고혈압 환자에서 혈장 고분자량 아디포넥틴 농도와 심장-대사위험인자와의 관련성 연구

Plasma Levels of High Molecular Weight Adiponectin are Associated with Cardiometabolic Risks in Patients with Hypertension

  • 정혜경 (연세대학교 의과대학 영동세브란스병원 영양팀) ;
  • 신민정 (영남대학교 식품영양학과)
  • Chung, Hye-Kyung (Department of Nutrition Services, Youngdong Severance Hospital, Yonsei University College of Medicine) ;
  • Shin, Min-Jeong (Department of Food and Nutrition, Yeungnam University)
  • 발행 : 2008.12.31

초록

고혈압 환자 110명을 대상으로 혈장 고분자량 아디포넥틴과 총 아디포넥틴 농도를 측정하고 심장-대사위험인자와의 관련성을 비교 평가한 연구 결과를 요약하면 다음과 같다. 1) 비만군과 비비만군으로 나누어 비교한 결과, 고분자량 아디포넥틴 농도는 비만군에서 유의적으로 낮았으나 총 아디포넥틴 농도는 두군간 유의적인 차이를 보이지 않았다. 2) 비만도를 나타내는 BMI 및 허리둘레의 경우 고분자량 아디포넥틴과 음의 상관관계를 보였으나 혈장 아디포넥틴과는 유의적인 상관관계를 보이지 않았다. 3) 혈액 지질 수준과의 상관성 평가시, 고분자량 아디포넥틴은 중성지방과 음의 상관관계를, 고밀도 콜레스테롤과는 양의 상관관계를 보였으며 혈장 아디포넥틴의 경우 단지고밀도 콜레스테롤과 유의적인 양의 상관관계를 보였다. 4) 인슐린 저항성 지표인 HOMA-IR의 경우 고분자량 아디포넥틴 및 혈장 아디포넥틴 모두와 음의 상관관계를 보였다. 5) 염증지표와의 상관성 분석 시, 고분자량 아디포넥틴은 C-반응성 단백질, IL-6과 강한 음의 상관 관계를 TNF-${\alpha}$, ICAM-1과 음의 경향을 보였으나 혈장 아디포넥틴은 C-반응성 단백질외에는 상관관계를 보이지 않았다. 또한 회귀분석 결과, 혈장 고분자량 아디포넥틴 농도는 C-반응성 단백질 수준을 예측하는 독립적 인자였다. 위의 결과로 보아 고분자량 아디포넥틴은 혈장 아디포넥틴보다 전반적으로 심장-대사위험인자와 더 많은 상관성을 보여주었다. 따라서 심혈관 질환 및 대사성증후군을 예측하고 반영하는 데 혈장 고분자량 아디포넥틴 수준이 총 아디포넥틴 수준보다 민감하고 정확한 지표로 활용될 수 있을 것이다.

In the present study, we comprehensively examined the associations of plasma levels of total adiponectin and high molecular weight (HMW) adiponectin with the features of cardiometabolic risks including body fat distribution, dyslipidemia, insulin resistance and inflammatory markers in a cross-sectional study of 110 treated hypertensive patients. Blood lipid profiles, high sensitivity C-reactive protein (hsCRP) and homeostasis model assessment of insulin resistance (HOMA- IR) derived from fasting glucose and insulin concentrations were determined. Plasma levels of tumor necrosis factor-${\alpha}$ (TNF-${\alpha}$), interleukin-6 (IL-6) and intercellular adhesion molecule-1 (ICAM-1) were analyzed using ELISA. The results showed that plasma levels of HMW-adiponectin were negatively associated with body mass index (BMI, r = - 0.203, p < 0.05) and waist circumference (r = -0.307, p < 0.01), which was not shown in total adiponectin. Plasma levels of HMW-adiponectin were negatively associated with triglyceride (r = -0.223, p < 0.05) and positively associated with HDL-cholesterol (r = 0.228, p < 0.05). Plasma levels of adiponectin were positively associated with HDL-cholesterol (r = 0.224, p < 0.05). Plasma levels of HMW-adiponectin were negatively associated with hsCRP (r = -0.276, p < 0.01) and IL-6 (r = -0.272, p < 0.01). In addition, there were weak associations between plasma levels of HMWadiponectin and TNF-${\alpha}$ (r = -0.163, p = 0.07) and ICAM-1 (r = -0.158, p = 0.09). However, there were no significant associations of total adiponectin with inflammatory markers except hsCRP (r = -0.203, p < 0.05). Stepwise multiple linear regression analysis showed that only plasma levels of HMW-adiponectin was an independent factor influencing serum levels of hsCRP, a marker of systemic low grade inflammation, after adjusting for age, gender, BMI, waist circumference, alcohol intake, smoking status, blood lipids, total adiponectin and drug use (p < 0.01). These results suggest that HMW-adiponectin, rather than total adiponectin, is likely to be closely associated with the features of cardiometabolic risks in treated hypertensive patients and might be effective biomarker for the prediction of cardiovascular disease.

키워드

참고문헌

  1. Korean National Statistcal Office. Change in leading causes of death; 2006
  2. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, And Treatment of High Blood Cholesterol In Adults (Adult Treatment Panel III). JAMA 2001; 285: 2486-2497 https://doi.org/10.1001/jama.285.19.2486
  3. Galassi A, Reynolds K, He J. Metabolic syndrome and risk of cardiovascular disease: a meta-analysis. Am J Med 2006; 119: 812-819 https://doi.org/10.1016/j.amjmed.2006.02.031
  4. Gami AS, Witt BJ, Howard DE, Erwin PJ, Gami LA, Somers VK, Montori VM. Metabolic syndrome and risk of incident cardiovascular events and death: a systematic review and meta-analysis of longitudinal studies. J Am Coll Cardiol 2007; 49: 403-414 https://doi.org/10.1016/j.jacc.2006.09.032
  5. Wilson PW, D'Agostino RB, Parise H, Sullivan L, Meigs JB. Metabolic syndrome as a precursor of cardiovascular disease and type 2 diabetes mellitus. Circulation 2005; 112: 3066-3072 https://doi.org/10.1161/CIRCULATIONAHA.105.539528
  6. Aronne LJ, Isoldi KK. Overweight and Obesity: Key Components of Cardiometabolic Risk. Clin Cornerstone 2007; 8: 29-37 https://doi.org/10.1016/S1098-3597(07)80026-3
  7. Despres JP, Lemieux I. Abdominal obesity and metabolic syndrome. Nature 2006; 444: 881-887 https://doi.org/10.1038/nature05488
  8. Ford ES, Giles WH, Mokdad AH. Increasing prevalence of the metabolic syndrome among U.S. adults. Diabetes Care 2004; 27: 2444-2449 https://doi.org/10.2337/diacare.27.10.2444
  9. South Korean ministry of health and social affairs. 2005 National Health and Nutrition survey: Health Examination; 2006
  10. Hotta K, Funahashi T, Bodkin NL, Ortmeyer HK, Arita Y, Hansen BC, Matsuzawa Y. Circulating concentrations of the adipocyte protein adiponectin are decreased in parallel with reduced insulin sensitivity during the progression to type 2 diabetes in rhesus monkeys. Diabetes 2001; 50: 1126-1133 https://doi.org/10.2337/diabetes.50.5.1126
  11. Arita Y, Kihara S, Ouchi N, Takahashi M, Maeda K, Miyagawa J, Hotta K, Shimomura I, Nakamura T, Miyaoka K, Kuriyama H, Nishida M, Yamashita S, Okubo K, Matsubara K, Muraguchi M, Ohmoto Y, Funahashi T, Matsuzawa Y. Paradoxical decrease of an adipose-specific protein, adiponectin, in obesity. Biochem Biophys Res Commun 1999; 257: 79-83 https://doi.org/10.1006/bbrc.1999.0255
  12. Weyer C, Funahashi T, Tanaka S, Hotta K, Matsuzawa Y, Pratley RE, Tataranni PA. Hypoadiponectimia in obesity and type 2 diabetes: close association with insulin resistance and hyperinsulinemia. J Clin Endocrinol Metab 2001; 86: 1930-1935 https://doi.org/10.1210/jc.86.5.1930
  13. Adamczak M, Wiecek A, Funahashi T, Chudek J, Kokot F, Matsuzawa Y. Decreased plasma adiponectin concentration in patients with essential hypertension. Am J Hypertens 2003; 16: 72-75 https://doi.org/10.1016/S0895-7061(02)03197-7
  14. Matsubara M, Maruoka S, Katayose S. Decreased plasma adiponectin concentrations in women with dyslipidemia. J Clin Endocrinol Metab 2002; 87: 2764-3769 https://doi.org/10.1210/jc.87.6.2764
  15. Hotta K, Funahashi T, Arita Y, Takahashi M, Matsuda M, Okamoto Y, Iwahashi H, Kuriyama H, Ouchi N, Maeda K, Nishida M, Kihara S, Sakai N, Nakajima T, Hasegawa K, Muraguchi M, Ohmoto Y, Nakamura T, Yamashita S, Hanafusa T, Matsuzawa Y. Plasma concentration of a novel adipose specific protein adiponectin in type 2 diabetic patients. Arterioscler Thromb Vasc Biol 2000; 20: 1595-1599 https://doi.org/10.1161/01.ATV.20.6.1595
  16. Yang WS, Lee WJ, Funahashi T, Tanaka S, Matsuzawa Y, Chao CL, Chen CL, Tai TY, Chuang LM. Plasma adiponectin levels in overweight and obese Asians. Obes Res 2002; 10: 1104-1110 https://doi.org/10.1038/oby.2002.150
  17. Whitehead JP, Richards AA, Hickman IJ, Macdonald GA, Prins JB. Adiponectin- a key adipokine in the metabolic syndrome. Diabetes Obes Metab 2006; 8: 264-280 https://doi.org/10.1111/j.1463-1326.2005.00510.x
  18. Nakano Y, Tobe T, Choi-Miura NH, Mazda T, Tomita M. Isolation and characterization of GBP28, a novel gelatin-binding protein purified from human plasma. J Biochem 1996; 120: 803-812 https://doi.org/10.1093/oxfordjournals.jbchem.a021483
  19. Pajvani UB, Du X, Combs TP, Berg AH, Rajala MW, Schulthess T, Engel J, Brownlee M, Scherer PE. Structure-function studies of the adipocyte secreted hormone Acrp30/adiponectin: implications for metabolic regulation and bioactivity. J Biol Chem 2003; 278: 9073-9085 https://doi.org/10.1074/jbc.M207198200
  20. Tsao TS, Tomas E, Murrey HE, Hug C, Lee DH, Ruderman NB, Heuser JE, Lodish HF. Role of disulfide bonds in Acrp30/adiponectin structure and signaling specificity: different oligomers activate different signal transduction pathways. J Biol Chem 2003; 278: 50810-50817 https://doi.org/10.1074/jbc.M309469200
  21. Waki H, Yamauchi T, Kamon J, Ito Y, Uchida S, Kita S, Hara K, Hada Y, Vasseur F, Froguel P, Kimura S, Nagai R, Kadowaki T. Impaired multimerization of human adiponectin mutants associated with diabetes: molecular structure and multimer formation of adiponectin. J Biol Chem 2003; 278: 40352-40363 https://doi.org/10.1074/jbc.M300365200
  22. Pajvani UB, Hawkins M, Combs TP, Rajala MW, Doebber T, Berger JP, Wagner JA, Wu M, Knopps A, Xiang AH, Utzschneider KM, Kahn SE, Olefsky JM, Buchanan TA, Scherer PE. Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J Biol Chem 2004; 279: 12152-12162 https://doi.org/10.1074/jbc.M311113200
  23. Tonelli J, Li W, Kishore P, Pajvani UB, Kwon E, Weaver C, Scherer PE, Hawkins M. Mechanisms of early insulin-sensitizing effects of thiazolidinediones in type 2 diabetes. Diabetes 2004; 53: 1621-1629 https://doi.org/10.2337/diabetes.53.6.1621
  24. Kobayashi H, Ouchi N, Kihara S, Walsh K, Kumada M, Abe Y, Funahashi T, Matsuzawa Y. Selective suppression of endothelial cell apoptosis by the high molecular weight form of adiponectin.Circ Res 2004; 94: e27-e31 https://doi.org/10.1161/01.RES.0000119921.86460.37
  25. Aso Y, Yamamoto R, Wakabayashi S, Uchida T, Takayanagi K, Takebayashi K, Okuno T, Inoue T, Node K, Tobe T, Inukai T, Nakano Y. Comparison of serum high-molecular weight (HMW) adiponectin with total adiponectin concentrations in type 2 diabetic patients with coronary artery disease using a novel enzymelinked immunosorbent assay to detect HMW adiponectin. Diabetes 2006; 55: 1954-1960 https://doi.org/10.2337/db05-1525
  26. Inoue T, Kotooka N, Morooka T, Komoda H, Uchida T, Aso Y, Inukai T, Okuno T, Node K. High molecular weight adiponectin as a predictor of long-term clinical outcome in patients with coronary artery disease. Am J Cardiol 2007; 100: 569-574 https://doi.org/10.1016/j.amjcard.2007.03.062
  27. Liu Y, Retnakaran R, Hanley A, Tungtrongchitr R, Shaw C, Sweeney G. Total and high molecular weight but not trimeric or hexameric forms of adiponectin correlate with markers of the metabolic syndrome and liver injury in Thai subjects. J Clin Endocrinol Metab 2007; 92: 4313-4318 https://doi.org/10.1210/jc.2007-0890
  28. Seino Y, Hirose H, Saito I, Itoh H. High molecular weight multimer form of adiponectin as a useful marker to evaluate insulin resistance and metabolic syndrome in Japanese men. Metabolism 2007; 56: 1493-1499 https://doi.org/10.1016/j.metabol.2007.06.015
  29. Sattar N, Watt P, Cherry L, Ebrahim S, Davey Smith G, Lawlor DA. High molecular weight adiponectin is not associated with incident coronary heart disease in older women: a nested prospective case-control study. J Clin Endocrinol Metab 2008; 93: 1846-1849 https://doi.org/10.1210/jc.2007-2603
  30. Mathews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: Insulin resistance and b-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 1985; 28: 412-419 https://doi.org/10.1007/BF00280883
  31. Cnop M, Havel PJ, Utzschneider KM, Carr DB, Sinha MK, Boyko EJ, Retzlaff BM, Knopp RH, Brunzell JD, Kahn SE. Relationship of adiponectin to body fat distribution, insulin sensitivity and plasma lipoproteins: evidence for independent roles of age and sex. Diabetologia 2003; 46: 459-469 https://doi.org/10.1007/s00125-003-1074-z
  32. Lara-Castro C, Luo N, Wallace P, Klein RL, Garvey WT. Adiponectin multimeric complexes and the metabolic syndrome trait cluster. Diabetes 2006; 55: 249-259 https://doi.org/10.2337/diabetes.55.01.06.db05-1105
  33. Kadowaki T, Yamauchi T, Kubota N, Hara K, Ueki K, Tobe K. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest 2006; 116: 1784- 1792 https://doi.org/10.1172/JCI29126
  34. Yamauchi T, Kamon J, Minokoshi Y, Ito Y, Waki H, Uchida S, Yamashita S, Noda M, Kita S, Ueki K, Eto K, Akanuma Y, Froguel P, Foufelle F, Ferre P, Carling D, Kimura S, Nagai R, Kahn BB, Kadowaki T. Adiponectin stimulates glucose utilization and fatty-acid oxidation by activating AMP-activated protein kinase. Nat Med 2002; 8: 1288-1295 https://doi.org/10.1038/nm788
  35. Szmitko PE, Teoh H, Stewart DJ, Verma S. Adiponectin and cardiovascular disease: state of the art? Am J Physiol Heart Circ Physiol 2007; 292: H1655-1663 https://doi.org/10.1152/ajpheart.01072.2006
  36. Ridker PM. Clinical application of C-reactive protein for cardiovascular disease detection and prevention. Circulation 2003; 107: 363-369 https://doi.org/10.1161/01.CIR.0000053730.47739.3C
  37. Heinrich PC, Castell JV, Andus T. Interleukin-6 and the acute phase response. Biochem J 1990; 265: 621-636 https://doi.org/10.1042/bj2650621
  38. Fasshauer M, Klein J, Neumann S, Eszlinger M, Paschke R. Hormonal regulation of adiponectin gene expression in 3T3-L1 adipocytes. Biochem Biophys Res Commun 2002; 290: 1084-1089 https://doi.org/10.1006/bbrc.2001.6307
  39. Bruun JM, Lihn AS, Verdich C. Regulation of adiponectin by adipose tissue-derived cytokines: in vivo and in vitro investigations in humans. Am J Physiol Endocrinol Metab 2003; 285: 527-533 https://doi.org/10.1152/ajpendo.00110.2003
  40. Ouchi N, Kihara S, Funahashi T, Nakamura T, Nishida M, Kumada M, Okamoto Y, Ohashi K, Nagaretani H, Kishida K, Nishizawa H, Maeda N, Kobayashi H, Hiraoka H, Matsuzawa Y. Reciprocal association of C-reactive protein with adiponectin in blood stream and adipose tissue. Circulation 2003; 107: 671-674 https://doi.org/10.1161/01.CIR.0000055188.83694.B3
  41. Devaraj S, Torok N, Dasu MR, Samols D, Jialal I. Adiponecti decreases C-reactive protein synthesis from endothelial cells. Evidence for an adipose tissue-vascular loop. Arterioscler Thromb Vasc Biol 2008; 28: 1368-1374 https://doi.org/10.1161/ATVBAHA.108.163303
  42. Libby P, Ridker PM, Maseri A. Inflammation and atherosclerosis. Circulation 2002; 105: 1135-1143 https://doi.org/10.1161/hc0902.104353
  43. Tabara Y, Osawa H, Kawamoto R, Tachibana-Iimori R, Yamamoto M, Nakura J, Miki T, Makino H, Kohara K. Reduced highmolecular- weight adiponectin and elevated high-sensitivity C-reactive protein are synergistic risk factors for metabolic syndrome in a large-scale middle-aged to elderly population: the Shimanami Health Promoting Program Study. J Clin Endocrinol Metab 2008; 93: 715-722 https://doi.org/10.1210/jc.2007-0397