depositions of CML significantly increased with an immunohistochemical score of 11·85 [5·92-14·60] at 40 weeks, to 33·17 [17·60-47·15] at 70 weeks ( P = 0·005). At the same time points, cerebral microvascular CML increased from 6·45; [4·78-7·30] to 12·99; [9·85-20·122] ( P = 0·003). DHA decreased CML in the intramyocardial vasculature at both 70 and 90 weeks, significant at 70 weeks [33·17; (17·60-47·15) vs. 14·73; (4·44-28·16) P = 0·037]. No such effects were found in the brain. Conclusions Accumulation of N(ε)-(carboxymethyl)lysine in the cerebral and cardiac microvasculature is age-induced and is prevented by DHA in the intramyocardial vessels of ApoE−/− mice. [ABSTRACT FROM AUTHOR]

Objective Growing evidence indicates that the metabolic syndrome (MS) is rooted in adverse exposures during fetal life. The aim of this study was to assess the possible associations between biomarkers of inflammation during third trimester of pregnancy and markers of MS in adult offspring. Methods High-sensitive C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), interleukin-1β (IL-1β) and interleuki-6 (IL-6) were measured in serum samples obtained in gestational week 30. Offspring were clinically examined at age 20 years. Analyses based on 439 mother-offspring dyads were adjusted for maternal smoking during pregnancy, height, prepregnancy body mass index (BMI), education, and offspring's sex. Offspring MS markers included waist circumference, BMI, blood pressure, HOMA insulin resistance, and plasma levels of fasting glucose, triglycerides, cholesterol fractions, insulin, and leptin. Results The median level was 2.8 (interquartile range = 3.3) µg/ml for CRP, for TNF-α: 5.7 (3.2) pg/ml, for IL-1β: 0.5 (0.4) pg/ml, and for IL-6: 1.1 (0.7) pg/ml. Concentrations were not significantly associated with MS markers in the offspring. The results remained essentially unchanged after correction for potential confounding. Conclusion Markers for subclinical inflammation in third trimester in healthy women were not associated with components of MS in their adult offspring. [ABSTRACT FROM AUTHOR]

We report on a 21-year-old pregnant patient with IgA nephropathy who was initiated on intensive hemodialysis (8 hours of hemodialysis 3 times a week) at a gestational age of 26 weeks on the basis of worsening kidney function resulting in rapidly progressive fatigue and difficulties in metabolic control. Throughout the pregnancy, and while on intensive hemodialysis, 24-hour ambulatory blood pressure control was within the target, and results of weekly 24-hour measurement of central hemodynamics and pulse wave velocity, and of serial levels of circulating (anti-)angiogenic factors were comparable to normal pregnancies. Estimated fetal growth evolved along the 50th percentile, and no polyhydramnios was detected. After induction for a sudden, unexplained increase in blood pressure, she delivered a healthy boy of 2480 g at a gestational age of 36 weeks. This case adds to the expanding literature that supports the use of intensive hemodialysis in pregnant patients with end-stage renal disease and illustrates, for the first time, the potential use of serial (anti-) angiogenic factors and 24-hour measurements of blood pressure and hemodynamic indices in order to facilitate monitoring of these complicated patients. [ABSTRACT FROM AUTHOR]

Background The complement system may be involved in the pathogenesis of alcoholic and nonalcoholic liver disease, although studies in humans are scarce. For this reason, we investigated whether circulating levels of activated complement factor 3 (C3a) were associated with hepatic steatosis and hepatocellular damage. Materials and methods Plasma C3a, aspartate aminotransferase ( AST), alanine aminotransferase ( ALT) and gamma-glutamyl transferase ( GGT) were determined in 523 individuals (61% men, age 59 ± 7 years). Liver enzymes ( LEs) were standardized and compiled into a LE score. Liver fat content was estimated using a predictive equation that has recently been validated with magnetic resonance spectrometry. Cross-sectional associations between C3a and liver fat or LE s were investigated with multiple linear regression analyses, stratified in no-to-moderate vs. heavy alcohol consumers (men: > 30 g/day; women: > 20 g/day). Results C3a was associated with liver fat percentage both in the no-to-moderate (β = 0·223; 95%CI 0·036; 0·409) and in the heavy alcohol consumers (β = 0·632; 95%CI 0·259-1·004; P-interactio n = 0·047). C3a was also associated with the LE score in heavy alcohol consumers (β = 0·917; 95%CI 0·443-1·392), but not in no-to-moderate alcohol consumers (β = 0·042; 95%CI −0·198 to 0·281; P-interaction = 0·001). Conclusions C3a levels, as a marker of complement activation, were associated with liver fat content and hepatocellular injury, at least in subjects who consume considerable amounts of alcohol daily. [ABSTRACT FROM AUTHOR]

Abdominal fat-related activation of the innate immune system and insulin resistance (IR) are implicated in the pathogenesis of cardiovascular diseases. Recent data support an important role of the adaptive immune system as well. In this study, we investigate the association between waist circumference and markers of systemic adaptive immune activation, and the potential mediating role of innate immune activation and/or IR herein. The study population consisted of 477 (304 men) individuals (mean age: 59.4 ± 7.0 years) in whom waist circumference, HOMA2-IR (IR derived from homeostasis model assessment), and markers of innate (C-reactive protein (CRP), interleukin (IL)-6, serum amyloid A (SAA)) and adaptive (neopterin, soluble CD25 (sCD25)) immune activation were measured. These markers were compiled into an adaptive and innate immune activation score by averaging the respective z-scores. After adjustments for age, sex, glucose metabolism, smoking status, prior cardiovascular disease, and other risk factors, waist circumference was associated with the adaptive (standardized regression coefficient β = 0.12 (95% confidence intervals: 0.04-0.20)) and the innate immune activation scores (β = 0.24 (0.17-0.31)), and with HOMA2-IR (β = 0.49 (0.42-0.56)). The innate immune activation score and HOMA2-IR were also positively associated with the adaptive immune activation score (β = 0.31 (0.21-0.40) and β = 0.11 (0.02-0.21), respectively). The association between waist circumference and the adaptive immune activation score was completely abolished when further adjusted for innate immune activation and HOMA2-IR (to β = −0.01 (−0.10-0.08)), and the specific mediation 'effects' attributable to each of these variables were 58% and 42%, respectively. We conclude that abdominal obesity is associated with systemic adaptive immune activation and that innate immune activation and IR constitute independent and equally important pathways explaining this association. [ABSTRACT FROM AUTHOR]

Background Complement C3, a central component of the innate immune system is increased in subjects with obesity and type 2 diabetes and is a novel risk factor for cardiovascular disease. We hypothesized that the strong association between insulin resistance and circulating amounts of C3 may be related to hepatic fat accumulation-independent of central obesity itself and of a general low-grade inflammatory response. Research question To what extent is the association between insulin resistance and C3 explained by plasma levels of alanine aminotransferase (ALT) as a surrogate of hepatic fat accumulation. Methods Cross-sectional analyses conducted in the Cohort on Diabetes and Atherosclerosis Maastricht (CODAM) study. Analyses were restricted to subjects with none-to-moderate alcohol consumption (n = 453, 61.4% men). Multiple linear regression analyses were used to investigate the association between HOMA2IR (main determinant) and circulating complement C3 (main outcome), and the mediating role of ALT herein. All analyses were adjusted for age, sex, presence of type 2 diabetes mellitus or heart disease, use of medication, smoking, alcohol consumption, waist circumference and inflammation. Results Insulin resistance (estimated as HOMA2IR) was strongly associated with circulating C3 (standardized regression coefficient β 0.40 [95% CI: 0.30; 0.49]) and also with ALT (β 0.44 [0.34; 0.54]), both adjusted for the above-mentioned covariates. The association between HOMA2IR and C3 was attenuated after further adjustment for ALT (β decreased to 0.34 [0.24; 0.44]). Concluding Remarks Plasma ALT can explain 14.2% of the strong association between insulin resistance and circulating concentrations of complement C3, independent of central obesity and general inflammation. [ABSTRACT FROM AUTHOR]

Background: The metabolic syndrome is associated with coronary artery disease (CAD) and with peripheral artery disease (PAD), but the underlying mechanisms explaining these associations have not yet been completely clarified. The aim was to investigate (i) whether endothelial dysfunction can explain the association between the metabolic syndrome and CAD and ⁄ or the severity of PAD, as measured by the ankle–arm index (AAIx); and (ii) whether any such mediation is independent of that from low-grade inflammation. Materials and methods We studied 539 subjects (232 men) aged 59Æ4 ± 6Æ9 years, with an increased risk of type 2 diabetes and cardiovascular diseases. Endothelial dysfunction and inflammation scores were calculated from three markers of endothelial dysfunction (soluble E-selectin, soluble vascular cell adhesion molecule-1 and von Willebrand factor) and six of inflammation (C-reactive protein, interleukin 6, soluble intercellular adhesion molecule-1, serum amyloid A, ceruloplasmin and haptoglobin). The association between the metabolic syndrome and CAD and ⁄ or PAD, and the mediating role of endothelial dysfunction herein was examined with logistic and linear regression analyses, all adjusted for age, sex and smoking. Results: Subjects with the metabolic syndrome (n = 289; 54%) had higher prevalence of CAD [OR (95%CI) = 1Æ75 (1Æ14; 2Æ69)] and lower AAIx [b (95% CI) = )0Æ036 ()0Æ056; )0Æ016)]. Endothelial dysfunction explained 6% of the association between the metabolic syndrome and CAD, and 19% of the association with AAIx, whereas low-grade inflammation explained 26% and 28% of these associations, respectively. Together, the two scores explained 24% and 36% of the association between the metabolic syndrome and CAD and AAIx, respectively. Conclusions: Endothelial dysfunction explains part of the association between the metabolic syndrome and the severity of PAD, but is not involved in the association between the metabolic syndrome and CAD. This indicates that the pathophysiologies of coronary and peripheral artery disease are essentially distinct. [ABSTRACT FROM AUTHOR]

Oxidative stress plays an important role in the pathophysiology of sickle cell disease (SCD). Plasma levels of advanced glycation end products (AGEs) are increased under oxidative conditions and are associated with disease severity in diabetes and inflammatory diseases. We investigated whether AGEs are increased in sickle cell patients and whether they are associated with SCD-related complications. Plasma levels of the AGEs pentosidine, Nε-(carboxymethyl)lysine (CML) and Nε-(carboxyethyl)lysine (CEL) were measured using single-column high performance liquid chromatography with fluorescence detection (pentosidine) and ultra performance liquid chromatography-tandem mass spectrometry (CML and CEL). Plasma levels of pentosidine and CML were increased in HbSS/HbSβ0-thalassaemia ( n = 60) and HbSC/HbSβ+-thalassaemia ( n = 42) patients during steady state as compared to healthy HbAA controls ( n = 30) without increments during painful crisis. CEL levels were comparable between all groups. Pentosidine and CML levels correlated significantly to haemolytic rate during the clinically asymptomatic state while pentosidine was significantly related to the number of haemolysis-related organ complications. The increased plasma AGE levels in sickle cell patients and their association with haemolysis and haemolysis-related complications suggest AGEs might be implicated in the pathophysiology of the haemolytic phenotype of SCD. Measurement of AGEs might be useful in predicting organ complications in SCD. [ABSTRACT FROM AUTHOR]

Aims: To investigate the relationship between advanced glycation end-products (AGEs) and diastolic function and the response to blood pressure treatment in patients with hypertension and diastolic dysfunction. [ABSTRACT FROM PUBLISHER]

Diabetic foot disease is an important complication of diabetes. The development and outcome of foot ulcers are related to the interplay between numerous diabetes-related factors such as nerve dysfunction, impaired wound healing and microvascular and/or macrovascular disease. The formation of advanced glycation end products (AGEs) has been recognized as an important pathophysiological mechanism in the development of diabetic complications. Several mechanisms have been proposed by which AGEs lead to diabetic complications such as the accumulation of AGEs in the extracellular matrix causing aberrant cross-linking, the binding of circulating AGEs to the receptor of AGEs (RAGE) on different cell types and activation of key cell signalling pathways with subsequent modulation of gene expression, and intracellular AGE formation leading to quenching of nitric oxide and impaired function of growth factors. In the last decade, many experimental studies have shown that these effects of AGE formation may play a role in the pathogenesis of micro- and macrovascular complications of diabetes, diabetic neuropathy and impaired wound healing. In recent years also, several clinical studies have shown that glycation is an important pathway in the pathophysiology of those complications that predispose to the development of foot ulcers. Currently, there are a number of ways to prevent or decrease glycation and glycation-induced tissue damage. Although not in the area of neuropathy or wound healing, recent clinical studies have shown that the AGE-breakers may be able to decrease adverse vascular effects of glycation with few side effects. Copyright © 2008 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Increased formation of the reactive dicarbonyl compound methylglyoxal (MGO) and MGO-derived advanced glycation end products (AGEs) seems to be implicated in endothelial dysfunction and the development of diabetic vascular complications. MGO reacts with arginine residues in proteins to generate the major glycated adducts 5-hydro-5-methylimidazolone (MG-H1) and argpyrimidine (AP). We investigated whether the free forms of these adducts contribute to vascular cell dysfunction by inhibition of endothelial nitric oxide synthase (eNOS). MG-H1 and AP were synthesized and purified by reversed-phase chromatography, and the conversion of labeled L-arginine to L-citrulline was used to monitor eNOS activity. In contrast to the endogenous eNOS inhibitor asymmetric dimethylarginine (half maximal inhibitory concentration, approximately 5 μmol/L), pathophysiological concentrations of MGO and MG-H1 and AP did not inhibit eNOS activity. Although MGO-derived AGEs are implicated in the development of diabetic vascular complications, this study indicates that this is not mediated via direct inhibition of eNOS activity. [ABSTRACT FROM AUTHOR]

Genetic variation in the receptor for advanced glycation end products (RAGE) gene may alter the expression and function of RAGE and affect disease development and outcome. We investigated whether single nucleotide polymorphisms (SNPs) in RAGE were associated with diabetes and parameters of glucose homeostasis. In total, nine SNPs of RAGE were analyzed in individuals with and without type 2 diabetes in CODAM: a cohort study of diabetes and atherosclerosis, Maastricht. A significant difference in genotype frequency of SNP rs3134945 was observed between the nondiabetic control subjects, subjects with impaired glucose metabolism, and diabetic patients. The C allele of this polymorphism was significantly associated with higher fasting glucose concentrations, 2-h postload glucose concentrations, insulin levels, and homeostasis model assessment of insulin resistance. These results indicate that SNP rs3134945 or a locus in linkage disequilibrium with this polymorphism may be involved in the development of insulin resistance and diabetes. Because the functionality of this polymorphism is not known, the mechanism whereby this polymorphism contributes to the development of insulin resistance and diabetes has to be further elucidated. [ABSTRACT FROM AUTHOR]

Abstract: In endothelial cells cultured under high glucose conditions, methylglyoxal is the major intracellular precursor in the formation of advanced glycation endproducts. We found that endothelial cells incubated with 30mM d-glucose produced approximately 2-fold higher levels of methylglyoxal but not 3-deoxyglucosone and glyoxal, as compared to 5mM d-glucose. Under hyperglycaemic conditions, the methylglyoxal-arginine adduct argpyrimidine as detected with a specific antibody, but not Ne-(carboxymethyl)lysine and Ne-(carboxyethyl)lysine, was significantly elevated. The glyoxylase I inhibitor HCCG and the PPARγ ligand troglitazone also increased argpyrimidine levels. Increased levels of argpyrimidine by glucose, HCCG and troglitazone are accompanied by a decrease in proliferation of endothelial cells. A 27kDa protein was detected as a major argpyrimidine-modified protein. With in-gel digestion and mass spectrometric analysis, we identified this major protein as heat-shock protein 27 (Hsp27). This argpyrimidine modification of Hsp27 may contribute to changes in endothelial cell function associated to diabetes. [Copyright &y& Elsevier]

Tumors are generally characterized by an increased glucose uptake and a high rate of glycolysis. Since one consequence of an elevated glycolysis is the nonenzymatic glycation of proteins, we studied the presence of advanced glycation end products (AGEs) in human cancer tissues. We detected the presence of the AGEs Nε-(carboxymethyl)lysine (CML) and argpyrimidine in several human tumors using specific antibodies. Because AGEs have been associated with the etiology of a variety of different diseases, these results suggest that CML and argpyrimidine could be implicated in the biology of human cancer. [ABSTRACT FROM AUTHOR]

Patients with renal impairment have an increased risk for cardiovascular disease, which may be the result of advanced glycation end products (AGEs). The aim of this study was to investigate the levels of AGE peptides in relation to kidney function and to study the relationship of AGE peptides with endothelial function and inflammation in type 1 diabetic patients. We measured plasma levels of AGE peptides with a simple fluorescent analytical procedure in patients with end-stage renal disease with or without diabetes and in 60 type 1 diabetic patients categorized as having normo-, micro-, or macroalbuminuria. Using enzyme-linked immunosorbent assays, we determined vascular cell adhesion molecule 1 (sVCAM-1), sE-selectin, plasminogen activator inhibitor 1 (PAI-1), tissue type-specific plasminogen activator (tPA), von Willebrand factor (vWF), and soluble thrombomodulin (sTM) to be markers of endothelial function and determined C-reactive protein (CRP) to be a marker of inflammation. AGE peptides were increased approximately fivefold in patients with end-stage renal disease, without difference between patients with or without diabetes. In type 1 diabetic patients, the increase of AGE peptides across the groups normo-, micro-, and macroalbuminuria (with medians [range] of 12.6% [7.8-27.2%], 12.1% [7.8-162%], and 46.5% [9.0-248.9%]) was associated with serum creatinine level and not with albumin excretion rate (AER). The relationship with serum creatinine decreased but remained significant after adjusting for age, sex, diabetes duration, hemoglobin A1c (HbA1c), AER, systolic and diastolic blood pressure (BP), and CRP in multiple linear-regression analysis. AGE peptide levels were significantly associated with sVCAM-1 and sTM, independently of serum creatinine. However, these relationships were no longer significant after adjusting for age, sex, diabetes duration, HbA1c, AER, systolic and diastolic BP, and CRP. This study shows that plasma levels of AGE peptides rise with renal impairment, as determined by serum creatinine. AGE peptides are associated with some markers of endothelial activation, which may suggest an involvement of AGE peptides in the acceleration of cardiovascular complications in type 1 diabetic patients with renal impairment. [ABSTRACT FROM AUTHOR]

The Maillard reaction is a process in which reducing sugars react spontaneously with amino groups in proteins to advanced glycation endproducts (AGEs). Although an elevated level of glucose had been thought to play a primary role in the Maillard reaction, on a molecular basis, glucose is among the least reactive sugars within biological systems. The formation of AGEs is now also known to result from the action of various metabolites other than glucose, which are primarily located intracellularly and participate in the non-enzymatic glycation reaction at a much faster rate, such as fructose, trioses and dicarbonyl compounds. In this review, we considered the glycation reaction with particular attention to the potential role of fructose and fructose metabolites. The two sources for fructose are an exogenous supply from the diet and the endogenous formation from glucose through the aldose reductase pathway. Despite its ∼eightfold higher reactivity, the contribution of extracellular glycation by fructose is considerably less than that by glucose, because of the low plasma concentration of fructose (5 mmol/L glucose vs 35 µmol/L fructose). Intracellularly, fructose is elevated in a number of tissues of diabetic patients in which the polyol pathway is active. In the cells of these tissues, the concentrations of fructose and glucose are of the same magnitude. Although direct evidence is not yet available, it is likely that the high reactivity of fructose and its metabolites may substantially contribute to the formation of intracellular AGEs and may contribute to alterations of cellular proteins, dysfunction of cells and, subsequently, to vascular complications. Copyright © 2004 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Summary We aimed to examine the effects of isocaloric fructose restriction on adipose tissue distribution and serum adipokines. Individuals with BMI >28 kg/m2 (n = 44) followed a 6‐week fructose‐restricted diet and were randomly allocated to (double‐blind) oral supplementation with fructose (control) or glucose (intervention) powder three times daily. Visceral (VAT) and subcutaneous (SAT) adipose tissue was quantified with MRI. Serum interleukin 6 and 8, tumour necrosis factor alpha and adiponectin levels were measured with sandwich immunoassay. BMI decreased in both groups, but the change did not differ between groups (−0.1 kg/m2, 95%CI: −0.3; 0.5). SAT decreased statistically significantly in the control group (−23.2 cm3, 95%CI: −49.4; −4.1), but not in the intervention group. The change in SAT did not differ between groups (29.6 cm3, 95%CI: −1.2; 61.8). No significant differences in VAT were observed within or between study arms. The VAT/SAT ratio decreased statistically significantly in the intervention group (−0.02, 95%CI: −0.04; −0.003) and the change was significantly different between groups (−0.03, 95%CI: −0.54; −0.003). Serum adipokine levels were not affected by the intervention. This study shows that a fructose‐restricted diet resulted in a favourable change in adipose tissue distribution, but did not affect serum adipokines. Further studies are warranted to clarify the underlying mechanisms how fructose affects adipose tissue distribution. [ABSTRACT FROM AUTHOR]

Key points Diabetes is associated with cognitive impairment, but the underlying mechanism remains unclear. Methylglyoxal (MGO), a precursor to advanced glycation endproducts (AGEs), is elevated in diabetes and linked to microvascular dysfunction. In this study, overexpression of the MGO‐detoxifying enzyme glyoxalase 1 (Glo1) was used in a mouse model of diabetes to explore whether MGO accumulation in diabetes causes cognitive impairment. Diabetes was induced with streptozotocin. Fasting blood glucose, cognitive function, cerebral blood flow, neurovascular coupling (NVC), Glo1 activity, MGO and AGEs were assessed. In diabetes, MGO‐derived hydroimidazolone‐1 increased in the cortex, and was decreased in Glo1‐overexpressing mice compared to controls. Visuospatial memory was decreased in diabetes, but not in Glo1/diabetes. NVC response time was slightly increased in diabetes, and normalised in the Glo1‐overexpressing group. No impact of diabetes or Glo1 overexpression on blood–brain barrier integrity or vascular density was observed. Diabetes induced a mild visuospatial memory impairment and slightly reduced NVC response speed and these effects were mitigated by Glo1. This study shows a link between MGO‐related AGE accumulation and cerebrovascular/cognitive functions in diabetes. Modulation of the MGO–Glo1 pathway may be a novel intervention strategy in patients with diabetes who have cerebrovascular complications. Diabetes is associated with an increased risk of stroke, cognitive decline, depression and Alzheimer's disease, but the underlying mechanism remains unclear. Methylglyoxal (MGO), a highly reactive by‐product of glycolysis, plays an important role in the development of diabetes‐associated microvascular dysfunction in the periphery and is detoxified by the enzyme glyoxalase 1. Diabetes reduced visuospatial memory in mice and slowed the neurovascular coupling response speed, which was improved by overexpression of glyoxalase 1. MGO formation and MGO‐derived advanced glycation endproduct (AGE) accumulation in the brain of diabetic mice are associated with a slight reduction in neurovascular coupling and mild cognitive impairment. The endogenous formation of MGO, and the accumulation of MGO‐derived AGEs, might be a potential target in reducing the risk of vascular cognitive impairment in people with diabetes. [ABSTRACT FROM AUTHOR]

Phospholipase A2 (PLA2) is a key enzyme in the release of arachidonic acid and subsequent production of eicosanoids, which play an important role in a variety of biological processes, including mitogenic signalling by epidermal growth factor (EGF). In a previous study [Spaargaren, M. et al. (1992) Biochem J. 287, 37–43] we identified the EGF-activated PLA2 as being similar to the recently cloned high-molecular-mass cytosolic phospholipase A2 (cPLA2). In the present study we demonstrate a rapid transient EGF-induced activation of this cPLA2 and an EGF-induced increase in phosphorylafion of the cPLA2. The EGF-induced activation of cPLA2 is reversed upon phosphatase treatment showing phosphorylation-dependent activation of the cPLA2. No direct association of the cPLA2 to the EGF receptor was detected under conditions where such an association with phospholipase C-γ was demonstrated. Phosphoamino acid analysis of this cPLA2 showed that EGF induced an increase in serine phosphorylation exclusively, no tyrosine phosphorylation being observed. EGF treatment of the cells resulted in a Ca2+-dependent translocation of the cPLA2 from the cytosol to the membrane fraction. This is due to an EGF-induced [Ca2+] rise which is dependent on the influx of extracellular Ca2+ via voltage-independent Ca2+ channels. It is shown that the Ca2+-dependent association of cPLA2 to membranes does not require accessory membrane molecules. [ABSTRACT FROM AUTHOR]

Interleukin-1β induces gene expression and secretion of group-II phospholipase A2 and release of prostaglandin E2 from rat mesangial cells. The interleukin-1β-induced synthesis of group-II phospholipase A2 is prevented by transforming growth factor-β2, whereas transforming growth factor-β2 potentiated the interleukin-1β-evoked prostaglandin E2 production. Transforming growth factor-β2 itself did not induce synthesis of group-II phospholipase A2, although it stimulated prostaglandin E2 formation. Here we describe the effect of interleukin-1β and transforming growth factor-β2 on a cytosolic phospholipase A2 activity and prostaglandin E2 formation in rat mesangial cells. Based on the resistance to dithiothreitol and migration profiles on a Mono-Q anion-exchange column and a Superose 12 gel-filtration column, the cytosolic phospholipase A2 activity was assigned to a high-molecular-mass phospholipase A2. Measured with 1-stearoyl-2-[1-14C]arachidonoylglycerophosphocholine as substrate, both interleukin-1β and transforming growth factor-β2 enhanced the high-molecular-mass phospholipase A2 activity. The stimulation of rat mesangial cells with interleukin-1β and transforming growth factor-β2 was time- and dose-dependent with maximal cytosolic phospholipase A2 activities at 10 nM and at 10 ng/ml respectively, after 24 h of stimulation. Under these conditions, interleukin-1β and transforming growth factor-β2 enhanced the cytosolic phospholipase A2 activity 2.2±0.6-fold and 2.5±0.6-fold, respectively. These results strongly suggest that an enhanced cytosolic high-molecular-mass phospholipase A2 activity is involved in the formation of prostaglandin E2 mediated by transforming growth factor-β2. Whether interleukin-1β induced group-II phospholipase A2 and/or interleukin-1β-enhanced cytosolic phospholipase A2 activity is involved in prostaglandin E2 formation in rat mesangial cells is discussed. [ABSTRACT FROM AUTHOR]

Phospholipase A2 (PLA2) is a key enzyme in the release of arachidonic acid and subsequent production of eicosanoids, which play an important role in a variety of biological processes, including mitogenic signalling by epidermal growth factor (EGF). In a previous study [Spaargaren, M. et al. (1992) Biochem J. 287, 37–43] we identified the EGF-activated PLA2 as being similar to the recently cloned high-molecular-mass cytosolic phospholipase A2 (cPLA2). In the present study we demonstrate a rapid transient EGF-induced activation of this cPLA2 and an EGF-induced increase in phosphorylafion of the cPLA2. The EGF-induced activation of cPLA2 is reversed upon phosphatase treatment showing phosphorylation-dependent activation of the cPLA2. No direct association of the cPLA2 to the EGF receptor was detected under conditions where such an association with phospholipase C-γ was demonstrated. Phosphoamino acid analysis of this cPLA2 showed that EGF induced an increase in serine phosphorylation exclusively, no tyrosine phosphorylation being observed. EGF treatment of the cells resulted in a Ca2+-dependent translocation of the cPLA2 from the cytosol to the membrane fraction. This is due to an EGF-induced [Ca2+] rise which is dependent on the influx of extracellular Ca2+ via voltage-independent Ca2+ channels. It is shown that the Ca2+-dependent association of cPLA2 to membranes does not require accessory membrane molecules. [ABSTRACT FROM AUTHOR]

We aimed to examine the effects of isocaloric fructose restriction on adipose tissue distribution and serum adipokines. Individuals with BMI >28 kg/m 2 (n = 44) followed a 6-week fructose-restricted diet and were randomly allocated to (double-blind) oral supplementation with fructose (control) or glucose (intervention) powder three times daily. Visceral (VAT) and subcutaneous (SAT) adipose tissue was quantified with MRI. Serum interleukin 6 and 8, tumour necrosis factor alpha and adiponectin levels were measured with sandwich immunoassay. BMI decreased in both groups, but the change did not differ between groups (-0.1 kg/m 2 , 95%CI: -0.3; 0.5). SAT decreased statistically significantly in the control group (-23.2 cm 3 , 95%CI: -49.4; -4.1), but not in the intervention group. The change in SAT did not differ between groups (29.6 cm 3 , 95%CI: -1.2; 61.8). No significant differences in VAT were observed within or between study arms. The VAT/SAT ratio decreased statistically significantly in the intervention group (-0.02, 95%CI: -0.04; -0.003) and the change was significantly different between groups (-0.03, 95%CI: -0.54; -0.003). Serum adipokine levels were not affected by the intervention. This study shows that a fructose-restricted diet resulted in a favourable change in adipose tissue distribution, but did not affect serum adipokines. Further studies are warranted to clarify the underlying mechanisms how fructose affects adipose tissue distribution., (© 2024 The Author(s). Clinical Obesity published by John Wiley & Sons Ltd on behalf of World Obesity Federation.)

Background: We evaluated the ability of 23 novel biomarkers representing several pathophysiological pathways to improve the prediction of cardiovascular event (CVE) risk in patients with type 2 diabetes mellitus beyond traditional risk factors., Methods and Results: We used data from 1002 patients with type 2 diabetes mellitus from the Second Manifestations of ARTertial disease (SMART) study and 288 patients from the European Prospective Investigation into Cancer and Nutrition-NL (EPIC-NL). The associations of 23 biomarkers (adiponectin, C-reactive protein, epidermal-type fatty acid binding protein, heart-type fatty acid binding protein, basic fibroblast growth factor, soluble FMS-like tyrosine kinase-1, soluble intercellular adhesion molecule-1 and -3, matrix metalloproteinase [MMP]-1, MMP-3, MMP-9, N-terminal prohormone of B-type natriuretic peptide, osteopontin, osteonectin, osteocalcin, placental growth factor, serum amyloid A, E-selectin, P-selectin, tissue inhibitor of MMP-1, thrombomodulin, soluble vascular cell adhesion molecule-1, and vascular endothelial growth factor) with CVE risk were evaluated by using Cox proportional hazards analysis adjusting for traditional risk factors. The incremental predictive performance was assessed with use of the c-statistic and net reclassification index (NRI; continuous and based on 10-year risk strata 0-10%, 10-20%, 20-30%, >30%). A multimarker model was constructed comprising those biomarkers that improved predictive performance in both cohorts. N-terminal prohormone of B-type natriuretic peptide, osteopontin, and MMP-3 were the only biomarkers significantly associated with an increased risk of CVE and improved predictive performance in both cohorts. In SMART, the combination of these biomarkers increased the c-statistic with 0.03 (95% CI 0.01-0.05), and the continuous NRI was 0.37 (95% CI 0.21-0.52). In EPIC-NL, the multimarker model increased the c-statistic with 0.03 (95% CI 0.00-0.03), and the continuous NRI was 0.44 (95% CI 0.23-0.66). Based on risk strata, the NRI was 0.12 (95% CI 0.03-0.21) in SMART and 0.07 (95% CI -0.04-0.17) in EPIC-NL., Conclusions: Of the 23 evaluated biomarkers from different pathophysiological pathways, N-terminal prohormone of B-type natriuretic peptide, osteopontin, MMP-3, and their combination improved CVE risk prediction in 2 separate cohorts of patients with type 2 diabetes mellitus beyond traditional risk factors. However, the number of patients reclassified to a different risk stratum was limited., (© 2016 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley Blackwell.)