Protein-Bound Plasma N\u3csup\u3eε\u3c/sup\u3e-(Carboxymethyl)lysine Is Inversely Associated with Central Obesity and Inflammation and Significantly Explain a Part of the Central Obesity-Related Increase in Inflammation: The Hoorn and CODAM Studies

Adipose tissue inflammation contributes to the development of complications, such as insulin resistance and type 2 diabetes mellitus. We previously reported that plasma levels of N ε -(carboxymethyl)lysine (CML) were decreased in obese subjects resulting from CML accumulation in adipose tissue and that this CML accumulation plays an important role in adipose tissue inflammation. The objective of this study is to investigate associations between obesity (body mass index, waist circumference, and trunk fat mass), plasma CML (as an inversely correlated marker of CML accumulation in adipose tissue), and low-grade inflammation (LGI) in a large sample of individuals whose weight status ranged from normal to morbid obesity. Approach and Results-We studied 1270 individuals of the Cohort on Diabetes and Atherosclerosis Maastricht Study and Hoorn Study, in whom protein-bound CML levels were measured by UPLC-Tandem MS (ultra performance liquid chromatography-tandem mass spectrometry), and 6 inflammatory markers were measured with multiarrays. These inflammatory markers were compiled into an LGI score. Multiple linear regression, adjusted for covariates, showed that (1) waist circumference was inversely associated with protein-bound CML plasma levels (standardized regression coefficient [β]=-0.357 [95% confidence interval:-0.414;-0.301] ); (2) protein-bound CML was inversely associated with LGI score (β=-0.073 [-0.130;-0.015]); and (3) the association between waist circumference and LGI (β=0.262 [0.203;0.321] ) was attenuated after adjustment for protein-bound CML plasma levels and other potential mediators (to β=0.202 [0.138;0.266]), with CML explaining the greatest portion of the attenuation (≈12%). Further analysis with dual-energy X-ray absorptiometry measures of body composition confirmed a strong inverse association of fat mass preferentially accumulated in the trunk with protein-bound CML plasma levels, significantly explaining ≈21% of the trunk fat-LGI association. Conclusions-Obesity, in particular central obesity, is characterized by greater levels of LGI but by lower levels of circulating CML; the latter significantly explaining a portion of the positive association between central obesity and inflammation

Protein-Bound Plasma N-epsilon-(Carboxymethyl) lysine Is Inversely Associated With Central Obesity and Inflammation and Significantly Explain a Part of the Central Obesity-Related Increase in Inflammation The Hoorn and CODAM Studies

- OBJECTIVE: Adipose tissue inflammation contributes to the development of complications, such as insulin resistance and type 2 diabetes mellitus. We previously reported that plasma levels of N(epsilon)-(carboxymethyl)lysine (CML) were decreased in obese subjects resulting from CML accumulation in adipose tissue and that this CML accumulation plays an important role in adipose tissue inflammation. The objective of this study is to investigate associations between obesity (body mass index, waist circumference, and trunk fat mass), plasma CML (as an inversely correlated marker of CML accumulation in adipose tissue), and low-grade inflammation (LGI) in a large sample of individuals whose weight status ranged from normal to morbid obesity. APPROACH AND RESULTS: We studied 1270 individuals of the Cohort on Diabetes and Atherosclerosis Maastricht Study and Hoorn Study, in whom protein-bound CML levels were measured by UPLC-Tandem MS (ultra performance liquid chromatography-tandem mass spectrometry), and 6 inflammatory markers were measured with multiarrays. These inflammatory markers were compiled into an LGI score. Multiple linear regression, adjusted for covariates, showed that (1) waist circumference was inversely associated with protein-bound CML plasma levels (standardized regression coefficient [beta]=-0.357 [95% confidence interval: -0.414; -0.301]); (2) protein-bound CML was inversely associated with LGI score (beta=-0.073 [-0.130;-0.015]); and (3) the association between waist circumference and LGI (beta=0.262 [0.203;0.321]) was attenuated after adjustment for protein-bound CML plasma levels and other potential mediators (to beta=0.202 [0.138;0.266]), with CML explaining the greatest portion of the attenuation ( approximately 12%). Further analysis with dual-energy X-ray absorptiometry measures of body composition confirmed a strong inverse association of fat mass preferentially accumulated in the trunk with protein-bound CML plasma levels, significantly explaining approximately 21% of the trunk fat-LGI association. CONCLUSIONS: Obesity, in particular central obesity, is characterized by greater levels of LGI but by lower levels of circulating CML; the latter significantly explaining a portion of the positive association between central obesity and inflammation

Mechanics of rolling tube on a mandrel through two grooved rolls

Background & Aims: Increased lipid peroxidation and inflammation are major factors in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). A lipoxidation product that could play a role in the induction of hepatic inflammation is N-epsilon-(carboxymethyl)lysine (CML). The aim of the present study was to investigate the relationship between steatosis and CML and to study the role of CML in hepatic inflammation. Methods: We included 74 obese individuals, which were categorized into 3 groups according to the grade of hepatic steatosis. CML accumulation in liver biopsies was assessed by immunohistochemistry and plasma CML levels were measured by mass spectrometry. Plasma CML levels were also determined in the hepatic artery, portal, and hepatic vein of 22 individuals, and CML fluxes across the liver were calculated. Hepatocyte cell lines were used to study CML formation during intracellular lipid accumulation and the effect of CML on pro-inflammatory cytokine expression. Gene expression levels of the inflammatory markers were determined in liver biopsies of the obese individuals. Results: CML accumulation was significantly associated with the grade of hepatic steatosis, the grade of hepatic inflammation, and gene expression levels of inflammatory markers PAI-1, IL-8, and CRP. Analysis of CML fluxes showed no release/uptake of CML by the liver. Lipid accumulation in hepatocytes, induced by incubation with fatty acids, was associated with increased CML formation and expression of the receptor for advanced glycation endproducts (RAGE), PAI-1, IL-8, IL-6, and CRP. Pyridoxamine and aminoguanidine inhibited the endogenous CML formation and the increased RAGE, PAI-1, IL-8, IL-6, and CRP expression. Incubation of hepatocytes with CML-albumin increased the expression of RAGE, PAI-1, and IL-6, which was inhibited by an antibody against RAGE. Conclusions: Accumulation of CML and a CML-upregulated RAGE-dependent inflammatory response in steatotic livers may play an important role in hepatic steatosis and in the pathogenesis of NAFLD. (C) 2011 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved

Association of Polymorphism in the Receptor for Advanced Glycation End Products (RAGE) Gene with Circulating RAGE Levels

Objective: The receptor for advanced glycation end products (RAGE)-ligand interaction has been linked to vascular complications. The family of soluble forms of RAGE (sRAGE) consists of splice variants and proteolytically cleaved and shed forms of RAGE. sRAGE may be a reflection of cell-bound RAGE. Because genetic variation in the RAGE gene may be associated with individual differences in sRAGE concentration and outcome, we investigated whether RAGE single-nucleotide polymorphisms (SNPs) were associated with circulating levels of sRAGE. Methods: Nine SNPs, covering the common RAGE gene variation, were genotyped in a Dutch cohort of subjects with normal glucose metabolism (n = 301), impaired glucose metabolism (n = 127), and type 2 diabetes mellitus (n = 146). We used linear regression analyses adjusted for age, sex, and glucose metabolism status to compare sRAGE levels across genotypes. Results: SNP rs2060700 (Gly82Ser) showed an association with sRAGE levels. Specifically, after adjustments for age, sex, and glucose metabolism, subjects with CT genotype had -527 pg/ml(95% confidence interval -724 to -330, P <0.001) lower sRAGE levels compared with the CC genotype (age, sex, and glucose metabolism adjusted mean +/-SE values of 836 +/- 99 and 1369 +/- 26 pg/ml, respectively, P <0.001). These results were confirmed in a subsample of a second cohort study of subjects with CT (n = 37) and CC genotype (n = 37). Immunoblotting using antibodies against amino acids 39-55 and 100-116 of RAGE also showed a similar decrease of sRAGE levels in the CT genotypes. No other SNPs showed an association with sRAGE levels. In addition, no associations between SNPs and the advanced glycation end products N(epsilon)-(carboxymethyl) lysine and N(epsilon)-(carboxyethyl) lysine were found. Conclusion: The CC genotype of SNP rs2070600 (Gly82Ser) was strongly associated with higher sRAGE levels in a Dutch population. The mechanism by which Gly82Ser polymorphism alters the sRAGE levels remains to be elucidated. (J Clin Endocrinol Metab 94: 5174-5180, 2009

The association between the-374T/A polymorphism of the receptor for advanced glycation endproducts gene and blood pressure and arterial stiffness is modified by glucose metabolism status: The Hoorn and CoDAM studies

Objectives: Receptor for advanced glycation endproducts (RAGE)-ligand interaction may lead to vascular complications. Genetic variation in RAGE has been shown to alter expression, activity of RAGE or both. We, therefore, investigated whether RAGE single-nucleotide polymorphisms (SNPs) and haplotypes were associated with vascular disease. Methods: Nine tag SNPs that cover the common RAGE gene variation were genotyped in 1291 individuals from two Dutch population-based cohort studies, aged 64.5 ± 8.6 years, with normal glucose metabolism (44%), impaired glucose metabolism (23%) or type 2 diabetes mellitus (33%). We used multiple regression analyses to compare prevalent cardiovascular disease and markers of atherosclerosis, blood pressure and arterial stiffness across genotypes, and examine effect modification by glucose metabolism status. Results: In unstratified analyses, no consistent associations between RAGE SNPs and prevalent cardiovascular disease and markers of atherosclerosis were found. However, the AA genotype of SNP rs1800624 (-374T/A) was consistently associated with lower SBP [-5.0 mmHg (95% confidence interval-10.4 to 0.3)] and DBP [-4.2 (-7.2 to-1.3)] , pulse pressure [-0.8 (-5.0 to 3.4)] as well as with less arterial stiffness [-0.56 SD (-1.04 to-0.09)] in individuals with normal glucose metabolism, but with higher SBP [6.2 (0.9-11.5)], DBP [2.1 (-0.7 to 5.0)] and pulse pressure [4.1 (-0.2 to 8.4)] in individuals with impaired glucose metabolism or type 2 diabetes mellitus (P for interaction ≤0.05 in all analyses). Similar results were found for a haplotype that includes the-374A allele. Conclusion: In individuals with normal glucose metabolism, the-374A allele of the RAGE gene is protectively associated with blood pressure and arterial stiffness, whereas in individuals with impaired glucose metabolism or type 2 diabetes mellitus, it is adversely associated with these variables. 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins