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1 대한내과학회지 : 제 73 권제 6 호 2007 당뇨병이없는한국성인에서인슐린저항성의임상지표 가톨릭대학교의과대학내과학교실 1, 예방의학교실 2, 충주시보건소 3 김지현 1 권혁상 1 박용문 2 임선영 2 이진희 2 이승환 1 임동준 1 홍순화 1 조재형 1 김성래 1 김동석 3 윤건호 1 이원철 2 차봉연 1 이광우 1 강성구 1 손호영 1 =Abstract= Best surrogate marker for insulin resistance in middle aged non-diabetic Korean ; Chungju metabolic syndrome study Ji-Hyun Kim, M.D. 1, Hyuk-Sang Kwon, M.D. 1, PhD, Yong-Moon Park, M.D., PhD 2, Sun-Young Lim 2, Jin-Hee Lee 2, Seung-Hwan Lee, M.D. 1, Dong-Joon Lim, M.D. 1, Soon-Hwa Hong, M.D. 1, Jae-Hyoung Cho, M.D. 1, Sung-Rae Kim, M.D., PhD 1, Dong-Suk Kim 3, Kun-Ho Yoon, M.D., PhD 1, Won-Chul Lee, M.D., PhD 2, Bong-Yun Cha, M.D., PhD 1, Kwang-Woo Lee, M.D., PhD 1, Sung-Koo Kang, M.D., PhD 1 and Ho-Young Son, M.D., PhD 1 Departments of Internal Medicine 1 and Preventive Medicine 2, The Catholic University of Korea, College of Medicine, Seoul, Korea; Chungju Health Center 3, Chungju, Korea Background : To investigate the best surrogate marker for insulin resistance in the non-diabetic middle-aged population in Korea. Methods : This study was performed from February to April in adults over 40 years of age living in Chungju City, South Korea, selected by stratified random cluster sampling. We analyzed the data from a total 6,149 non-diabetic subjects that completed a survey consisting of anthropometric measurement and blood chemistry. We defined the highest quartile of the homeostasis model for insulin resistance (HOMA-IR) as the insulin resistant group in our study population. We also analyzed the correlation of various anthropometric (body mass index, waist circumference, waist to hip ratio, waist to height ratio) and biochemical parameters (total cholesterol to HDL cholesterol ratio, non-hdl cholesterol level, triglycerides to HDL cholesterol ratio and level of triglycerides) with insulin resistance using simple and multiple regression analysis for detecting the insulin resistance group. Results : By simple regression analysis, among the anthropometric parameters including the body mass index, waist circumference, waist to hip ratio, waist to height ratio, and the biochemical parameters, including the total cholesterol to HDL cholesterol ratio, non-hdl cholesterol level, triglyceride to HDL cholesterol ratio and triglycerides level, the body mass index was the best surrogate marker for insulin resistance (95% CI ). The cut-off value of the body mass index was 24.6 kg/m 2 (male; 24.7, female; 24.6 kg/m 2 ), with a sensitivity of 62.6% and specificity of 66.9%. Multiple logistic regression analysis for insulin resistance also gave the same results. Furthermore, the cut-off value of the body mass index for the metabolic syndrome as defined by NCEP-ATP III was also 24.1 kg/m 2 (male; 24.0, female; 24.2 kg/m 2 ). Conclusions : Our study results suggest that the body mass index was the best surrogate marker for insulin resistance of a non-diabetic population and its cut-off value was approximately 24 kg/m 2. (Korean J Med 73: , 2007) Key Words : Insulin resistance, Metabolic syndrome Received : Accepted : Correspondence to : Ho-Young Son, M.D., PhD, Division of Endocrinology and Metabolism, Department of Internal Medicine, Kangnam St. Mary s Hospital, The Catholic University of Korea, 505 Banpo-dong, Seocho-gu, Seoul , Korea hys@catholic.ac.k

2 -The Korean Journal of Medicine : Vol. 73, No. 6, 서론 대사증후군은혈압, 허리둘레, 혈장포도당농도, 중성지방, 고밀도콜레스테롤과같이밀접하게연관된임상적인수치와검사실결과들의집합으로진단하며이는궁극적으로죽상동맥경화증및심혈관질환의위험인자로알려져있다 1, 2). 최근이에대한수많은연구들이이루어지고있는데대사증후군의유병률은인종에따라매우다양하게나타나며 3) International Diabetes Federation (IDF) 4) 을포함하여 2001년발표된 National Cholesterol Education Program-Third Adult Treatment Panel (NCEP- ATP III) 5), World Health Organization (WHO) 6), American College of Endocrinology-American Association of clinical Endocrinologist (ACE-AACE) 7), European group for the study of Insulin Resistance (EGIR) 8) 에서도대사증후군을각각다양하게정의하고있다 9). 또한대사증후군의기준이불완전하고이론적근거가제대로갖추어지지않아허리둘레측정방법에대한적절한합의가없으며당뇨병을대사증후군정의에포함시킬것인지도애매하다. 결과적으로당뇨병이나임상적으로심혈관질환이있는사람을대사증후군에포함시키는것이현행지침에추가적으로유용한임상적정보를제공하지않을뿐아니라대사증후군의치료가결국각요소의치료와다를바가없어 2005년미국당뇨병학회와유럽당뇨병학회에서는대 사증후군이실제적인증후군이아니며그렇기때문에일 차진료시에이와같이진단해서는안된다고언급된바 있다 10). 이에비해인슐린저항성증후군은질환이아니라각개인에서여러가지밀접하게연관된대사성이상소견들과이와관련된임상증후군의발생이증가하는신체적인상태를나타낸것이다 11). 이러한인슐린저항성증후군은대사증후군과는다른것으로실제로환자를대사증후군으로진단하는것보다인슐린저항성이있다는것을확인하는것이훨씬더중요하다고할수있다. 인슐린저항성은당뇨병이없는사람에서심혈관질환으로인한사망률증가와관련이있고 12, 13), 향후당뇨병발생고위험군의예측인자로볼수있다 3). 인슐린저항성이오랜기간동안대사증후군의주요병리기전으로생각되어 14, 15) 왔지만인슐린저항성평가가표준화되어있지않고이미인슐린저항성을잘나타내는지표로널리알려진 fasting insulin, HOMA-IR 16), QUICKI 17) 등은실제임상에서측정하는것이쉽지않기때문에일상적으로인슐린 저항성을측정하기는어렵다. 그래서저자들은당뇨병이없는한국의성인에서일반적으로쉽게측정할수있는생화학적지표나신체계측지표중에서인슐린저항성을가장잘나타낼수있는단일지표가무엇인지에대한연구를시행하였다. 대상및방법 1. 대상본충주대사증후군연구는 2003년부터 2005년까지매해 2월부터 4월까지충주시에살고있는 40세이상의성인에서시행되었고이들은무작위층화추출 (stratified random cluster sampling) 방식으로채택되었다. 이들중에신체계측지표측정과혈액화학검사를시행하여당뇨병이없는총 6,149 (2,461 남자와 3,688 여자 ) 명의자료를분석하였다. 본연구는강남성모병원의 IRB에서승인되었고모든참가자로부터동의서를받았다. 2. 변수의정의와측정당뇨병의기왕력이있거나공복혈당이 126 mg/dl 이상인경우에당뇨병으로진단하여이에해당하지않는경우를본연구의대상으로하였고, 나이와성별을조사하였다. 연구대상자의신체측정은훈련된조사원이직접신장과체중, 허리둘레 (WC) 와둔부둘레를측정하고이를이용하여체질량지수와허리-둔부둘레비 (WHR), 허리둘레-신장비 (WHtR) 를산출하였다. 혈압측정은수은주혈압계를사용하여간접적으로측정하였고, 이러한과정과커프크기의선정은 American Heart Association 의기준을따랐다. 혈청지질농도측정시에총콜레스테롤과중성지방은 Enzymatic calorimetric test, 고밀도및저밀도콜레스테롤은 Selective inhibition method 를사용하여측정하였다. 본연구에서신체계측지표변수로체질량지수와허리둘레, 허리-둔부둘레비 (WHR), 허리둘레-신장비 (WHtR) 를사용하였고, 생화학적변수로는혈청지질농도를이용하여산출한총콜레스테롤 / 고밀도콜레스테롤비 (TC/HDL), non-hdl 콜레스테롤, 중성지방 / 고밀도콜레스테롤비 (TG/HDL) 와중성지방 (TG) 을사용하였다 18-20). 저자들은본연구집단에서인슐린저항성지표 (HOMA- IR) 의상위사분위계수를인슐린저항성군으로정의하였고인슐린저항성지표 (HOMA-IR) 는 [fasting insulin (μ IU/mL) fasting plasma glucose (mmol/l) / 22.5] 로

3 -Ji-Hyun Kim, et al : Best surrogate marker for insulin resistance - Table 1. Clinical characteristics of the study subjects (N=6149) Male (N=2461) Female (N=3688) p-value Age (years) (kg/m 2 ) Waist circumference (cm) Waist-hip ratio Fasting plasma glucose (mmol/l) cholesterol (mmol/l) Triglyceride (mmol/l) HDL-cholesterol (mmol/l) LDL-cholesterol (mmol/l) Systolic blood pressure (mmhg) Diastolic blood pressure (mmhg) 61.8± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± Values are mean±sd., body mass index Table 2. Simple regression analysis for insulin resistance Parameters Genders Point estimate ( 95% CI ) TG/HDL HDL WC TG , body mass index; HDL, HDL cholesterol; TG, triglyceride; WC, waist circumference; TG/HDL, triglyceride/hdlcholesterol ratio 구하였다 16, 21). 3. 통계적분석모든통계분석은 SAS (ver. 8.01) 를이용하여시행하였다. 인슐린저항성군과의연관성을확인하기위해다양한신체계측지표변수 ( 체질량지수, 허리둘레 (WC), 허리둘레- 둔부둘레비 (WHR), 허리둘레-신장비 (WHtR)) 와생화 학적변수 ( 총콜레스테롤 / 고밀도콜레스테롤비 (TC/HDL), non-hdl 콜레스테롤, 중성지방 / 고밀도콜레스테롤비 (TG/HDL), 중성지방 (TG)) 를단순회귀분석과다중회귀분석을이용하였고, ROC 곡선을이용하여각변수의 cut-off value 를구하였다. 유의성수준은 p value 가 0.05 이하일때통계적으로유의한것으로판정하였다

4 - 대한내과학회지 : 제 73 권제 6 호통권제 568 호 Table 3. Multiple regression analysis for insulin resistance Model 1 Model 2 Parameters Estimate (95% CI) Parameters Estimate (95% CI) TG WC TG/HDL WC Adjusted by WC, TG, HDL, SBP, DBP, glucose,, TG*HDL, WC*, SBP*DBP SBP, systolic blood pressure; DBP, diastolic blood pressure Adjusted by WC, TG*HDL, SBP, DBP, glucose,, WC*, SBP*DBP Table 4. Cut-off value of various parameters for insulin resistance in non-diabetic population Parameters Gender Cut-off value Sensitivity (95% CI) Specificity (95% CI) TG/HDL non-hdl TC/HDL ( ) 56.1 ( ) 65.3 ( ) 48.3 ( ) 68.3 ( ) 46.0 ( ) 70.1 ( ) 64.2 ( ) 61.3 ( ) 51.4 ( ) 47.4 ( ) 51.5 ( ) 66.9 ( ) 77.2 ( ) 60.5 ( ) 67.1 ( ) 54.0 ( ) 66.8 ( ) 46.9 ( ) 55.2 ( ) 53.2 ( ) 67.8 ( ) 74.5 ( ) 65.7 ( ) TG ( ) 62.8 ( ) 38.0 ( ) 74.4 ( ) 57.3 ( ) 75.4 ( ), body mass index; non-hdl, non HDL cholesterol; WHtR, waist to height ratio; TC/HDL, total cholesterol to HDL cholesterol ratio; TG/HDL, triglyceride/hdl-cholesterol ratio; TG, triglyceride; WC, waist circumference; WHR, waist to hip ratio 결과전체연구대상자의평균연령은 61.8세 ( 남자 61.6세, 여자 61.9세 ) 였으며남녀에따라각신체계측지표와생화학적검사결과는차이를보였다 ( 표 1). 본연구집단에서산출한인슐린저항성지표의상위사분위계수는 1.7 ( 남 : 1.53, 여 :1.82) 이었고, 이이상의수치에해당하는경우인슐린저항성군으로분류하였다. 인슐린저항성에대한단순회귀분석에서는신체계측지표변수와생화학적변수들중에서체질량지수의추정치 (point estimate) 가 (95% 신뢰구간 ) 로가장높았으며다음으로 TG/HDL 추정치가 1.111로높게나타났다 ( 표 2). 다중회 귀분석모델에서도 WC, TG, HDL, SBP, DBP, 혈당,, TG*HDL, WC*, SBP*DBP 로보정한모델 1과 WC, TG*HDL, SBP, DBP, 혈중포도당농도,, WC*, SBP*DBP 로보정한모델 2에서체질량지수의추정치는각각 (95% 신뢰구간 ) 와 (95% 신뢰구간 ) 로가장높게나타났다 ( 표 3). 이러한결과는인슐린저항성의다른지표인공복시인슐린수치나 QUICKI를이용한분석에서도마찬가지로나타나체질량지수가인슐린저항성과가장연관성이좋았다. 결론적으로신체계측지표변수인체질량지수, 허리둘레, 허리둘레-둔부둘레비, 허리둘레-신장비와대사지표인총콜레스테롤 /HDL 콜레스테롤비 (TC/HDL), non-hdl 콜레스

5 - 김지현외 16 인 : 인슐린저항성의임상지표 - 테롤, 중성지방 / 고밀도콜레스테롤비 (TG/HDL ratio), 중성지방 (TG) 중에서체질량지수가모든지표를통틀어인슐린저항성에대한연관성이가장높은것으로나타났고체질량지수의 cut-off value 는남여공히 24.6 kg/m 2 ( 민감도 62.6%, 특이도 66.9%) 이었다 ( 표 4). 또한 NCEP-ATP III 기준을적용하여산출한체질량지수의 cut-off value 도 24.1 kg/m 2 으로비슷한결과를보였다. 고찰대사증후군이아직까지뚜렷한심혈관질환이나당뇨병을진단받지않은심혈관질환의고위험군을미리발견하기위한선별방법으로유용하다고생각되지만여기에는여러가지한계점들이있다. 우선대사증후군의유병률이인종에따라다르고각기구에서발표하는대사증후군의정의가매우다양하기때문에모든경우에일률적으로적용하기는어려운점이있으며대사증후군의기준이애매하거나불완전하여일차진료시진단하기에도적절하지않고진단이되더라도치료에다른추가적인유용성을보여주지는않아실제환자를대사증후군으로진단하는것보다오랜기간동안대사증후군의주요병리기전으로생각되어왔던인슐린저항성여부를확인하는것이훨씬더중요하다고할수있다. 인슐린저항성은단순히인슐린에대한포도당이용에결함이있는것을뜻하는것이아니라심혈관질환의위험도를뚜렷하게증가시키는대사성이상으로 22-27) 당뇨병과심혈관질환의강력한예측인자이다 28). 이러한인슐린저항성지표를확인하는것은질환의치료와전반적인유병률을감소시키는데에특히중요하지만 29) 실제로인슐린저항성이나인슐린민감도를분류하는절대적인기준이없고 30) 인슐린저항성평가가표준화되어있지않기때문에임상에서일상적으로인슐린저항성을측정하기는매우어렵다. 또한공복시인슐린수치, HOMA-IR, QUICKI 등이인슐린저항성을잘나타내는지표라는것이이미알려져있으나이들은일차의료기관에서쉽게측정할수없으므로당뇨병이없는한국의성인에서보다쉽게측정할수있는생화학적지표나신체계측지표중에서인슐린저항성을가장잘나타낼수있는단일지표를알수있다면임상에유용하게적용할수있을것으로기대되어본연구를진행하였다. 본연구에서 HOMA-IR 수치가 1.7 이상인경우가인슐린저항성군으로정의되었는데이는 Juan 등 31) 이인슐린저항성의기준으로사용한수치인 2.6이나한 국인의대사증후군진단을위한인슐린저항성지표로서 Lee 등 32) 이제시한 3.04 보다는낮은기준이지만이는대상인구수, 범위및특성, 인슐린측정방법에따른차이에기인한것으로생각되며이를토대로분석한결과를살펴보면당뇨병이없는한국의성인에서는여러가지신체계측지표와대사지표들가운데체질량지수가유의하게인슐린저항성에대한가장좋은단일지표로나타났으며 cut-off value 는 24.6 kg/m 2 ( 남자 ; 24.7, 여자 ; 24.6 kg/m 2 ) 이었다. 이는 NCEP-ATP III에서정의된대사증후군의진단을위해산출한체질량지수의 cut-off value (24.1 kg/m 2 ( 남자 ; 24.0, 여자 ; 24.2 kg/m 2 )) 와도비슷하게나타났다. 대규모역학연구에서당뇨병과인슐린저항성의위험도는체질량지수로측정되어진체지방의양에따라증가한다고나타났으며 33) 과체중이나비만인사람들에서인슐린저항성과대사증후군, 당뇨병, 고혈압, 심혈관질환의위험도가훨씬높게나타난다고보고하였다 34, 35). National Institute of Health 에서는과체중및비만한성인의위험도증가를선별할수있는것으로체질량지수와허리둘레를사용한분류체계를만들었는데 36) 여기에서는허리둘레의측정이체질량지수보다당뇨병과심혈관질환의위험도를더정확하게평가할수있다고하였다 37). NCEP- ATP III 정의도비만의측정에허리둘레의중요성을강조하였는데이것이체질량지수에의해결정된비만도보다인슐린저항성및그결과와더밀접하게관련되어있는지표이다. 그러나허리둘레는일상적으로측정하지않으며측정치가일정하지않은데비해체질량지수는허리둘레와연관성이아주높고키와체중으로쉽게계산할수있어서대부분의의료기관에서일상적으로측정한다. 게다가어떤사람들은허리둘레측정의재현성이좋지않고허리둘레측정방법이의료기관들사이에서표준화되어있지않다고주장하였다 38). 비록체질량지수가항상인슐린저항성을나타내지는않지만저자들은본연구결과에따라인슐린저항성이있는인구를대사증후군이라고진단하는대신에이를확인하는간단한방법을제시하고자하였다. 본연구의결과는당뇨병이없는성인에서쉽게측정할수있는생화학적지표나신체계측지표중에서인슐린저항성의가장좋은단일지표가체질량지수임을확인하였고, 그 cut-off value 를제시하였다. 그리고저자는체질량지수가일차진료기관에서도쉽게측정할수있다는

6 -The Korean Journal of Medicine : Vol. 73, No. 6, 것이추가적인장점이라고생각한다. 체질량지수가언제나인슐린저항성을나타내지는않지만인슐린저항성과심혈관질환의위험도를평가하는간단한방법이며인슐린저항성을나타내는다른생화학적지표와함께사용된다면인슐린저항성을가진인구를더쉽게확인할수있을것으로생각된다. 요약 목적 : 당뇨병을가지지않은한국성인에서인슐린저항성을가장잘나타낼수있는단일지표가무엇인지를알아보고자하였다. 방법 : 충주지역에거주하는 40세이상인구총 6,149 명을대상으로각종신체계측지표및대사지표중에서인슐린저항성지표 (HOMA-IR) 의상위사분위수에해당하는집단을 인슐린저항성군 으로정의할때이를가장잘반영하는지표를분석하기위해단순회귀분석과다중회귀분석방법을이용하여각각비교하였다. 결과 : 일상적으로비교적쉽게측정할수있는신체계측지표인체질량지수, 허리둘레, 허리둘레-둔부둘레비, 허리둘레-신장비와대사지표인총콜레스테롤 /HDL 콜레스테롤비 (TC/HDL), non-hdl 콜레스테롤, 중성지방 / 고밀도콜레스테롤비 (TG/HDL ratio), 중성지방 (TG) 중에서체질량지수가모든지표를통틀어인슐린저항성에대한진단적가치가가장우수한것으로분석되었다. 체질량지수의 cut off value 는남, 여공히 24 kg/m 2 이었다. 결론 : 당뇨병이없는한국성인에서인슐린저항성을가장잘반영할수있는단일지표는체질량지수였고, 24 kg/m 2 이상일경우인슐린저항성이있다고할수있겠다. 중심단어 : 인슐린저항성, 대사증후군 REFERENCES 1) Meigs JB. Invited commentary: insulin resistance syndrome? syndrome X? multiple metabolic syndrome? a syndrome at all?: factor analysis reveals patterns in the fabric of correlated metabolic risk factors. Am J Epidemiol 152: , ) Liese AD, Mayer-Davis EJ, Haffner SM. Development of the multiple metabolic syndrome: an epidemiologic perspective. Epidemiol Rev 20: , ) Hanley AJ, Wagenknecht LE, D'Agostino RB Jr, Zinman B, Haffner SM. Identification of subjects with insulin resistance and beta-cell dysfunction using alternative definitions of the metabolic syndrome. Diabetes 52: , ) International Diabetes Federation. The International Diabetes Federation Consensus Worldwide Definition of the Metabolic Syndrome. April 14, ) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. 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 285: , ) World Health Organization. Definition, diagnosis and classification of diabetes: mellitus and its complications: part 1. diagnosis and classification of diabetes mellitus. Geneva, World Health Organization, ) Einhorn D, Reaven GM, Cobin RH, Ford E, Ganda OP, Handelsman Y, Hellman R, Jellirger PS, Kendall D, Krauss RM, Neufeld ND, Petak SM. American College of Endocrinology position statement on the insulin resistance syndrome. Endocr Pract 9: , ) Balkau B, Charles MA. Comment on the provisional report from the WHO consultation. Diabet Med 16: , ) Alberti KG, Zimmet P, Shaw J. The metabolic syndrome: a new worldwide definition. Lancet 366: , ) Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: time for a critical appraisal: joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 28: , ) DeFronzo RA, Ferrannini E, Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and ASCVD. Diabetes Care 14: , ) Isomaa B, Almgren P, Tuomi T, Forsen B, Lahti K, Nissen M, Taskinen MR, Groop L. Cardiovascular morbidity and mortality associated with the metabolic syndrome. Diabetes Care 24: , ) Ford ES, Giles WH, Dietz WH. Prevalence of metabolic syndrome among US adults. JAMA 287: , ) Karter AJ, Mayer-Davis EJ, Selby JV, D Agostino RB Jr, Haffner SM, Sholinsky P, Bergman R, Saad MF, Hamman RF. Insulin sensitivity and abdominal obesity in African-American, Hispanic, and non-hispanic white men and women. Diabetes 45: , ) Howard BV, Mayer-Davis EJ, Goff D, Zaccaro DJ, Laws A, Robbins DC, Saad MF, Selby J, Hamman RF, Krauss RM, Haffner SM. Relationships between insulin resistance and lipoproteins in nondiabetic

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한국성인에서초기황반변성질환과 연관된위험요인연구

한국성인에서초기황반변성질환과 연관된위험요인연구 한국성인에서초기황반변성질환과 연관된위험요인연구 - - i - - i - - ii - - iii - - iv - χ - v - - vi - - 1 - - 2 - - 3 - - 4 - 그림 1. 연구대상자선정도표 - 5 - - 6 - - 7 - - 8 - 그림 2. 연구의틀 χ - 9 - - 10 - - 11 -