Original Article http://dx.doi.org/10.12997/jla.2015.4.1.7 pissn 2287-2892 eissn 2288-2561 JLA Effects of the Serum Adiponectin to Tumor Necrosis Factor-α (TNF-α) Ratio on Carotid Intima-Media Thickness in Newly Diagnosed Type 2 Diabetic Patients Kwang Youn Kim, Jung Ae Hong, Ha Won Hwang, Sun Ho Lee, Ju Ri Park, Sung Hoon Yu, Jun Goo Kang, Ohk Hyun Ryu, Seong Jin Lee, Eun Gyung Hong, Doo-Man Kim, Jae Myung Yoo, Sung Hee Ihm, Moon Gi Choi, Hyung Joon Yoo, Chul Sik Kim Division of Endocrinology, Department of Internal Medicine, College of Medicine, Hallym University, Korea 처음진단된제 2 형당뇨병환자에서아디포넥틴대종양괴사인자 - 알파농도의비율이경동맥내중막두께에미치는영향 김광윤, 홍정애, 황하원, 이선호, 박주리, 유성훈, 강준구, 류옥현, 이성진, 홍은경, 김두만, 유재명, 임성희, 최문기, 유형준, 김철식 한림대학교의과대학내과학교실내분비내과 Objectives: Type 2 diabetes, a leading cause of cardiovascular disease, is well known for its association with accelerated atherosclerosis. Adiponectin and tumor necrosis factor - alpha (TNF-α), which are produced and secreted in adipose tissue, have been suggested as predictors for cardiovascular disease. However, little is known about the influence of adiponectin and TNF-α ratio on the progression of carotid atherosclerosis in newly diagnosed type 2 diabetic patients. This study was conducted to evaluate the influence of serum adiponectin/tnf-α levels on the progression of carotid atherosclerosis. Methods: One hundred eleven newly diagnosed type 2 diabetes patients were enrolled. Anthropometric and biochemical data including serum adiponectin, TNF-α were measured for each participant. Also we measured carotid intima-media thickness (CIMT) at baseline and at 1 year follow-up (n=81). We finally examined the relationship among serum adiponectin over TNF-α levels (ADPN/TNF-α), baseline CIMT, and progression of CIMT at 1 year. Results: ADPN/TNF-α negatively correlated with baseline CIMT (r=-0.231, p=0.025). Moreover, progression of CIMT was significant at 1 year (0.011±0.138 mm). There was a negative correlation between ADPN/TNF-α and progression of CIMT at 1 year (r=-0.172, p=0.038). In multiple regression analysis, age and HbA1c were found to be independent risk factors for baseline CIMT. However, only HbA1c was an independent risk factor for the progression of CIMT. Conclusion: ADPN/TNF-α was negatively associated with baseline CIMT and the progression of CIMT at 1 year. Overall glycemic control is the most important factor in the progression of CIMT in patients with type 2 diabetes. Key Words: Diabetes Mellitus, Type 2, Adiponectin, TNF-α, Carotid Atherosclerosis, Carotid Intima Media Thickness Received: Revised: Accepted: October 10, 2013 April 30, 2015 May 15, 2015 Corresponding Author: Chul Sik Kim, Division of Endocrinology, Department of Internal Medicine, College of Medicine, Hallym University, 22, Gwanpyeong-ro 170beon-gil, Dongan-gu, Anyang-si, Gyeonggi-do 431-796, Korea Tel: +82-31-386-2269, Fax: +82-31-380-2269, E-mail: ironeat@gmail.com This is an Open Access article distributed under the terms of the creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. www.lipid.or.kr Copyright c 2015 The Korean Society of Lipidology and Atherosclerosis 7
J Lipid Atheroscler 2015;4(1):7-15 JOURNAL OF LIPID AND ATHEROSCLEROSIS 서론 제2형당뇨병환자에서는고혈당, 인슐린저항성, 고혈압및이상지질혈증등이복합적으로작용을하여죽상동맥경화증을일으키게된다. 1 최근제2형당뇨병환자에서죽상동맥경화증을유발하는새로운위험요인을규명하기위한연구및죽상동맥경화증을조기에발견하기위한시도가활발히진행되고있는데 2 그중 B-mode 초음파를이용하여측정하는경동맥내중막두께 (carotid intima-media thickness, CIMT) 는죽상동맥경화증정도를잘나타내며심혈관질환의대리표지자로잘알려져있다. 3,4 단면적연구에서밝혀진제2형당뇨병환자의 CIMT에영향을미치는요인으로는나이, 당뇨병유병기간, 성별, 콜레스테롤, 혈압, 체질량지수등이있으며 2 전향적인분석에서는제2형당뇨병환자의 CIMT 의진행에영향을주는요인으로혈당조절상태, 5,6 인슐린저항성, 5 혈소판활성도 7 등이있다. 아디포넥틴 (adiponectin, ADPN) 과종양괴사인자- 알파 (tumor necrosis factor-alpha, TNF-α) 는지방세포에서특이적으로발현되고분비되는아디포사이토카인으로 8 아디포넥틴은제2형당뇨병환자 9 및관상동맥질환환자에서농도가낮은것으로알려져있으며 10 인슐린저항성발생에도중요한역할을한다. 11 TNF-α 또한비만및인슐린저항성과관련이많으며당뇨병관련합병증발생에도관련이있다. 12-14 한편아디포넥틴과 TNF-α는상호억제하는작용을가지고있는데, 이로인해아디포넥틴의농도가낮고 TNF-α의농도가높은경우죽상동맥경화증이동반될가능성이더욱높을수있다. 15 따라서본연구에서는제2형당뇨병환자에서초기혈청아디포넥틴대 TNF-α의농도비율 (ADPN/TNF-α) 이낮은경우죽상동맥경화증의진행을심화시켜차후심혈관질환의발생이증가될수있음을규명하고자하였다. 대상및방법 1. 연구대상 본원내분비내과외래에내원한환자중처음으로제2형당뇨병을진단받고연구에동의한 111명을연속적으로모집하였다. 이들로부터병력청취, 신체검진, 생화학검사및 CIMT 를측정하였으며 1년이지난후해당검사를다시시행하였다. 그중 1년간격으로 2번의 CIMT 검사를완료한 81명을최종적으로분석하였다. 제1형당뇨병, 관상동맥질환, 뇌혈관질환, 말초혈관질환, 신기능저하 ( 혈중 creatinine 수치가 2.0 mg/dl 이상으로정의 ), 간기능장애 ( 혈중 alanine aminotransferase 또는 aspartate aminotransferase가정상상한치의 3배이상인경우로정의 ), 부신피질호르몬사용, 임신, 악성종양이나심한감염상태, 쿠싱증후군, 말단비대증, 갑상선기능이상, 여성호르몬투여중, 알코올중독및약물남용등인경우는연구에포함시키지않았다. 또한 1년의추적관찰기간중 CIMT의진행에유의한영향을미칠가능성이높은 thiazolidinedione 계통의약물을사용하는경우, 분석에서제외하였다. 5 대상자에서당뇨병진단은 1985년도에정해진세계보건기구기준을따랐으며 16 당뇨병성고혈압의진단은수축기혈압 130 mmhg 이상또는이완기혈압 80 mmhg 이상이거나 17 고혈압약물을복용중인경우로하였으며, 이상지질혈증은 LDL 콜레스테롤이 100 mg/dl 이상, HDL 콜레스테롤이남자의경우 40 mg/dl 미만, 여자의경우 50 mg/dl 미만또는지질강하제를복용하는경우로하였다. 위연구는본원임상시험심사위원회의승인을받았으며각각의환자에게서서면동의서를받았다. 2. 신체검사각환자에서혈압은앉은상태에서심장높이에서혈압계를사용하여측정하였다. 신체계측은공복상태에서가벼운복장을한상태에서시행하였으며체질량지수는몸무게 (kilogram) 를키 (meter) 제곱한값으로나누어계산하였다 (kg/m 2 ). 허리둘레는선상태로양발을약 30 cm 벌린자세에서갈비뼈의가장아랫부분과장골능사이의가운데부위를줄자를사용하여측정하였다. 3. 생화학검사 10시간이상의금식후오전에혈액검사를시행하였다. 혈당은 hexokinase법을이용한자동측정기 (Hitachi 747; Roche, Montclair, NJ, USA), 당화혈색소 (HbA1c) 는고성능액체크로마토그래피 (high-performance liquid chromatography) 원리를이용한자동측정기 (Variant II; Bio-Rad Laboratories, Hercules, CA, USA) 로측정하였다. 인슐린농도는 INS-IRMA kit (BioSource, Europe, SA, Nivelles, Belgium) 를사용하여측정하였다. 총콜레스테롤및 HDL 콜레스테롤은직접효소법 (Hitachi 747; Daiichi, Tokyo, Japan), 중성지방은효소비색법 (Hitachi 747; Roche, Japan/Germany) 을이용하여측정하였 8 www.lipid.or.kr
Kwang Youn Kim, et al.: Effects of the Serum Adiponectin to TNF-α Ratio on Carotid Intima-Media Thickness 으며 LDL 콜레스테롤은 Friedewald 공식을이용하여계산하였다. 인슐린저항성은 homeostasis model assessment method [HOMA-IR, 공복인슐린 (μu/ml) 공복혈당 (mmol/l)/22.5] 을이용하여구하였다. 혈청아디포넥틴과 TNF-α는각각상용키트 (AdiopMark; MESDIA, Seoul, Korea / R&D Systems, MN, USA) 의프로토콜을따라 enzyme-linked immunosorbent assay (ELISA) 법을이용하여측정하였다. 한편아디포넥틴및 TNF-α 측정의변이계수는각각 4.7%, 4.2% 이었다. 4. 경동맥내중막두께측정환자의 CIMT 는한명의검사자가 8 MHz 선형탐침 (Sequoia C512; Siemens, Munich, Germany) 을이용한 B-mode 초음파로측정을하였다. CIMT 는좌측과우측경동맥의종단면을따라총경동맥이내경동맥과외경동맥으로분리되는분지점의근위부에위치한총경동맥의원벽 (far wall) 에서내중막두께가최고인지점을정하고이지점과이를중심으로근위 10 mm, 원위 10 mm 위치에서측정하였다. 측정의재현성을위하여계산한 CIMT 측정의일간변이계수는 4.9% 였다. CIMT 측정이예정된부위에석회화되고혈관의내강내로돌출된병변인죽전 (plaque) 이있는경우에는죽전이포함되지않은근위부에서측정하였다. 평균 CIMT 는좌측과우측의 CIMT 를측정값 6곳의평균으로구하였으며 CIMT 의진행 (ΔCIMT) 는 1년후측정한평균 CIMT 값에서이전에시행한평균 CIMT 값을뺀값으로정하였으며 ΔCIMT 가 0보다큰경우죽상동맥경화증의진행으로간주하였다. 7 5. 통계연속형변수자료는평균 ± 표준편차로제시하였다. 중성지방및아디포넥틴대 TNF-α 농도의비율 (ADPN/TNF-α) 은정규분포를따르지않아자연로그로치환한후통계자료로이용하였다. 1년동안 CIMT가진행한군과진행하지않은군으로나누어양군의생화학적, 임상적특징의차이를 t-test로비교하였다. 또한 ADPN/TNF-α 와초기 CIMT 값및 ΔCIMT 와의관계를알아보기위하여상관분석을시행하였으며, 초기 CIMT 값및 ΔCIMT 에미치는요인을알아보기위하여다중다단계회귀분석을시행하였다. 자료의통계분석은 SPSS (Windows version 18.0, SPSS Inc. IL, USA) 를이용해시행하였으며 p 값이 0.05 미만인경우통계적으로유의하다고판단하였다. 결과 대상자중여성의비율은약 46% 였으며연구참여당시평균나이는 47세였고약 1/3은흡연을하는중이었으며 42% 에서는고혈압이동반되어있었으며평균혈압은 126.9±14.7 mmhg 이었고 HOMA-IR 은 2.6±1.7 이었다. HbA1c 는 7.5±1.7%, HDL 콜레스테롤은 48.9±12.9 mg/dl, 자연로그로치환후계산한중성지방값은 5.07±0.53이었으며, LDL 콜레스테롤은 115.6± 37.9 mg/dl 이었다. 한편 1년후에대상자들의평균 HbA1c 는 6.8±1.6%, HDL 콜레스테롤은 49.3±13.4 mg/dl, 중성지방은 5.08±0.54( 자연로그로치환후 ), LDL 콜레스테롤은 89.2±35.3 mg/dl 로 HbA1c 와 LDL 콜레스테롤의유의한감소가있었다 ( 각각 p=0.008, p<0.001; by paired t-test). 한편연구시작당시평균 CIMT는 0.745 mm였으며 1년후에는 0.756 mm로 0.011 mm의유의한증가가있었다 (p= 0.001). 본연구에서는 CIMT의진행유무에따라두군으로나누었는데, 진행군에서는 1년동안 0.032 mm의 CIMT 의증가가있었으며, 비진행군에서는 CIMT 가 1년동안 0.013 mm 감소하였다. CIMT 진행군의초기혈당상태는비진행군에비하여불량했으며 ADPN/TNF-α는유의하게낮았다. 한편비만정도, 혈압, 인슐린저항성, 콜레스테롤측면에서는양군간에유의한차이가없었다 (Table 1). 한편대상자의 1년의연구기간동안약물사용은큰변화가없었는데, 이들은메트포민제를가장많이사용하였으며설폰요소제는그절반정도에서사용되었다. 유의하게사용이증가된경구용혈당강하제는 Dipeptidyl peptidase-4 (DPP4) 저해제로초기에는 37% 에서사용하였으나 1년후에는 56% 정도로사용비율이증가하였다. 처음부터인슐린제를투여한대상자는 4.9% 로적었으며 1년후에는 7.4% 로약간증가하였으나유의한변화는아니었다. 아스피린은약 1/2에서복용하였으며, 사용혈압약중레닌-안지오텐신계통 (renin angiotensin system) 억제약물이가장많았으며다음으로칼슘길항제였다. 한편초기에대상자의 43.2% 에서스타틴제을사용했으며 1년후에는 59.3% 로사용비율이증가하였다 (Table 2). 한편진행군과비진행군사이의유의한약제변화의차이는없었다 ( 자료제시하지않음 ). 연구시작시점에서아디포넥틴농도가 CIMT와유의한음의연관성이있었지만 (r=-0.162, p=0.043; 아디포넥틴농도는자연로그로치환후계산 ) CIMT의 1년동안의진행과는유의한 www.lipid.or.kr 9
J Lipid Atheroscler 2015;4(1):7-15 JOURNAL OF LIPID AND ATHEROSCLEROSIS Table 1. Baseline clinical and biochemical characteristics of the subjects according to progression of carotid intima-media thickness All patients Progression No progression p value Number (%) 81 44 (54.3) 37 (45.7) Mean ΔCIMT (mm/yr) 0.011±0.138 0.032±0.045-0.013±0.026 0.000 Age (years) 47.4±10.7 48.4±9.3 46.2±11.8 0.361 Female (%) 45.7 43.2 48.6 0.623 Current smoker (%) 35.8 36.4 35.1 0.909 Body mass index (kg/m 2 ) 25.2±3.1 25.6±3.1 24.8±3.2 0.259 Waist circumference (cm) 88.9±7.7 89.8±8.0 87.9±7.5 0.274 Hypertension (%) 42.0 40.9 43.2 0.832 Systolic blood pressure (mmhg) 126.9±14.7 127.1±16.1 126.7±15.5 0.910 Diastolic blood pressure (mmhg) 79.1±9.2 79.9±9.6 78.1±9.3 0.396 Hypercholesterolemia (%) 61.7 63.6 59.5 0.700 HbA1c (%) 7.5±1.7 7.9±1.8 7.1±1.7 0.043 HOMA-IR 2.6±1.7 2.7±1.9 2.5±1.5 0.598 Total cholesterol (mg/dl) 196.2±39.4 199.3±42.1 192.6±35.2 0.438 HDL cholesterol (mg/dl) 48.9±12.9 48.2±13.9 49.7±11.3 0.594 Ln [triglyceride (mg/dl)] 5.07±0.53 5.10±0.59 5.03±0.45 0.547 LDL cholesterol (mg/dl) 115.6±37.9 118.2±36.6 112.4±39.5 0.498 Ln [ADPN/TNF-α] 8.30±0.77 8.12±0.76 8.49±0.79 0.036 Medications Metformin (%) 87.7 88.6 86.5 0.770 Sulfonylurea or meglitinide (%) 43.2 40.9 45.9 0.649 DPP4 inhibitors (%) 37.0 38.6 35.1 0.745 α-glucosidase inhibitors (%) 8.6 9.1 8.1 0.875 Insulins (%) 4.9 4.5 5.4 0.859 Aspirin (%) 53.1 54.5 51.4 0.774 β-blockers (%) 3.7 4.5 2.7 0.662 Ca-blockers (%) 11.1 11.4 10.8 0.937 RAS inhibition (%) 30.9 29.5 32.4 0.779 Statins (%) 43.2 43.2 43.2 0.996 Data are presented as mean±sd. CIMT; carotid intima-media thickness, LDL; indicates low-density lipoprotein, HDL; high-density lipoprotein, HOMA-IR; homeostatic model assessment for insulin resistance, TNF-α; Tumor necrosis factor-α, DPP4; dipeptidyl peptidase-4, RAS; renin angiotensin system 관련은없는것으로나타났다 (r=-0.124, p=0.072; 아디포넥틴농도는자연로그로치환후계산 ). TNF-α 농도의경우연구시작시점에서 CIMT 와양의연관성이있었으나통계적으로유의하지는않았으며 (r=0.070, p=0.072; TNF-α 농도는자연로그로치환후계산, 0.001), 1년동안의 CIMT 진행과도마찬가지였다 (r= 0.058, p=0.113; TNF-α 농도는자연로그로치환후계산 ). 한편아디포넥틴및 TNF-α 농도의비율과 CIMT, CIMT의진행을상관분석한결과 ADPN/TNF-α 비율은낮을수록경동맥의죽상동맥경화증이심한것으로나타났으며 (r=-0.231, p=0.025, Fig. 1), 이러한경향이있는경우이후 1년동안의죽상동맥경화증이유의하게점점진행되는경향을보였다 (r=-0.172, p=0.038, Fig. 2). 한편어떠한요인이 CIMT에영향을미치는지를알아보기 Table 2. Differences in medication use in 1 year ㅤ Baseline 1 year later p value Metformin (%) 87.7 84.0 0.503 Sulfonylurea or meglitinide (%) 43.2 40.7 0.752 DPP4 inhibitors (%) 37.0 55.6 0.018 α-glucosidase inhibitors (%) 8.6 6.2 0.551 Insulins (%) 4.9 7.4 0.517 Aspirin (%) 53.1 53.1 1.000 β-blockers (%) 3.7 4.9 0.701 Ca-blockers (%) 11.1 14.8 0.486 RAS inhibitors (%) 30.9 34.6 0.618 Statins (%) 43.2 59.3 0.041 DPP4; dipeptidyl peptidase-4, RAS; renin angiotensin system 위한다중회귀분석에는기존에 CIMT 와연관이있는것으로알려져있는위험인자인나이, 성별, 흡연, 신체계측치수, 혈압, 혈당, 10 www.lipid.or.kr
Kwang Youn Kim, et al.: Effects of the Serum Adiponectin to TNF-α Ratio on Carotid Intima-Media Thickness 1.4.6 1.2 1.0.8.6.4.2 5 6 7 8 9 10 11 Log transformed ADPN/TNF-alpha Fig. 1. Correlation between serum adiponectin/tnf-α level (log transformed) and baseline CIMT. r=-0.231, p=0.025. TNF-α; Tumor necrosis factor-α, CIMT; carotid artery intima-media thickness.4.2 0.0 -.2 -.4 5 6 7 8 9 10 11 Log transformed ADPN/TNF-alpha Fig. 2. Correlation between serum adiponectin/tnf-α level and progression of CIMT. r=-0.172, p=0.038. TNF-α; Tumor necrosis factor-α, CIMT; carotid artery intimamedia thickness Table 3. Multivariate logistic regression modeling for predictors of carotid artery intima-media thickness in type 2 diabetic patients Parameters tested β p value Age (years) 0.332 0.037 Gender (Female=0, Male=1) 0.195 0.184 Smoking (No=0, Yes=1) 0.202 0.162 BMI (kg/m 2 ) 0.183 0.192 WC (cm) 0.144 0.262 Systolic blood pressure (mmhg) 0.062 0.616 Diastolic blood pressure (mmhg) 0.147 0.251 HbA1c (%) 0.447 0.014 HOMA-IR 0.153 0.211 HDL-C (mg/dl) -0.083 0.597 Ln [Triglyceride (mg/dl)] 0.052 0.767 LDL-C (mg/dl) 0.252 0.096 Ln [Adiponenctin (ng/ml)/tnf-α (pg/ml)] -0.196 0.139 CIMT; carotid artery intima-media thickness, LDL-C; low density lipoprotein cholesterol, BMI; body mass index, WC; waist circumference, HOMA-IR; homeostatic model assessment for insulin resistance, HDL-C; high density lipoprotein cholesterol, TNF-α; Tumor necrosis factor-α 콜레스테롤농도및 ADPN/TNF-α 등을포함하였다. 분석결과나이 (β=0.332, p=0.037) 와혈당조절상태가 (β=0.447, p= 0.014, Table 3) CIMT 에유의한영향을미치는요인으로나타났다 (Table 3). 또한 1년동안의 CIMT의증가에유의한영향을미치는요인으로는혈당조절상태만이유의한것으로나타났다 (β= 0.313, p=0.038, Table 4). Table 4. Multivariate logistic regression modeling for predictors of progression of carotid artery intima-media thickness in type 2 diabetic patients Parameters tested β p value Baseline mean CIMT (mm) 0.102 0.419 Age (years) 0.195 0.086 Gender (Female=0, Male=1) 0.016 0.916 Smoking (No=0, Yes=1) 0.172 0.192 BMI (kg/m 2 ) 0.020 0.858 WC (cm) 0.031 0.725 Systolic blood pressure (mmhg) 0.023 0.865 Diastolic blood pressure (mmhg) 0.081 0.723 HbA1c (%) 0.313 0.038 HOMA-IR 0.123 0.315 HDL-C (mg/dl) -0.067 0.748 Ln [Triglyceride (mg/dl)] 0.018 0.902 LDL-C (mg/dl) 0.008 0.902 Ln [Adiponenctin (ng/ml)/tnf-α(pg/ml)] -0.115 0.326 CIMT; carotid artery intima-media thickness, BMI; body mass index, WC; waist circumference, HOMA-IR; homeostatic model assessment for insulin resistance, HDL-C; high density lipoprotein cholesterol, LDL-C; low density lipoprotein cholesterol, TNF-α; Tumor necrosis factor-α 고찰 제2형당뇨병환자에서죽상동맥경화증관련심혈관질환으로인한사망률은제2형당뇨병이없는사람들에비해 2-4배정도 www.lipid.or.kr 11
J Lipid Atheroscler 2015;4(1):7-15 JOURNAL OF LIPID AND ATHEROSCLEROSIS 높은것으로알려져있으며, 18 제2형당뇨병환자의전체사망원인의 70-80% 는심혈관질환인것으로알려져있다. 19 제2형당뇨병환자의죽상동맥경화증발생은고혈당, 인슐린저항성, 이상지질혈증, 고혈압, 혈액응고장애등의복합한작용으로일어난다. 20 때문에제2형당뇨병환자에서죽상동맥경화증발생을감소시키기위해서는적절히혈당을낮춰야할뿐아니라고혈압, 이상지질혈증에대한치료등종합적인관리가필요하다. 21 지방조직에서생산분비되는아디포사이토카인에는아디포넥틴, 렙틴, 레지스틴, TNF-α, plasminogen-activator inhibitor type 1 (PAI-1), 아딥신등이있는데그중아디포넥틴은인슐린저항성및당대사에중요한역할을한다. 11 또한제2형당뇨병환자, 9 비만환자, 22 관상동맥질환환자에서 10 아디포넥틴농도가감소되어있으며, 전향적연구에서아디포넥틴농도가낮은사람은높은경우보다심혈관질환발생확률이높으며, 23 제2형당뇨병환자에서도아디포넥틴농도가낮은경우향후심혈관질환의발생확률이높은것으로알려져있다. 24 TNF-α 또한비만, 인슐린저항성및죽상동맥경화증발생과관련이있으며 12,13,25,26 이와연관되어 TNF-α를억제시키는치료를하는경우죽상동맥경화증의감소가나타날수있다. 27 한편아디포넥틴과 TNF-α 는지질대사, 인슐린저항성, 염증반응에서로반대작용을가지고있으며또한서로생산과활성을억제하는작용을가지고있다. 28,29,30 때문에아디포넥틴의농도가낮고 TNF-α의농도가높은경우에는죽상동맥경화증이발생및진행할가능성이더욱높을수있다. 15 최근제2형당뇨병환자와같이심혈관질환고위험군에서죽상동맥경화증을조기에발견하기위하여 CIMT 측정이많이사용되고있는데 CIMT는제2형당뇨병환자의대혈관합병증발생과밀접한관련이있는것으로알려져있다. 3 하지만이러한결과는주로단면연구에서나타나는것으로, 전향적인연구에서 CIMT 에영향을미치는인자가무엇인지에대한연구는그리많지않다. 7 이전에관상동맥우회수술을받은 146명의남성을대상으로한연구에서 CIMT의진행률이 3배클경우이후약 9년동안에관상동맥질환이발생할확률이 3배이상증가하였으며, 31 CIMT 의진행과심혈관질환발생예측에대한메타분석에서 CIMT 가연간 0.1 mm 증가하는경우뇌졸중발생위험을 18%, 심근경색발생위험이 15% 높아지는것으로보고되었다. 4 이러한결과는단면적으로얻은 CIMT 값뿐아니라일정기간 CIMT의진행도심혈관질환발생의조기표지자로활용될수있음을의미하며 32 이에대한예방적약물치료를결정하는데도움이될수있음을 뜻한다. 33 한편 CIMT의진행에영향을미치는위험요인으로는당뇨병, 고혈압, 흡연, 낮은 HDL cholesterol, 높은 LDL cholesterol, 중성지방등이있으며 34 제2형당뇨병환자를대상으로한연구에서는인슐린저항성, 5 혈당 5,6 그리고혈소판활성도 7 등이 CIMT의진행에미치는위험요인으로알려져있다. 최근아디포넥틴이높은경우 CIMT가낮음을보이는여러연구가보고되었는데, 35-37 이러한아디포넥틴의항죽상동맥경화효과는염증유발물질및혈관유착물질생성억제, 38 대식세포제거수용체하향조절및혈관평활근세포증식억제효과때문으로알려져있다. 39 TNF-α의경우, 그농도가높을경우 CIMT가높게나타나며, 40 실제 TNF-α를낮추는치료를하는경우 CIMT 의진행이억제된연구결과들이여럿보고되고있다. 27,41,42 하지만저자가파악한바로는이제까지처음진단된제2형당뇨병환자를대상으로초기 ADPN/TNF-α 농도와 CIMT의진행을관찰한연구는시행된적이없다. 처음진단된제2형당뇨병환자를대상으로시행한본연구에서초기 ADPN/TNF-α 농도는단면적분석에서 CIMT와유의한음의상관관계가나타났을뿐아니라 1년동안의 CIMT 진행과도유의한음의상관관계를가졌다. 즉초기아디포넥틴농도가낮고 TNF-α 농도가높을수록차후죽상동맥경화증의진행이빨라진다. 하지만이러한상관관계에도불구하고초기 ADPN/TNF-α 비율은 CIMT 및향후진행에독립적인영향을미치는위험요인은아닌것으로나타났는데, 가능한이유로는제2형당뇨병환자에서는고혈당과같이죽상동맥경화증진행과관련된전통적인위험요인이강력하게작용을하기때문에죽상동맥경화증의진행에상대적으로초기 ADPN/TNF-α 농도의기여가크게나타나지않았을수도있다는점을들수있다. 또한 CIMT의진행을보기에는 1년의기간이좀적었거나또는여러당뇨병관련치료약물의사용이유의한 CIMT 의진행을억제하였을가능성도있다. 또한본연구에포함된대상자들이처음당뇨병을진단받은집단이기때문에각종대사지표가비교적양호한상태였으므로 CIMT 상태및진행이저명하지않았을수도있다. 본연구에는여러제한점이있다. 먼저이연구는단면분석이기때문에 ADPN/TNF-α 와 CIMT 와의인과관계가불명확할수있으며, 비록연구대상자들의 1년의연구기간동안에약물치료의유의한차이가없었으나사용한약물의용량의변화는파악하지못한점이다. 결론적으로본연구에서 ADPN/TNF-α은 CIMT로파악되는 12 www.lipid.or.kr
Kwang Youn Kim, et al.: Effects of the Serum Adiponectin to TNF-α Ratio on Carotid Intima-Media Thickness 죽상동맥경화증및그진행과유의한연관이있었으나독립적인위험요인은아니었으며혈당조절상태만이 CIMT진행에가장영향을주는요인으로나타났다. 하지만이와관련된좀더추가연구및장기간의연구가필요할것으로생각한다. 요약 배경 : 경동맥내중막두께 (carotid intima-media thickness, CIMT) 는죽상동맥경화증의지표로서심혈관질환의발생과밀접한관련이있다. 하지만이러한연관성은대부분단면적으로실시된연구에서나타난결과이며전향적인연구에서 CIMT 의진행에영향을미치는요인에대한연구는부족한상태이다. 본연구에서는제2형당뇨병환자에서초기혈청아디포넥틴의농도와종양괴사인자-알파 (tumor necrosis factor-alpha, TNF-α) 의비율 (ADPN/TNF-α) 이낮은경우죽상동맥경화증의진행이심화되어심혈관질환의발생이증가될수있음을알아보고자하였다. 방법 : 처음진단받은제2형당뇨병환자 111명을모집하였다. 이들에게서신체검사와생화학적검사를시행하였으며 ADPN/ TNF-α 값을구하였다. CIMT 측정을위한경동맥초음파검사는내원당시및 1년이지난후시행하였다 (n=81 명 ). 두번의검사에서 CIMT가증가한경우를경동맥죽상동맥경화증의진행으로간주하였다. 결과 : 내원당시 ADPN/TNF-α와 CIMT와는유의한음의상관관계가있었다 (r=-0.231, p=0.025). CIMT 은 1년후에유의한증가가있었다 (0.011±0.138 mm, p=0.001). 또한 ADPN/TNFα와 1년동안 CIMT의진행과도유의한관계가관찰되었다 (r= -0.172, p=0.038). 한편 CIMT에영향을주는위험요인으로는나이 (β=0.332, p=0.037), HbA1c (β=0.447, p=0.014) 등이이었으며, 1년동안의 CIMT 진행에영향을주는요인은 HbA1c (β=0.311, p=0.042) 뿐이었다. 결론 : 본연구에서 ADPN/TNF-α 은죽상동맥경화증및그진행과연관이있었으나독립적인위험요인에는미치지못하였으며혈당조절상태가죽상동맥경화증의진행에가장영향을주는요인으로나타났다. ACKNOWLEDGEMENT 본연구는 2007 년한국지질 동맥경화학회연구비를수혜받아 수행되었음. 참고문헌 1. Wilson PW, Kannel WB, Silbershatz H, D'Agostino RB. Clustering of metabolic factors and coronary heart disease. Arch Intern Med 1999;159:1104-1109. 2. Yokoyama H, Katakami N, Yamasaki Y. Recent advances of intervention to inhibit progression of carotid intimamedia thickness in patients with type 2 diabetes mellitus. Stroke 2006;37:2420-2427. 3. Kim CS, Kim HJ, Won YJ, Kim DJ, Kang ES, Ahn CW, et al. Normative values of carotid artery intima-media thickness in healthy Korean adults and estimation of macrovascular diseases relative risk using this data in type 2 diabetes patients. Diabetes Res Clin Pract 2006; 72:183-189. 4. Lorenz MW, Markus HS, Bots ML, Rosvall M, Sitzer M. Prediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and metaanalysis. Circulation 2007;115:459-467. 5. Langenfeld MR, Forst T, Hohberg C, Kann P, Lübben G, Konrad T, et al. Pioglitazone decreases carotid intimamedia thickness independently of glycemic control in patients with type 2 diabetes mellitus: results from a controlled randomized study. Circulation 2005;111: 2525-2531. 6. Katakami N, Yamasaki Y, Hayaishi-Okano R, Ohtoshi K, Kaneto H, Matsuhisa M, et al. Metformin or gliclazide, rather than glibenclamide, attenuate progression of carotid intima-media thickness in subjects with type 2 diabetes. Diabetologia 2004;47:1906-1913. 7. Fateh-Moghadam S, Li Z, Ersel S, Reuter T, Htun P, Plöckinger U, et al. Platelet degranulation is associated with progression of intima-media thickness of the common carotid artery in patients with diabetes mellitus type 2. Arterioscler Thromb Vasc Biol 2005;25:1299-1303. 8. Maeda K, Okubo K, Shimomura I, Funahashi T, Matsuzawa Y, Matsubara K. cdna cloning and expression of a novel adipose specific collagen-like factor, apm1 (AdiPose Most abundant Gene transcript 1). Biochem Biophys Res Commun 1996;221:286-289. www.lipid.or.kr 13
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