Annals of Occupational and Environmental Medicine

The Korean Society of Occupational & Environmental Medicine (대한직업환경의학회)
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Relationship Between Urinary t, t-muconic Acid and Insulin Resistance in the Elderly

노인인구에서 요중 뮤콘산과 인슐린저항성의 관련성

  • Park, Hyun-Seung (Department of Preventive Medicine, College of Medicine, Seoul National University) ;
  • Seo, Jeong-Cheol (Department of Preventive Medicine, College of Medicine, Seoul National University) ;
  • Kim, Jin-Hee (Institute of Environmental Medicine, Seoul National University Medical Research Center) ;
  • Bae, Sang-Hyuk (Institute of Environmental Medicine, Seoul National University Medical Research Center) ;
  • Lim, Youn-Hee (Department of Epidemiology and Biostatistics, School of Public Health, Seoul National University) ;
  • Cho, Soo-Hun (Department of Preventive Medicine, College of Medicine, Seoul National University) ;
  • Hong, Yun-Chul (Department of Preventive Medicine, College of Medicine, Seoul National University)
  • 박현승 (서울대학교 의과대학 예방의학교실) ;
  • 서정철 (서울대학교 의과대학 예방의학교실) ;
  • 김진희 (서울대학교 의학연구센터 환경의학연구소) ;
  • 배상혁 (서울대학교 의학연구센터 환경의학연구소) ;
  • 임연희 (서울대학교 보건대학원 보건통계학과) ;
  • 조수헌 (서울대학교 의과대학 예방의학교실) ;
  • 홍윤철 (서울대학교 의과대학 예방의학교실)
  • Published : 2011.12.31
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Abstract

Objectives: To examine the associations between the urinary t, t-muconic acid (t, t-MA) concentration and three indices of insulin resistance; namely, the homeostasis assessment of insulin resistance (HOMAIR) index, blood insulin level and fasting glucose level. Methods: A panel study was performed on the elderly at a public health care center population in the northern area of Seoul between 2008 and 2010. The participants were 560 elderly, over 60 years of age whose urinary t, t-MA and insulin resistance indices had been measured; questionnaires were completed by these participants. A generalized linear mixed (GLM) analysis was adjusted for age, sex, drinking, urinary cotinine, exercise, vitamin intake and body mass index, at a significance level of p<0.05. Results: A total of 411 participants were finally analyzed after excluding those with diabetes and only one visit to the public health care center. Higher urinary t, t-MA concentrations were linearly associated with the HOMA-IR index, blood insulin level and fasting glucose level in the simple and fully adjusted GLM models. Although there were few limitations, a portion of insulin resistance was proven to be explained by exposure to benzene using r-squared. A significant relationship was also observed between urinary t, t-MA and malondialdehyde (MDA) using the same GLM models. Conclusions: Urinary t, t-MA is related to the development of insulin resistance which is a key factor for development of diabetes and its complications induced by oxidative stress.

목적: 생활환경에서의 저농도 벤젠 노출이 당뇨의 발생과 진행에 밀접하게 관련된 인슐린 저항성의 지표들과 어떤 연관성을 가지는지 살펴보고, 산화손상기전이 이와 관련이 있는지 연구하고자 하였다. 방법: 60세 이상인 서울시 성북구에 거주하는 노인 411명을 대상으로 벤젠의 노출지표인 요중 t,t-MA과 인슐린 저항성의 지표인 공복시 혈당, 혈중 인슐린 및 HOMAIR index와 산화손상지표인 요중 MDA를 반복적으로 측정하였다. 요중 t,t-MA와 인슐린 저항성 지표들은 generalized linear mixed (GLM) analysis를 통하여 관련성이 있는지 분석하였고, 추가적으로 모델의 설명력을 계산하였다. 또한 설문지 조사를 시행하여 인구학적특성과 생활습관, 질병력 및 환경적인 노출을 조사하여 분석시 보정하였다. 결과: 요중 t,t-MA은 아무것도 보정하지 않은 단순 모델(model 1)과 설문지에서 얻어진 연령, 성별, 음주여부, 규칙적인 운동여부, 종합비타민제 섭취여부, 요중 코티닌 수치 및 체질량지수를 보정한 모델(model 2) 그리고 여기에 추가적으로 $PM_{10}$, $SO_{2}$, $O_{3}$, $NO_{2}$,및 CO 같은 대기오염물질을 보정한 모델(model 3) 모두에서 인슐린 저항성의 세 지표와 매우 유의한(p<0.001)관련을 보이고 있었고, 동시에 동일한 모델들을 사용하여 GLM 분석을 시행하였을 때, 요중 MDA와도 유의한(p<0.001)관련성을 보였다. 요중 t,t-MA와 인슐린 저항성 관계를 파악하기 위하여 구축된 GLM 분석 모델들은 인슐린저항성의 지표 중 혈중 인슐린, HOMA-IR index 그리고 공복시 혈당 순으로 여러 한계점에도 불구하고 일정 부분 설명력을 갖는 것으로 나타났다. 결론: 요중 t,t-MA는 우리나라의 노령인구에서 인슐린 저항성의 지표들과 밀접한 관련이 있는 것으로 나타났으며, 그 기전으로는 산화손상기전이 관련되었을 수 있다.

Keywords

References

  1. Kim S, Vermeulen R, Waidyanatha S, Johnson BA, Lan Q, Rothman N, Smith MT, Zhang L, Li G, Shen M, Yin S, Rappaport SM. Using urinary biomarkers to elucidate dose-related patterns of human benzene metabolism. Carcinogenesis 2006;27:772-81.
  2. Dougherty D, Garte S, Barchowsky A, Zmuda J, Taioli E. Nqo1, Mpo, Cyp2e1, Gstt1 and Gstm1 polymorphisms and biological effects of benzene exposure--a literature review. Toxicol Lett 2008;182:7-17. https://doi.org/10.1016/j.toxlet.2008.09.008
  3. Rappaport SM, Kim S, Lan Q, Li G, Vermeulen R, Waidyanatha S, Zhang L, Yin S, Smith MT, Rothman N. Human benzene metabolism following occupational and environmental exposures. Chem Biol Interact 2010;184:189-95. https://doi.org/10.1016/j.cbi.2009.12.017
  4. National Institute of Environmental Research. Report of air quality in Korea 2009. National Institute of Environmental Research. Incheon. 2010. pp 86-8. (Korean)
  5. Weisel CP. Benzene exposure: An overview of monitoring methods and their findings. Chem Biol Interact 2010;184:58-66. https://doi.org/10.1016/j.cbi.2009.12.030
  6. Mansi A, Bruni R, Capone P, Paci E, Pigini D, Simeoni C, Gnerre R, Papacchini M, Tranfo G. Low occupational exposure to benzene in a petrochemical plant: modulating effect of genetic polymorphisms and smoking habit on the urinary T,T-Ma/Spma ratio. Toxicol Lett 2011;
  7. Johnson ES, Langard S, Lin YS. A critique of benzene exposure in the general population. Sci Total Environ 2007;374:183-98. https://doi.org/10.1016/j.scitotenv.2006.11.045
  8. Khalade A, Jaakkola MS, Pukkala E, Jaakkola JJ. Exposure to benzene at work and the risk of leukemia: A systematic review and meta-analysis. Environ Health 2010;9:31. https://doi.org/10.1186/1476-069X-9-31
  9. Vlaanderen J, Lan Q, Kromhout H, Rothman N, Vermeulen R. Occupational benzene exposure and the risk of lymphoma subtypes: A meta-analysis of cohort studies incorporating three study quality dimensions. Environ Health Perspect 2011;119:159-67. https://doi.org/10.1289/ehp.1103660
  10. Lan Q, Zhang L, Li G, Vermeulen R, Weinberg RS, Dosemeci M, Rappaport SM, Shen M, Alter BP, Wu Y, Kopp W, Waidyanatha S, Rabkin C, Guo W, Chanock S, Hayes RB, Linet M, Kim S, Yin S, Rothman N, Smith MT. Hematotoxicity in workers exposed to low levels of benzene. Science 2004;306:1774-6. https://doi.org/10.1126/science.1102443
  11. Sorensen M, Autrup H, Moller P, Hertel O, Jensen SS, Vinzents P, Knudsen LE, Loft S. Linking exposure to environmental pollutants with biological effects. Mutat Res 2003;544:255-71. https://doi.org/10.1016/j.mrrev.2003.06.010
  12. Barreto G, Madureira D, Capani F, Aon-Bertolino L, Saraceno E, Alvarez-Giraldez LD. The role of catechols and free radicals in benzene toxicity: An oxidative DNA damage pathway. Environ Mol Mutagen 2009;50:771-80. https://doi.org/10.1002/em.20500
  13. Schulz E, Gori T, Munzel T. Oxidative stress and endothelial dysfunction in hypertension. Hypertens Res 2011;34:665-73. https://doi.org/10.1038/hr.2011.39
  14. Sugamura K, Keaney JF, Jr. Reactive oxygen species in cardiovascular disease. Free Radic Biol Med 2011;51(5):978-92. https://doi.org/10.1016/j.freeradbiomed.2011.05.004
  15. Maritim AC, Sanders RA, Watkins JB, 3rd. Diabetes, oxidative stress, and antioxidants: A review. J Biochem Mol Toxicol 2003;17:24-38. https://doi.org/10.1002/jbt.10058
  16. Singh B, Saxena A. Surrogate markers of insulin resistance: A review. World J Diabetes 2010;1:36-47. https://doi.org/10.4239/wjd.v1.i2.36
  17. Keskin M, Kurtoglu S, Kendirci M, Atabek ME, Yazici C. Homeostasis model assessment is more reliable than the fasting glucose/insulin ratio and quantitative insulin sensitivity check index for assessing insulin resistance among obese children and adolescents. Pediatrics 2005;115:e500-3. https://doi.org/10.1542/peds.2004-1921
  18. Recchia A. R-squared measures for two-level hierarchical linear models using sas. Journal of Statistical Software 2010;32:1-9.
  19. Ragas AM, Oldenkamp R, Preeker NL, Wernicke J, Schlink U. Cumulative risk assessment of chemical exposures in urban environments. Environ Int 2011;37:872-81. https://doi.org/10.1016/j.envint.2011.02.015
  20. Protano C, Guidotti M, Manini P, Petyx M, La Torre G, Vitali M. Benzene exposure in childhood: role of living environments and assessment of available tools. Environ Int 2010;36:779-87. https://doi.org/10.1016/j.envint.2010.06.003
  21. Lovreglio P, Barbieri A, Carrieri M, Sabatini L, Fracasso ME, Doria D, Drago I, Basso A, D'Errico MN, Bartolucci GB, Violante FS, Soleo L. Validity of new biomarkers of internal dose for use in the biological monitoring of occupational and environmental exposure to low concentrations of benzene and toluene. Int Arch Occup Environ Health 2010;83:341-56. https://doi.org/10.1007/s00420-009-0469-7
  22. Qu Q, Shore R, Li G, Su L, Jin X, Melikian AA, Roy N, Chen LC, Wirgin I, Cohen B, Yin S, Li Y, Mu R. Biomarkers of benzene: urinary metabolites in relation to individual genotype and personal exposure. Chem Biol Interact 2005;153-154:85-95.
  23. Manini P, De Palma G, Andreoli R, Poli D, Petyx M, Corradi M, Mutti A, Apostoli P. Biological monitoring of low benzene exposure in italian traffic policemen. Toxicol Lett 2008;181:25-30. https://doi.org/10.1016/j.toxlet.2008.06.865
  24. Fustinoni S, Buratti M, Campo L, Colombi A, Consonni D, Pesatori AC, Bonzini M, Farmer P, Garte S, Valerio F, Merlo DF, Bertazzi PA. Urinary T,Tmuconic acid, S-phenylmercapturic acid and benzene as biomarkers of low benzene exposure. Chem Biol Interact 2005;153-154:253-6.
  25. Hoet P, De Smedt E, Ferrari M, Imbriani M, Maestri L, Negri S, De Wilde P, Lison D, Haufroid V. Evaluation of urinary biomarkers of exposure to benzene: correlation with blood benzene and influence of confounding factors. Int Arch Occup Environ Health 2009;82:985-95. https://doi.org/10.1007/s00420-008-0381-6
  26. Ruppert T, Scherer G, Tricker AR, Adlkofer F. Trans,Trans-Muconic acid as a biomarker of non-occupational environmental exposure to benzene. Int Arch Occup Environ Health 1997;69:247-51. https://doi.org/10.1007/s004200050143
  27. Cocco P, Tocco MG, Ibba A, Scano L, Ennas MG, Flore C, Randaccio FS. Trans,Trans-Muconic acid excretion in relation to environmental exposure to benzene. Int Arch Occup Environ Health 2003;76:456-60. https://doi.org/10.1007/s00420-002-0413-6
  28. Tirosh A, Rudich A, Potashnik R, Bashan N. Oxidative stress impairs insulin but not platelet-derived growth factor signalling in 3t3-L1 adipocytes. Biochem J 2001;355:757-63.
  29. Brownlee M. The pathobiology of diabetic complications: A unifying mechanism. Diabetes 2005;54:1615-25. https://doi.org/10.2337/diabetes.54.6.1615
  30. Facchini FS, Hua NW, Reaven GM, Stoohs RA. Hyperinsulinemia: The missing link among oxidative stress and age-related diseases? Free Radic Biol Med 2000;29:1302-6. https://doi.org/10.1016/S0891-5849(00)00438-X
  31. Evans JL, Maddux BA, Goldfine ID. The molecular basis for oxidative stress-induced insulin resistance. Antioxid Redox Signal 2005;7:1040-52. https://doi.org/10.1089/ars.2005.7.1040
  32. Fridlyand LE, Philipson LH. Reactive species and early manifestation of insulin resistance in type 2 diabetes. Diabetes Obes Metab 2006;8:136-45. https://doi.org/10.1111/j.1463-1326.2005.00496.x
  33. Houstis N, Rosen ED, Lander ES. Reactive oxygen species have a causal role in multiple forms of insulin resistance. Nature 2006;440:944-8. https://doi.org/10.1038/nature04634
  34. Garcia-Bailo B, El-Sohemy A, Haddad PS, Arora P, Benzaied F, Karmali M, Badawi A. Vitamins D, C, and E in the prevention of type 2 diabetes mellitus: modulation of inflammation and oxidative stress. Biologics 2011;5:7-19.
  35. Henriksen EJ, Diamond-Stanic MK, Marchionne EM. Oxidative stress and the etiology of insulin resistance and type 2 diabetes. Free Radic Biol Med 2011;51:993-9. https://doi.org/10.1016/j.freeradbiomed.2010.12.005
  36. Thiering E, Bruske I, Kratzsch J, Thiery J, Sausenthaler S, Meisinger C, Koletzko S, Bauer CP, Schaaf B, von Berg A, Berdel D, Lehmann I, Herbarth O, Kramer U, Wichmann HE, Heinrich J. Prenatal and postnatal tobacco smoke exposure and development of insulin resistance in 10 year old children. Int J Hyg Environ Health 2011;214(5):361-8. https://doi.org/10.1016/j.ijheh.2011.04.004
  37. Verdina A, Galati R, Falasca G, Ghittori S, Imbriani M, Tomei F, Marcellini L, Zijno A, Vecchio VD. Metabolic polymorphisms and urinary biomarkers in subjects with low benzene exposure. J Toxicol Environ Health A 2001;64:607-18. https://doi.org/10.1080/152873901753246214
  38. Gobba F, Rovesti S, Borella P, Vivoli R, Caselgrandi E, Vivoli G. Inter-individual variability of benzene metabolism to trans,trans-muconic acid and its implications in the biological monitoring of occupational exposure. Sci Total Environ 1997;199:41-8. https://doi.org/10.1016/S0048-9697(97)05480-6