title: Protein-Bound Plasma Nε-(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.
abstract: 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(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.
  
  
  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.
authors.affiliation: From the Department of Internal Medicine (K.H.J.G., M.P.H.v.d.W., M.M.v.G., C.J.H.v.d.K., C.D.A.S., C.G.S.), CARIM School for Cardiovascular Diseases (K.H.J.G., I.F., M.P.H.v.d.W., M.M.v.G., C.J.H.v.d.K., C.D.A.S., C.G.S.), Department of Clinical Epidemiology and Medical Technology Assessment (KEMTA) (I.F.), Department of General Surgery (S.S.R.), and NUTRIM School for Nutrition, Toxicology and Metabolism (S.S.R.), Maastricht University Medical Centre, The Netherlands; Division of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine and Biomedical Sciences, The University of Queensland, Brisbane, Australia (I.F.); and Department of Epidemiology and Biostatistics and EMGO Institute for Health and Care Research, Vrije Universiteit Medical Center, Amsterdam, The Netherlands (J.M.D., G.N.).
authors.forename: Katrien H J
authors.initials: KH
authors.lastname: Gaens
authors.affiliation: From the Department of Internal Medicine (K.H.J.G., M.P.H.v.d.W., M.M.v.G., C.J.H.v.d.K., C.D.A.S., C.G.S.), CARIM School for Cardiovascular Diseases (K.H.J.G., I.F., M.P.H.v.d.W., M.M.v.G., C.J.H.v.d.K., C.D.A.S., C.G.S.), Department of Clinical Epidemiology and Medical Technology Assessment (KEMTA) (I.F.), Department of General Surgery (S.S.R.), and NUTRIM School for Nutrition, Toxicology and Metabolism (S.S.R.), Maastricht University Medical Centre, The Netherlands; Division of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine and Biomedical Sciences, The University of Queensland, Brisbane, Australia (I.F.); and Department of Epidemiology and Biostatistics and EMGO Institute for Health and Care Research, Vrije Universiteit Medical Center, Amsterdam, The Netherlands (J.M.D., G.N.).
authors.forename: Isabel
authors.initials: I
authors.lastname: Ferreira
authors.affiliation: From the Department of Internal Medicine (K.H.J.G., M.P.H.v.d.W., M.M.v.G., C.J.H.v.d.K., C.D.A.S., C.G.S.), CARIM School for Cardiovascular Diseases (K.H.J.G., I.F., M.P.H.v.d.W., M.M.v.G., C.J.H.v.d.K., C.D.A.S., C.G.S.), Department of Clinical Epidemiology and Medical Technology Assessment (KEMTA) (I.F.), Department of General Surgery (S.S.R.), and NUTRIM School for Nutrition, Toxicology and Metabolism (S.S.R.), Maastricht University Medical Centre, The Netherlands; Division of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine and Biomedical Sciences, The University of Queensland, Brisbane, Australia (I.F.); and Department of Epidemiology and Biostatistics and EMGO Institute for Health and Care Research, Vrije Universiteit Medical Center, Amsterdam, The Netherlands (J.M.D., G.N.).
authors.forename: Marjo P H
authors.initials: MP
authors.lastname: van de Waarenburg
authors.affiliation: From the Department of Internal Medicine (K.H.J.G., M.P.H.v.d.W., M.M.v.G., C.J.H.v.d.K., C.D.A.S., C.G.S.), CARIM School for Cardiovascular Diseases (K.H.J.G., I.F., M.P.H.v.d.W., M.M.v.G., C.J.H.v.d.K., C.D.A.S., C.G.S.), Department of Clinical Epidemiology and Medical Technology Assessment (KEMTA) (I.F.), Department of General Surgery (S.S.R.), and NUTRIM School for Nutrition, Toxicology and Metabolism (S.S.R.), Maastricht University Medical Centre, The Netherlands; Division of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine and Biomedical Sciences, The University of Queensland, Brisbane, Australia (I.F.); and Department of Epidemiology and Biostatistics and EMGO Institute for Health and Care Research, Vrije Universiteit Medical Center, Amsterdam, The Netherlands (J.M.D., G.N.).
authors.forename: Marleen M
authors.initials: MM
authors.lastname: van Greevenbroek
authors.affiliation: From the Department of Internal Medicine (K.H.J.G., M.P.H.v.d.W., M.M.v.G., C.J.H.v.d.K., C.D.A.S., C.G.S.), CARIM School for Cardiovascular Diseases (K.H.J.G., I.F., M.P.H.v.d.W., M.M.v.G., C.J.H.v.d.K., C.D.A.S., C.G.S.), Department of Clinical Epidemiology and Medical Technology Assessment (KEMTA) (I.F.), Department of General Surgery (S.S.R.), and NUTRIM School for Nutrition, Toxicology and Metabolism (S.S.R.), Maastricht University Medical Centre, The Netherlands; Division of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine and Biomedical Sciences, The University of Queensland, Brisbane, Australia (I.F.); and Department of Epidemiology and Biostatistics and EMGO Institute for Health and Care Research, Vrije Universiteit Medical Center, Amsterdam, The Netherlands (J.M.D., G.N.).
authors.forename: Carla J H
authors.initials: CJ
authors.lastname: van der Kallen
authors.affiliation: From the Department of Internal Medicine (K.H.J.G., M.P.H.v.d.W., M.M.v.G., C.J.H.v.d.K., C.D.A.S., C.G.S.), CARIM School for Cardiovascular Diseases (K.H.J.G., I.F., M.P.H.v.d.W., M.M.v.G., C.J.H.v.d.K., C.D.A.S., C.G.S.), Department of Clinical Epidemiology and Medical Technology Assessment (KEMTA) (I.F.), Department of General Surgery (S.S.R.), and NUTRIM School for Nutrition, Toxicology and Metabolism (S.S.R.), Maastricht University Medical Centre, The Netherlands; Division of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine and Biomedical Sciences, The University of Queensland, Brisbane, Australia (I.F.); and Department of Epidemiology and Biostatistics and EMGO Institute for Health and Care Research, Vrije Universiteit Medical Center, Amsterdam, The Netherlands (J.M.D., G.N.).
authors.forename: Jacqueline M
authors.initials: JM
authors.lastname: Dekker
authors.affiliation: From the Department of Internal Medicine (K.H.J.G., M.P.H.v.d.W., M.M.v.G., C.J.H.v.d.K., C.D.A.S., C.G.S.), CARIM School for Cardiovascular Diseases (K.H.J.G., I.F., M.P.H.v.d.W., M.M.v.G., C.J.H.v.d.K., C.D.A.S., C.G.S.), Department of Clinical Epidemiology and Medical Technology Assessment (KEMTA) (I.F.), Department of General Surgery (S.S.R.), and NUTRIM School for Nutrition, Toxicology and Metabolism (S.S.R.), Maastricht University Medical Centre, The Netherlands; Division of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine and Biomedical Sciences, The University of Queensland, Brisbane, Australia (I.F.); and Department of Epidemiology and Biostatistics and EMGO Institute for Health and Care Research, Vrije Universiteit Medical Center, Amsterdam, The Netherlands (J.M.D., G.N.).
authors.forename: Giel
authors.initials: G
authors.lastname: Nijpels
authors.affiliation: From the Department of Internal Medicine (K.H.J.G., M.P.H.v.d.W., M.M.v.G., C.J.H.v.d.K., C.D.A.S., C.G.S.), CARIM School for Cardiovascular Diseases (K.H.J.G., I.F., M.P.H.v.d.W., M.M.v.G., C.J.H.v.d.K., C.D.A.S., C.G.S.), Department of Clinical Epidemiology and Medical Technology Assessment (KEMTA) (I.F.), Department of General Surgery (S.S.R.), and NUTRIM School for Nutrition, Toxicology and Metabolism (S.S.R.), Maastricht University Medical Centre, The Netherlands; Division of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine and Biomedical Sciences, The University of Queensland, Brisbane, Australia (I.F.); and Department of Epidemiology and Biostatistics and EMGO Institute for Health and Care Research, Vrije Universiteit Medical Center, Amsterdam, The Netherlands (J.M.D., G.N.).
authors.forename: Sander S
authors.initials: SS
authors.lastname: Rensen
authors.affiliation: From the Department of Internal Medicine (K.H.J.G., M.P.H.v.d.W., M.M.v.G., C.J.H.v.d.K., C.D.A.S., C.G.S.), CARIM School for Cardiovascular Diseases (K.H.J.G., I.F., M.P.H.v.d.W., M.M.v.G., C.J.H.v.d.K., C.D.A.S., C.G.S.), Department of Clinical Epidemiology and Medical Technology Assessment (KEMTA) (I.F.), Department of General Surgery (S.S.R.), and NUTRIM School for Nutrition, Toxicology and Metabolism (S.S.R.), Maastricht University Medical Centre, The Netherlands; Division of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine and Biomedical Sciences, The University of Queensland, Brisbane, Australia (I.F.); and Department of Epidemiology and Biostatistics and EMGO Institute for Health and Care Research, Vrije Universiteit Medical Center, Amsterdam, The Netherlands (J.M.D., G.N.).
authors.forename: Coen D A
authors.initials: CD
authors.lastname: Stehouwer
authors.affiliation: From the Department of Internal Medicine (K.H.J.G., M.P.H.v.d.W., M.M.v.G., C.J.H.v.d.K., C.D.A.S., C.G.S.), CARIM School for Cardiovascular Diseases (K.H.J.G., I.F., M.P.H.v.d.W., M.M.v.G., C.J.H.v.d.K., C.D.A.S., C.G.S.), Department of Clinical Epidemiology and Medical Technology Assessment (KEMTA) (I.F.), Department of General Surgery (S.S.R.), and NUTRIM School for Nutrition, Toxicology and Metabolism (S.S.R.), Maastricht University Medical Centre, The Netherlands; Division of Epidemiology and Biostatistics, School of Public Health, Faculty of Medicine and Biomedical Sciences, The University of Queensland, Brisbane, Australia (I.F.); and Department of Epidemiology and Biostatistics and EMGO Institute for Health and Care Research, Vrije Universiteit Medical Center, Amsterdam, The Netherlands (J.M.D., G.N.). C.Schalkwijk@maastrichtuniversity.nl.
authors.forename: Casper G
authors.initials: CG
authors.lastname: Schalkwijk
mesh_terms: D015502:Absorptiometry, Photon; D050154:Adiposity; D000328:Adult; D000368:Aged; D015415:Biomarkers / Q000097:blood; D015992:Body Mass Index; D002853:Chromatography, Liquid; D003430:Cross-Sectional Studies; D018450:Disease Progression; D005260:Female; D006801:Humans; D007249:Inflammation / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology; D018836:Inflammation Mediators / Q000097:blood*; D016014:Linear Models; D008239:Lysine / Q000031:analogs & derivatives* / Q000097:blood; D008297:Male; D008875:Middle Aged; D015999:Multivariate Analysis; D009426:Netherlands / Q000453:epidemiology; D056128:Obesity, Abdominal / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology / Q000503:physiopathology; D009767:Obesity, Morbid / Q000097:blood* / Q000175:diagnosis / Q000453:epidemiology / Q000503:physiopathology; D011446:Prospective Studies; D012307:Risk Factors; D053719:Tandem Mass Spectrometry; D055105:Waist Circumference
chemical_list: D015415:Biomarkers; D018836:Inflammation Mediators; C048496:N(6)-carboxymethyllysine; D008239:Lysine
keywords: advanced glycation endproducts; biomarkers; central obesity; epidemiology; inflammation