혈중렙틴농도와동맥경화증의관계 공민규외 대상및방법 1. 연구대상 2011 년 1월부터 12월까지내원한 20세이상의제2형당뇨병환자중이전에관상동맥질환이나뇌혈관질환등의진행된동맥경화증이있거나혈청크레아티닌이 3 mg/dl 이상이거나신사구체여과율 (glomerular filtrat

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1 Soonchunhyang Medical Science 18(1):38-42, June 2012 pissn: I eissn: ORIGINAL ARTICLE 제 2 형당뇨병환자에서혈중렙틴농도와동맥경화증의관계 공민규, 염석천, 추진우, 박형규 순천향대학교서울병원내과 Relationship between Serum Leptin Levels and Atherosclerosis in Type 2 Diabetes Patients Min-Gyu Kong, Seok-Chun Yeum, Jin-Woo Choo, Hyeong-Kyu Park Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, Seoul, Korea Objective: Many studies have suggested that leptin is a possible cause of atherosclerosis and is proposed as a cardiovascular risk factor in obese patients. Several studies have shown that serum leptin is associated with pulse wave velocity (PWV) and carotid intima-media thickness (IMT). But the relevance of serum leptin levels for predicting incident cardiovascular disease is less clear. In this study, we investigated the relationship between serum leptin levels and aortic PWV, carotid IMT in type 2 diabetes (T2DM) patients. Methods: Patients with end-stage renal disease or advanced atherosclerosis, systemic infection were excluded. A total of 116 patients (60 male/56 female; age, 59± 14 years) were included. Serum leptin levels, aortic PWV and carotid IMT were measured. Results: Aortic PWV was significantly associated with age (r= 0.28, P< 0.005). Carotid IMT was significantly related to age (r= 0.46, P< 0.001), low density lipoprotein (LDL) (r= 0.22, P< 0.05), lipoprotein (a) (r= 0.23, P< 0.05) and estimated glomerular filteration rate (r= , P< 0.01). There was no correlation between leptin and aortic PWV or carotid IMT. In multivariate analyses, aortic PWV was associated with age (P= 0.007). Carotid IMT was significantly related to age (P< 0.001), LDL (P= 0.01). Conclusion: Serum leptin was not associated with aortic PWV or carotid IMT in T2DM patients. Keywords: Leptin; Atherosclerosis; Type 2 diabetes mellitus 서론많은연구에서렙틴이동맥경화와관련이있다고알려졌으며특히비만한환자에서심혈관질환의위험인자로제시되어왔다 [1]. 비만은동맥경화의중요한위험인자이나그기전은잘알려져있지않다. 지방세포는렙틴, 아디포넥틴 (adiponectin), 레지스틴등의호르몬을생산하며이들호르몬은혈관을비롯한여러장기의증식을일으키며염증반응을야기하고교감신경계항진, 혈관평활근의증식과세포부착물질의생산을통해동맥경화를일으킨다고알려져있다 [2,3]. 고렙틴혈증은심혈관질환의위험인자인대사증후군의구성요소로제시된바있으며 Söderberg 등 [4] 은남성과폐 경후여성에서렙틴이비정상적인섬유소용해 (fibrinolysis) 와관련이있음을밝힌바있다. 일부역학연구들에서렙틴은고혈압환자에서심근두께와연관이있었고심근경색의위험인자였다 [5,6]. 무증상의초기동맥경화의표지자인경동맥내중막두께 (carotid intima-media thickness) 는관상동맥질환의발생과관련이있으며 [7], Ciccone 등 [8] 의연구에서혈중렙틴농도와경동맥내중막두께는유의한상관관계가있었다. 또한동맥의경화도를나타내는동맥맥파전파속도 (pulse wave velocity) 도혈중렙틴농도와관련성이있음이보고되었다 [9,10]. 이에저자등은제2형당뇨병환자에서혈중렙틴농도와동맥맥파전파속도및경동맥의내중막두께와의상관관계를알아보고자본연구를진행하였다. Correspondence to: Hyeong-Kyu Park Department of Internal Medicine, Soonchunhyang University Seoul Hospital, Soonchunhyang University College of Medicine, 59 Daesagwan-ro, Yongsan-gu, Seoul , Korea Tel: , Fax: , hkpark@schmc.ac.kr Received: May 8, 2012 / Accepted after revision: Jun. 11, Soonchunhyang Medical Research Institute This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( 38

2 혈중렙틴농도와동맥경화증의관계 공민규외 대상및방법 1. 연구대상 2011 년 1월부터 12월까지내원한 20세이상의제2형당뇨병환자중이전에관상동맥질환이나뇌혈관질환등의진행된동맥경화증이있거나혈청크레아티닌이 3 mg/dl 이상이거나신사구체여과율 (glomerular filtration rate) 이 30 ml/min 이하인경우또는급성대사합병증이있거나전신감염이있는환자를제외한총 116 명의환자를대상으로하였다. 단변량분석을통하여동맥맥파전파속도와경동맥내중막두께와상관관계가있는임상인자를조사하고다변량분석을통해맥파전파속도와경동맥내중막두께에영향을미치는독립적임상인자를조사하였다. 혈중렙틴농도가남녀간에유의한차이가관찰되어남자와여자로나누어통계분석을하였다. 맥파전파속도와경동맥내중막두께에영향을미칠수있는인슐린, 스타틴, 티아졸리딘디온계열약제의영향을배제하기위해최근 3개월동안이들약제를사용하지않은환자만을따로분석하였다. 또한혈중렙틴농도에영향을미칠수있는인자중체질량지수가 25 이상과미만인경우로나누어분석하고비만도를보다잘반영한다고알려진체지방률을측정한환자군을별도로분석하였다. 본연구는순천향대학교임상연구심의위원회에의해승인되었다. 2. 체지방률, 맥파전파속도및경동맥내중막두께측정비만도평가를위해키 (m) 와몸무게 (kg) 를측정하여체질량지수 (kg/m 2 ) 를계산하였으며체지방률 (body fat, %) 은 Inbody 520 (Biospace, Seoul, Korea) 기기를이용하여측정하였다. 대동맥맥파전파속도 (aortic pulse wave velocity) 는자동파형분석기 (PP- 1000; Hanbyul Meditech Co. Ltd., Jeonju, Korea) 를사용하여측정하였다. 환자는 5분이상안정을취한후앙와위에서대동맥, 상지, 하지에서동맥맥파속도를측정하였으며동맥맥파전파속도 (m/ sec) 는두지점사이의거리를맥파전달시간으로나눈값으로정의하였다. 경동맥내중막두께는고해상도 B-모드초음파기기 (Philips IE 33; Philips Medical Systems, Markham, ON, Canada) 로측정하였다. 총경동맥에서경동맥의팽대부로이행하는경계부로부터근위부 1 cm 구간의원위벽을측정하였다. 경동맥내중막두께는초음파상혈관내강과혈관내막의경계로부터혈관중막과외막의경계부위까지두께를측정하여좌우총경동맥내중막두께의평균치를계산하였다. 3. 통계분석모든연속변수는평균 ± 표준편차로표시하였으며남녀간의차이는 Student t-test 를시행하였다. 동맥맥파전파속도, 경동맥내중막두께, 혈중렙틴농도에영향을미치는유의한변수를찾기위 해 Pearson s correlation coefficient 분석법을사용하였으며, 유의 한변수들을보정한후상관관계분석을위해다변량회귀분석을시 행하였다. 통계분석을위해사용한컴퓨터통계프로그램은 PASW statistics ver. 18 (IBM, New York, NY, USA) 이었으며유의확률 P< 0.05 를통계적으로의미있는것으로하였다. 결과 총대상환자수는 116 명이었으며남자는 60 명, 여자는 56 명으로 평균나이는 59 세였다. 남녀를비교하였을때체중, 체지방률, high density lipoprotein 콜레스테롤, 아포단백 A, 혈중렙틴농도는여 자가남성에비해높았고체중과당화혈색소는남자가더높았으며 동맥맥파전파속도나경동맥내중막두께는남녀간에차이가없 었다 (Table 1). 단변량분석에서혈중렙틴농도는체질량지수, 체지방률, 당화혈 색소, 혈중 C- 펩티드농도그리고 C-reactive protein (CRP) 농도와 유의한상관관계가있었으며동맥맥파전파속도와는상관관계가 관찰되지않았다. 동맥맥파전파속도는나이와유의한상관관계 가있었다. 경동맥내중막두께는나이, 혈중 low density lipoprotein (LDL) 콜레스테롤, 아포단백 A 와유의한양의상관관계에있 Table 1. Baseline characteristics of study subjects Men Women Total P-value No. patients Age (yr) 57± 12 61± 15 59± Weight (kg) 71± 13 63± 13 67± Body mass index (kg/m 2 ) 24.8± ± ± Body fat (%) 26.5± ± ± Total (mg/dl) 179± ± ± (mg/dl) 105± ± ± Triglyceride (mg/dl) 187± ± ± (mg/dl) 39± 9 47± 15 43± Apolipoprotein A 118± ± ± Apolipoprotein B 98± 29 92± 28 95± Lipoprotein (a) 16± 18 17± 17 16± C-peptide (ng/ml) 2.3± ± ± Hemoglobin A1c (%) 10.2± ± ± C-reactive protein (mg/dl) 0.3± ± ± Leptin (ng/ml) 5.6± ± ± 8.5 < 0.01 Albumin/creatinin ratio (μg/mg) 37.7± ± ± filteration rate (ml/min) 100± ± ± Pulse wave velocity (m/sec) 8.4± ± ± Mean-carotid intima-media thickness (mm) Values are presented as mean± SD. 0.64± ± ± Soonchunhyang Medical Science 18(1):

3 Kong M-G, et al. Relationship between Serum Leptin Levels and Atherosclerosis 었으며신사구체여과율과유의한음의상관관계에있었으나혈중 렙틴농도와는관계가없었다 (Table 2). 혈중렙틴농도가남녀간 에유의한차이가관찰되어남녀별로분석하였을때남자에서는 혈중렙틴농도가나이, 체질량지수, C- 펩티드농도, 신사구체여과 율과관계가있었으나여자에서는체질량지수, 체지방률, C- 펩티드 Table 2. Correlation between leptin, pulse wave velocity (PWV), mean carotid intima-media thickness (CIMT) and clinical parameters Leptin PWV Mean-CIMT r P-value r P-value r P-value Age < Body mass index < Body fat < Hemoglobin A1c C-peptide Total Triglyceride Apolipoprotein A Apolipoprotein B Lipoprotein (a) C-reactive protein Leptin filteration rate PWV Mean-CIMT Table 3. Correlation between leptin and clinical parameters in men and women Leptin (men) Leptin (women) r P-value r P-value Age Body mass index < Body fat Hemoglobin A1c C-peptide Total Triglyceride Apolipoprotein A Apolipoprotein B Lipoprotein (a) C-reactive protein filteration rate Pulse wave velocity Mean-carotid intima-media thickness 농도, 당화혈색소와관계가있었다 (Table 3). 다변량분석에서혈중렙틴농도는체질량지수 (P<0.001), CRP 농도 (P= 0.022) 와유의한양의상관관계에있었으며, 동맥맥파전 파속도는나이 (P= 0.007) 와유의한상관관계가있었고경동맥내 중막두께에유의한영향을미치는것은나이 (P< 0.001) 와 LDL 콜 레스테롤수치 (P= 0.01) 였다. 혈중렙틴농도와동맥맥파전파속 도, 경동맥내중막두께와는관련이없었다. 동맥맥파전파속도나 체지방률에영향을주는인슐린, 스타틴, 티아졸리딘디온계열약 제의사용여부와혈중렙틴농도에영향을미치는체질량지수에 따라 4 그룹으로나누어분석하였을때 4 그룹모두에서렙틴농도는 동맥맥파전파속도, 경동맥내중막두께와관련이없었다 (Table 4). Table 4. Correlation between leptin and pulse wave velocity (PWV) or mean carotid intima-media thickness (CIMT) according to drug use and body mass index (BMI) Leptin PWV Mean-CIMT r P-value r P-value Medication, BMI Medication, BMI < No medication, BMI No medication, BMI < Patients were divided into 4 groups: 1) medication (statin, thiazolidione, and insulin) and BMI 25; 2) medication and BMI < 25; 3) no medication (at least 3 months ago) and BMI 25; 4) no medication and BMI < 25. Table 5. Correlation between leptin, pulse wave velocity (PWV), mean carotid intima-media thickness (CIMT) and clinical parameters in patients who received body fat measurement Leptin PWV Mean-CIMT r P-value r P-value r P-value Age < Body mass index < Body fat Hemoglobin A1c C-peptide Total Triglyceride Apolipoprotein A Apolipoprotein B Lipoprotein (a) C-reactive protein < Leptin filteration rate PWV Mean-CIMT Soonchunhyang Medical Science 18(1):38-42

4 혈중렙틴농도와동맥경화증의관계 공민규외 렙틴이체지방률과유의한상관관계가관찰되어체지방률을측정한 42명의환자만을대상으로분석하였을때혈중렙틴농도는체질량지수, 체지방률그리고 CRP 농도와유의한상관관계가관찰되었으며이는전체환자를대상으로분석한결과와유사하였다. 동맥맥파전파속도는나이, 총콜레스테롤농도와유의한상관관계가있었으나혈중렙틴농도와유의한상관관계는없었다. 경동맥내중막두께는나이와신사구체여과율과유의한상관관계에있었으나역시혈중렙틴농도와는유의한상관관계가없었다 (Table 5). 다변량분석에서혈중렙틴농도는체질량지수 (P= 0.004), CRP 농도 (P< 0.001) 와유의한양의상관관계에있었으며동맥맥파전파속도는나이 (P= 0.018) 와양의상관관계를총콜레스테롤농도 (P = 0.02) 와음의상관관계에있었다. 경동맥내중막두께는나이와유의한상관관계 (P= 0.017) 를보여전체환자를분석한결과와큰차이가없었다. 고찰본연구는제2형당뇨병환자에서혈청렙틴농도와큰혈관의동맥경화도의지표로알려진동맥맥파전파속도와초기경동맥죽상경화증의지표인경동맥내중막두께와의관계를알아보고자시행되었다. 동맥경화는심혈관질환의중요한위험인자이다. 동맥맥파전파속도와경동맥내중막두께가동맥의경화도를나타내는지표로잘알려져있고심혈관질환의예측인자로사용되고있다. 혈중렙틴농도가동맥맥파전파속도와경동맥내중막두께와관련이있다는연구결과들이있으며렙틴이향후심혈관질환발생의예측인자로사용될수있을지관심이모아지고있다 [7-10]. Windham 등 [11] 이건강한환자를대상으로한연구에의하면비만할수록렙틴이증가하며그에따라동맥맥파전파속도가증가하여렙틴이동맥경화를일으키는데관련이있다고보고하였다. 또한 Windham 등 [11] 의연구에서렙틴과동맥맥파전파속도의관계는비만과독립적인관계가있어렙틴생산을증가시키는비만이외의다른인자에의해동맥경화가진행될수있다고보고하였다. 혈중렙틴농도는정상혈압인사람보다고혈압환자에서높다는연구가있고 [12] 흡연이렙틴농도를증가시킨다는보고도있다 [13]. 또한동맥경화와급 만성염증과의관련성이알려져있다 [14]. 본연구에서혈중렙틴농도는당화혈색소, C-펩티드농도이외에체질량지수, 체지방률과유의한양의상관관계가있었으며이는비만과동맥경화증의관련성을나타낸다. 이들변수를보정하였을때혈중렙틴농도는체질량지수, CRP 농도와양의상관관계에있었다. 이는동맥경화발생에있어렙틴이비만이외의기전으로생각되는염증과관련이있음을반영한다고생각된다. 남녀를비교하였을때남자에서만혈중렙틴농도가나이, 신사구체여과율과상관관계를보였으며이는적은대상수와렙틴농도에영향을미치는 남녀간의흡연율차이등의영향이있을것으로생각된다. 동맥경화도의지표중하나인동맥맥파전파속도에영향을미치는인자로는체질량지수가높을수록 [15], 남성에서, 나이가많을수록, 신사구체여과율이감소할수록, 혈압이높을수록, 단백뇨가있을때, 공복혈당과당화혈색소가높을수록, 총콜레스테롤과총중성지방농도가높을수록증가한다는연구가있다 [16]. 또한일부연구에서혈중렙틴농도와관련이있다는것이알려졌다 [9,10]. 본연구에서동맥맥파전파속도는나이와유의한상관관계가있었으나렙틴과의관련성은없었다. 동맥맥파전파속도에영향을미치는인자들이다양함을고려할때동맥맥파전파속도에대한렙틴의영향은상대적으로적을가능성이있을것으로생각되며향후추가적인연구가필요하다. 총경동맥내중막두께에영향을주는인자는연구마다다양하게보고되어있다. Reinehr 등 [17] 의연구에의하면경동맥내중막두께에영향을미치는인자로는체질량지수, 수축기혈압, 혈당치, CRP 등이있었다. Magyar 등 [18] 은 86명의이상지질혈증군과 30명의정상지질혈증군을대상으로한연구에서다중회귀분석결과총경동맥내중막두께는총콜레스테롤수치와양의상관관계가있으나중성지방과는관련이없음을발표하였다. Ciccone 등 [8] 의연구에따르면경동맥내중막두께는혈중렙틴농도와유의한상관관계가있었다. 반면경동맥내중막두께가혈중렙틴농도와관련이없다는연구도있으며 Constantinides 등 [19] 의연구에의하면경동맥내중막두께는혈중아디포넥틴농도와상관관계가있으나혈중렙틴농도와는상관관계가없다고보고하였다. 본연구에서경동맥내중막두께는나이와 LDL 수치가높을수록증가하였으나총콜레스테롤, 중성지방그리고혈중렙틴농도와상관관계는없었다. 체질량지수보다비만도를보다잘반영하는체지방률을측정한환자들만을따로분석한결과에서도혈중렙틴농도가체지방이증가함에따라증가하였지만동맥맥파전파속도, 경동맥내중막두께와혈중렙틴농도와의관련성은없는것으로나타났다. 본연구는렙틴농도에영향을미칠수있는흡연, 고혈압유무및치료여부등을고려하지않았고동맥맥파전파속도와경동맥내중막두께의측정이기술자의존적이라는점그리고대상자수가적었다는제한점이있다. 결론적으로, 혈중렙틴농도는동맥맥파전파속도및경동맥내중막두께와유의한상관관계가관찰되지않았다. 향후렙틴농도와동맥경화와의관계규명을위해서는흡연, 고혈압치료약제등동맥경화에영향을미치는인자들을고려한좀더많은환자를대상으로한전향적연구가필요할것이다. 또한제2형당뇨병환자에서렙틴이외의아디포넥틴, 레지스틴등동맥경화와관련된다른지방세포호르몬 (adipokine) 에대한추가연구가필요하다고생각된다. Soonchunhyang Medical Science 18(1):

5 Kong M-G, et al. Relationship between Serum Leptin Levels and Atherosclerosis 감사의글 본연구는순천향대학교학술연구비의일부지원으로수행하였다. REFERENCES 1. Leyva F, Godsland IF, Ghatei M, Proudler AJ, Aldis S, Walton C, et al. Hyperleptinemia as a component of a metabolic syndrome of cardiovascular risk. Arterioscler Thromb Vasc Biol 1998;18: Beltowski J. Leptin and atherosclerosis. Atherosclerosis 2006;189: Zieman SJ, Melenovsky V, Kass DA. Mechanisms, pathophysiology, and therapy of arterial stiffness. Arterioscler Thromb Vasc Biol 2005;25: Söderberg S, Olsson T, Eliasson M, Johnson O, Ahrén B. Plasma leptin levels are associated with abnormal fibrinolysis in men and postmenopausal women. J Intern Med 1999;245: Paolisso G, Tagliamonte MR, Galderisi M, Zito GA, Petrocelli A, Carella C, et al. Plasma leptin level is associated with myocardial wall thickness in hypertensive insulin-resistant men. Hypertension 1999;34: Söderberg S, Ahrén B, Jansson JH, Johnson O, Hallmans G, Asplund K, et al. Leptin is associated with increased risk of myocardial infarction. J Intern Med 1999;246: Salonen JT, Salonen R. Ultrasonographically assessed carotid morphology and the risk of coronary heart disease. Arterioscler Thromb 1991;11: Ciccone M, Vettor R, Pannacciulli N, Minenna A, Bellacicco M, Rizzon P, et al. Plasma leptin is independently associated with the intima-media thickness of the common carotid artery. Int J Obes Relat Metab Disord 2001;25: Singhal A, Farooqi IS, Cole TJ, O Rahilly S, Fewtrell M, Kattenhorn M, et al. Influence of leptin on arterial distensibility: a novel link between obesity and cardiovascular disease? Circulation 2002;106: Schutte R, Huisman HW, Schutte AE, Malan NT. Leptin is independently associated with systolic blood pressure, pulse pressure and arterial compliance in hypertensive African women with increased adiposity: the POWIRS study. J Hum Hypertens 2005;19: Windham BG, Griswold ME, Farasat SM, Ling SM, Carlson O, Egan JM, et al. Influence of leptin, adiponectin, and resistin on the association between abdominal adiposity and arterial stiffness. Am J Hypertens 2010; 23: Henriksen JH, Holst JJ, Moller S, Andersen UB, Bendtsen F, Jensen G. Elevated circulating leptin levels in arterial hypertension: relationship to arteriovenous overflow and extraction of leptin. Clin Sci (Lond) 2000;99: Nicklas BJ, Tomoyasu N, Muir J, Goldberg AP. Effects of cigarette smoking and its cessation on body weight and plasma leptin levels. Metabolism 1999;48: Schnabel R, Larson MG, Dupuis J, Lunetta KL, Lipinska I, Meigs JB, et al. Relations of inflammatory biomarkers and common genetic variants with arterial stiffness and wave reflection. Hypertension 2008;51: Wildman RP, Mackey RH, Bostom A, Thompson T, Sutton-Tyrrell K. Measures of obesity are associated with vascular stiffness in young and older adults. Hypertension 2003;42: Ohya Y, Iseki K, Iseki C, Miyagi T, Kinjo K, Takishita S. Increased pulse wave velocity is associated with low creatinine clearance and proteinuria in a screened cohort. Am J Kidney Dis 2006;47: Reinehr T, Kiess W, de Sousa G, Stoffel-Wagner B, Wunsch R. Intima media thickness in childhood obesity: relations to inflammatory marker, glucose metabolism, and blood pressure. Metabolism 2006;55: Magyar MT, Paragh G, Katona E, Valikovics A, Seres I, Csiba L, et al. Serum s have a more important role than triglycerides in determining intima-media thickness of the common carotid artery in subjects younger than 55 years of age. J Ultrasound Med 2004;23: Constantinides A, van Pelt LJ, van Leeuwen JJ, de Vries R, Tio RA, van der Horst IC, et al. Carotid intima media thickness is associated with plasma lipoprotein-associated phospholipase A2 mass in nondiabetic subjects but not in patients with type 2 diabetes. Eur J Clin Invest 2011; 41: Soonchunhyang Medical Science 18(1):38-42

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저작자표시 - 비영리 - 변경금지 2.0 대한민국 이용자는아래의조건을따르는경우에한하여자유롭게 이저작물을복제, 배포, 전송, 전시, 공연및방송할수있습니다. 다음과같은조건을따라야합니다 : 저작자표시. 귀하는원저작자를표시하여야합니다. 비영리. 귀하는이저작물을영리목적으로이용할수없습니다. 변경금지. 귀하는이저작물을개작, 변형또는가공할수없습니다. 귀하는, 이저작물의재이용이나배포의경우,