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1 대한내과학회지 : 제 71 권제 1 호 2006 한국남성비알코올성지방간에서혈청 adipokine 농도변화에영향을미치는요인 성균관대학교의과대학강북삼성병원내과학교실, 한림대학교의과대학진단방사선과학교실 2, 미즈메디병원내과학교실 3 오세용 조용균 유태우 박정호 김홍주 박동일 손정일 전우규김병익 정찬희 이은정 이원영 김선우 오기원 윤은주 2 오은숙 3 =Abstract= Factors affecting serum levels of adipokines in Korean male patients with nonalcoholic fatty liver disease Se Yong Oh, M.D., Yong Kyun Cho, M.D., Tae Woo Yoo, M.D., Jung Ho Park, M.D., Hong Joo Kim, M.D., Dong Il Park, M.D., Chong Il Sohn, M.D., Woo Kyu Jeon, M.D., Byung Ik Kim, M.D., Chan Hee Jung, M.D., Eun Jung Rhee, M.D., Won Young Lee, M.D., Sun Woo Kim, M.D., Ki Won Oh, M.D, Eun Joo Yun, M.D. 2 and Eun Sook Oh, M.D. 3 Department of Internal Medicine, Kangbuk Samsung Hospital, Sungkyunkwan University School of Medicine, Seoul, Korea; Department of Radiology, College of Medicine, Hallym University 2, Pyungchon, Korea; Department of Internal Medicine, MizMedi Hospital 3, Seoul, Korea Background : Adipokines are associated with various metabolic disorders including insulin resistance, obesity and dyslipidemia. Metabolic disorders have also been reported to be associated with nonalcoholic fatty liver disease (NAFLD). We aimed to estimate changes in serum adipokines levels according to the degrees of steatosis and to determine independent factors influencing serum adipokines levels in Korean male patients with NAFLD. Methods : 65 Korean male patients were subjected. The degrees of steatosis were stratified into the three groups, Group I: normal liver (27 subjects), Group II: mild fatty liver (24 subjects) and Group III: moderate to severe fatty liver (14 subjects), according to ultrasonographic liver findings. The anthropometric parameters, fasting serum adipokine levels including leptin, adiponectin and resistin were measured in all subjects. The level of insulin resistance was estimated using the. Results : Serum leptin levels were significantly different among the three groups (mean±sd: Group I (2.052±1.071), Group II (2.879±1.016), Group III (4.457±1.965 ng/ml), p<0.001). Serum adiponectin and resistin levels were not significantly different among the three groups (p=0.184, p=0.649, 접수 : 2005년 5월 31일 통과 : 2005년 12월 12일 교신저자 : 조용균, 서울시종로구평동 108, 성균관대학교의과대학강북삼성병원내과학교실 ( ) choyk2004.cho@samsung.com

2 -Se Yong Oh, et al : Serum levels of adipokines in patients with NAFLD - respectively). BMI and were independent factors of changes in serum leptin levels (p=0.026, p=0.001, respectively), but independent factors of changes in serum adiponectin and resistin levels were not observed. Conclusions : Our study support a indirect role to induce metabolic disorder for leptin in the pathogenesis of NAFLD, but do not support roles for adiponectin and resistin in the pathogenesis of NAFLD. BMI and were only independent factors of changes in serum leptin levels. (Korean J Med 71:58-66, 2006) Key Words : Fatty liver, Leptin, Adiponectin, Resistin 서론비알코올성지방간질환은알코올성과바이러스성간질환을제외한만성간질환의많은부분을차지한다 1-4). 간내괴사염증성변화나섬유화증이동반되지않는단순지방간부터간내괴사염증성변화와간세포의변화그리고다양한정도의섬유화를동반하며간경변증이나간암으로진행할수있는비알코올성지방간염의질환군을포괄한다 5, 6). 비알코올성지방간질환의발생기전은중성지방형태로간세포내지방축적이며이과정은내장지방저장증가, 말초지질분해증가등에의한간으로유리지방산운반증가를일으키는인슐린저항성이중요한역할을한다 6). 단순지방간이비알코올성지방간염으로의진행은산화스트레스, 지질과산화, 비정상적인사이토카인의생산그리고지방산대사장애와인슐린저항성등대사질환과관련성이있다 7-9). 지방세포에서주로분비되는 adipokine은여러종류가규명되고있으며그중에서 leptin은중추신경계특히시상하부에작용하여음식물섭취억제, 에너지소비자극, 체중감소, 체조성그리고간과말초조직에서지질고갈등대사기능에관여하나 10-13), 사람에서혈청 leptin 농도의증가가비만, 인슐린저항성, 고혈압등과관련성이있다 11, 12, 14). Adiponectin 은포도당생성억제, 지질합성감소, 인슐린수용체기질과 adiponectin 수용체를발현하는다양한장기에서인슐린이용을증가시켜간과말초인슐린감수성을향상시킨다 10-12, 15). Resistin은 cysteine 이풍부한혈중단백질로간내포도당생산증가, 인슐린저항성그리고사람에서비만증가와연관성이있다 11, 12, 16-19). 이와같이 adipokine 이인슐린저항성및감수성, 이상지질혈증, 당뇨병그리고비만등대사질환 과의연관성이알려지면서 10-15), 비알코올성지방간질환의발생기전에중요한역할을할것으로생각된다 10-15, 18, 20). 현재까지비알코올성지방간질환과 adipokine 의연관성이확실히정립되어있지않다. 이에저자들은지방간정도에따른혈청 adipokine 농도의변화를관찰함으로써이의연관성및혈청 adipokine 농도변화에영향을미치는독립적위험인자를알아보고자하였다. 대상및방법 1. 대상 2002년 1월부터 2002년 12월까지미즈메디병원에서건강검진을시행한무증상의한국성인남자 65명 ( 평균 54.57±6.30세 ) 을대상으로하였다. B형간염표면항원양성, C형간염항체양성, transferrin 포화도 > 50%, 하루 20 g 이상의알코올을섭취하는경우그리고자가면역성, 대사성그리고유전성간질환을가진경우는연구대상에서제외하였다. 본연구는미즈메디병원의윤리위원회로부터승인을받았고, 모든연구대상자들로부터사전동의서를받아시행하였다. 2. 신체계측모든연구대상자들에서나이그리고신체계측지표로써신장과체중을측정하여계산식 (kg/m 2 ) 에의해체질량지수를구하였고, 허리둘레 (cm), 엉덩이둘레 (cm), 허리 / 엉덩이둘레비, 수축기와이완기혈압을측정하였다. 엉덩이둘레는흉곽과장골능선의중간부위에서측정하였고, 엉덩이둘레는전상장골극부위에서측정하였다. 혈압은 10분이상안정을취한후앉은자세에서수축기및이완기혈압을 2회이상측정한후평균값으로정하였다. 인슐린저항성정도를알아보기위한지표로서

3 - 대한내과학회지 : 제 71 권제 1 호통권제 551 호 ) 를다음계산식을이용하여구하였다. = [fasting insulin (μiu/ml) fasting blood glucose (mmol/l)] / 지방간정도의측정복부초음파 (ASPEN; Acuson, Pennsylvania, USA) 에서지방간정도는 Kurtz 등 22) 에의해고안된교정기준을기초로하여간밝기 (brightness of the liver), 메아리발생감쇠 (attenuation of echogenicity), 불선명혈관 (blurred vessels), 신장대간의대조비 (liver-to-kidney contrast ratio) 에따라 Group I: 정상간 (27명), Group II: 경도지방간 (24명), Group III: 중등도이상의지방간 (14명) 세군으로분류하였다. 4. 생화학적검사및혈청 adipokine 농도의측정혈청에서 aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (γ-gtp), 공복혈당및인슐린, 총콜레스테롤, 고밀도지단백콜레스테롤, 저밀도지단백콜레스테롤그리고중성지방을측정하였다. 공복혈당및인슐린은 8 시간금식후공복혈액을채혈하여혈당은 hexokinase method 로측정하였고, 인슐린은 BioSource INS-IRMA Kit (BioSource, Belgium) 를사용하여방사면역계수측정법 (immunoradiometric assay) 으로측정하였고, 변이계수 (coefficient of variation) 는 intra-assay 1.6~2.2%, inter-assay 6.1~6.5% 이었다. 총콜레스테롤, 고밀도지단백콜레스테롤, 저밀도지단백콜레스테롤, 중성지방은 12시간금식후공복혈액을채혈하여총콜레스테롤과중성지방은 enzymatic calorimetric test로측정하였고, 고밀도지단백콜레스테롤은 selective inhibition 방법으로측정하였고, 저밀도지단백콜레스테롤은 homogenous enzymatic calorimetric test로측정하였다. 혈청 adipokine 농도는 8시간이상금식후아침 8시에서 9시사이에공복혈액을채혈하여혈청 leptin 농도는방사면역측정법 Kit (radioimmunoassay (RIA), LINCO Research, USA), 혈청 adiponectin 농도는효소결합면역흡착검사법 Kit (enzyme-linked immunosorbent assay (ELISA), B-Bridge International, Japan) 그리고혈청 resistin 농도는효소면역측정법 Kit (enzyme immunoassay (EIA), Phoenix Pharmaceutical, USA) 를이용하여측정하였고, 변이계수는각각 intra-assay 3.4~8.3%, 4.6~5.8% 그리고 <5%; inter-assay 3.0~6.2%, 3.2~7.3% 그리고 <14% 이었다. 5. 통계분석모든통계분석은 SPSS 11.0 for window 를이용하였다. 연속변수의통계수치는평균 ± 표준편차로표시하였고, 세군간에연속변수의통계적유의성은정규성여부에따라 Kruskal-Wallis test 또는 One-Way ANOVA test를사용하여검정하였다. 또한지방간과혈청 adipokine 농도변화에영향을미치는독립적위험인자를결정하기위하여다중회귀분석을시행하였다. 모든통계학적유의성은 p 값이 0.05 미만인경우로판정하였다. 결과 1. 지방간정도에따른세군간의임상적및신체계측적특징나이는지방간이심할수록감소하였으나세군간에유의한차이는없었고, 수축기와이완기혈압은지방간정도에따른세군간에일정한상관관계를보이지않았고유의한차이가없었다 ( 표 1). 체질량지수, 허리둘레, 엉덩이둘레그리고허리 / 엉덩이둘레비는지방간이심할수록증가하였고, 세군간에유의한차이가있었다 ( 표 1). 2. 지방간정도에따른세군간의생화학적특징 γ-gtp는지방간정도에따른세군간에일정한상관관계를보이지않았고유의한차이가없었고, 총콜레스테롤과저밀도지단백콜레스테롤은지방간이심할수록증가하였으나세군간에유의한차이는없었다 ( 표 1). 공복혈당, 공복인슐린,, AST, ALT 그리고중성지방은지방간이심할수록증가하였고, 고밀도지단백콜레스테롤은지방간이심할수록감소하였으며세군간에유의한차이가있었다 ( 표 1). 3. 지방간정도에따른세군간의혈청 adipokine 농도변화혈청 leptin 농도는지방간이심할수록증가하였고 ( 평균 ± 표준편차 : Group I (2.052±1.071), Group II (2.879 ±1.016), Group III (4.457±1.965 ng/ml)) 세군간에유의한차이가있었다 (p<0.001)( 표 2). 혈청 adiponectin 농도는지방간이심할수록감소하였으나 ( 평균 ± 표준편

4 - 오세용외 15 인 : 비알코올성지방간에서혈청 adipokine 농도변화 - Table 1. Baseline characteristics of the three groups: normal liver (Group I), mild fatty liver (Group II), moderate to severe fatty liver (Group III) Variable Group I (n=27) Group II (n=24) Group III (n=14) p value Age (year) BMI (Kg/m 2 ) Sys BP (mmhg) Dia BP (mmhg) FG (mg/dl) FI (μiu/ml) AST (IU/l) ALT (IU/l) γ-gtp (IU/l) T-chol (mg/dl) TG (mg/dl) HDL-chol (mg/dl) LDL-chol (mg/dl) 59.96± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± ± * <0.001 <0.001 <0.001 < <0.001 * * <0.001 * * * * * <0.001 * * * Values are mean±sd. Univariate analysis were carried out using Kruskal-Wallis test or One-Way ANOVA test depending on the normality of the distribution. BMI, body mass index; WC, waist circumference; HC, hip circumference;, waist/hip circumference ratio; Sys BP, systolic blood pressure; Dia BP, diastolic blood pressure;, homeostasis model assessment-insulin resistance; FG, fasting glucose; FI, fasting insulin; AST, aspartate transaminase; ALT, alanine transaminase; γ-gtp, gamma-glutamyl transpeptidase; T-chol, total cholesterol; TG, triglyceride; HDL-chol, high density lipoprotein cholesterol; LDL-chol, low density lipoprotein cholesterol Table 2. Univariate analysis for serum adipokine levels of the three groups: normal liver (Group I), mild fatty liver (Group II), moderate to severe fatty liver (Group III) Variable Leptin (ng/ml) Adipo (μg/ml) Resistin (ng/ml) Group I (n = 27) 2.052± ± ±14.87 Group II (n = 24) 2.879± ± ±13.09 Group III (n = 14) 4.457± ± ±10.67 p value <0.001 * * Values are mean±sd. Univariate analysis were carried out using * Kruskal-Wallis test or One-Way ANOVA test depending on the normality of the distribution. Adipo, adiponectin 차 : Group I (8.513±5.104), Group II (6.226±2.615), Group III (6.134±3.010 μg/ml)) 세군간에유의한차이가없었다 (p=0.184)( 표 2). 혈청 resistin 농도는지방간이심할수록증가하였으나 ( 평균 ± 표준편차 : Group I (77.65±14.87), Group II (81.16±13.09), Group III (79.11±10.67 ng/ml)) 세군간에유의한차이가없었다 (p=0.649)( 표 2). 4. 지방간에영향을미치는독립적위험인자세지방간군을종속변수로단변량분석에서지방간정도와유의한연관성이있었던체질량지수, 허리둘레, 엉덩이둘레, 허리 / 엉덩이둘레비,, 공복혈당, 공복인슐린, AST, ALT, 중성지방, 저밀도지단백콜레스

5 -The Korean Journal of Medicine : Vol. 71, No. 1, Table 3. Multiple logistic regression analysis of risk factors for fatty liver: mild fatty liver (Group II), moderate to severe fatty liver (Group III) Variable Group II Group III Beta p value Beta p value BMI (Kg/m 2 ) FG (mg/dl) FI (μiu/ml) AST (IU/l) ALT (IU/l) TG (mg/dl) HDL-chol (mg/dl) Leptin (ng/ml) Multiple logistic regression analysis was carried out based on the results of univariate analysis. References are normal liver (Group I). BMI, body mass index; WC, waist circumference; HC, hip circumference;, waist/hip circumference ratio;, homeostasis model assessment-insulin resistance; FG, fasting glucose; FI, fasting insulin; AST, aspartate transaminase; ALT, alanine transaminase; TG, triglyceride; HDL-chol, high density lipoprotein cholesterol Table 4. Multiple linear regression analysis of risk factors for leptin Variable Beta p value Age (year) Fatty liver BMI (Kg/m 2 ) R 2 =0.535 BMI, body mass index; WC, waist circumference; HC, hip circumference;, waist/hip circumference ratio;, homeostasis model assessmentinsulin resistance Table 5. Multiple linear regression analysis of risk factors for adiponectin Variable Beta p value Age (year) Fatty liver BMI (Kg/m 2 ) R 2 =0.133 BMI, body mass index; WC, waist circumference; HC, hip circumference;, waist/hip circumference ratio;, homeostasis model assessment-insulin resistance 테롤그리고 leptin을독립변수로하여다중회귀분석을시행하였을때, 중성지방만이지방간의중요한독립적위험인자이었다 (p=0.010, Group II; p=0.021, Group III)( 표 3). 5. 혈청 adipokine 농도변화에영향을미치는독립적위험인자혈청 adipokine 농도와지방간, 비만그리고인슐린 저항성과의독립적연관성을알아보기위하여혈청 adipokine 농도를종속변수로나이, 지방간그리고비만신체계측지표로써체질량지수, 허리둘레, 엉덩이둘레, 허리 / 엉덩이둘레비그리고인슐린저항성지표로써 를독립변수로하여다중선형회귀분석을시행하였을때, 지방간은세 adipokine 의혈청농도변화와독립적연관성이없었다 ( 표 4, 5, 6). 또한비만신체계측

6 -Se Yong Oh, et al : Serum levels of adipokines in patients with NAFLD - Table 6. Multiple linear regression analysis of risk factors for resistin Variable Beta p value Age (year) Fatty liver BMI (kg/m 2 ) R 2 =0.103 BMI, body mass index; WC, waist circumference; HC, hip circumference;, waist/hip circumference ratio;, homeostasis model assessmentinsulin resistance 지표들과 중체질량지수와 은혈청 leptin 농도변화에중요한독립적위험인자이었으나 ( 각각 p=0.026, p=0.001) 나이, 허리둘레, 엉덩이둘레그리고허리 / 엉덩이둘레비는혈청 leptin 농도변화와독립적연관성이없었다 ( 표 4). Adiponectin 과 resistin의혈청농도변화에영향을미치는어떤독립적위험인자도관찰할수없었다 ( 표 5, 6). 고찰 비알코올성지방간질환의발생에 kupffer 세포의활성화와내독소에대한감수성증가, tumor necrosis factor (TNF)-α 신호전달증강그리고부착분자 (adhesion molecule) 과발현이중요한기전이다 26, 27, 30). 동물실험 1, 5, 13, 23) 에서 leptin은직접또는간유동내피세포 (sinusoidal endothelial cell) 또는 Kupffer 세포에서 tumor necrosis factor (TNF)-α, interleukin (IL)-6, IL-12와 transforming growth factor (TGF)-β1 같은사이토카인의생산을유도하여간접적으로간의성상세포활성화 (activated hepatic stellate cell) 에작용하여염증성반응및콜라겐생산을유도하여섬유화반응을일으킨다. 사람을대상으로한연구 14, 24) 에서지방간정도와혈청 leptin 농도간에독립적연관성이있었으나그와는반대의결과 2) 도있다. 본연구에서혈청 leptin 농도가지방간이심할수록유의하게증가하였지만독립적위험인자는아니었다. 또한혈청 leptin 농도변화에나이, 체질량지수, 당뇨병그리고 등이독립적위험인자이나 2, 5, 25), 본연구에서비만신체계측지표들 중체질량지수와 만이혈청 leptin 농도와독립적양의상관이관찰되었다. 이러한결과들로부터 leptin은대사질환과관련성이있음을알수있었다. 또한혈청 leptin 농도가지방간이심할수록증가하는것은비만과인슐린저항성이세군간에유의한차이로인한결과로생각할수있으며, 따라서 leptin은비알코올성지방간질환의발생에직접적원인이기보다는간접적으로대사장애를유도함으로써관여할것으로생각된다. Adiponectin 은 AdipoRI 과 AdipoRII 두개의수용체가있어 AdipoRI 은골격근, AdipoRII는간에서주로발현되며 4, 9, 11, 26) 8, 9, 26-29), 대사작용뿐만아니라항염증작용및항죽종형성작용, 항섬유화에중요한역할 8-12, 15) 을한다. 이러한작용은시험관내연구에서 adiponectin 투여가리포다당질 (lipopolyssaccharide) 등의내독소에의해분비되는 TNF-α와 kupffer 세포의포식작용을억제하여간손상을억제하였다 26, 30) 3, 29). 사람을대상으로한연구 에서지방간정도는인슐린저항성과는독립적으로혈청 adiponectin 농도와음의상관을보여 adiponectin 이지방간발생에방어효과가있었다. 본연구에서혈청 adiponectin 농도는지방간이심할수록감소하였으나통계적유의성은없었다. 따라서 adiponectin 이비알코올성지방간질환의발생에연관성이있는지알수없었다. 그러나 Group I과 Group II 두군간에는 adiponectin 농도에유의한차이가있었으나, 두군과 Group III와는유의한차이가없었던것은 Group III의연구대상자의수가적었기때문일것으로생각된다. 또한비만신체계측지표들과 중혈청 adiponectin 농도변화에대한어떤독립적위험인자도관찰할수없었다. 따라서 aidponectin 과대사질환과의연관성을확인할수없었다. Resistin은제2형당뇨병환자를대상으로한연구 31) 에서혈청 reisistin 농도와간내지방함유량및인슐린저항성과양의상관이관찰되었다. 따라서 resistin이인슐린저항성증가를유도하여비알콜성지방간질환의발생에관여할것으로생각되나, 사람에서 resistin 이인슐린저항성과관련성이없다는연구 15, 32) 가있어정확한발생기전은확립되어있지않다. 본연구에서 resistin은지방간이심할수록증가하였으나통계적유의성은없었다. 따라서 resistin 이비알코올성지방간질환의발생에관련성이있는지알수없었다. 또한비만신체계측지표들과 중혈청 resistin 농도변화에대한어

7 - 대한내과학회지 : 제 71 권제 1 호통권제 551 호 떤독립적위험인자도관찰할수없었다. 따라서 resistin 과대사질환과의연관성을확인할수없었다. 본연구에서대사증후군, 당뇨병그리고비만환자등을포함하여연구를시행했더라면더사실에근접한연구결과를얻었을것으로생각한다. 본연구의제한점으로첫째, 간조직검사를시행하지않아지방간정도를정확히정량화할수없었고, 간내염증성변화및섬유화정도를정확히알수없어비알코올성지방간염을완전히배제할수없었다. 그러나많은연구들에서지방간은간조직검사를시행하지않고복부초음파로진단및지방간정도를측정하였다. 둘째, 연구대상자의수가적었고셋째, 남자만을연구대상으로하여통계오차및선택오차가있을수있다. 그러나대규모전향적연구의예비적연구로써의미가있을것으로생각한다. 결론적으로본연구에서 leptin과비알코올성지방간질환이대사질환과관련성이있음을알수있었고, leptin은비알코올성지방간질환의발생에대사장애를유도함으로써간접적으로관여함을알수있었다. 그러나 adiponectin과 resistin이대사질환과관련성이있는지확인할수없었고, 비알코올성지방간질환의발생에관련성이있는지알수없었다. 체질량지수와 HOMA- IR는혈청 leptin 농도변화에영향을미치는중요한독립적위험인자임을알수있었으나, 혈청 adiponectin과 resistin 농도변화에영향을미치는독립적위험인자는관찰할수없었다. 앞으로 leptin, adiponectin 그리고 resistin 등의 adipokine 과비알코올성지방간질환그리고대사증후군과의연관성에대한이론적근거를정립함에있어본연구가도움이될수있을것이며, 많은대규모전향적연구가필요할것으로생각된다. 요약목적 : Adipokine은인슐린저항성, 비만그리고이상지질혈증등의다양한대사질환과관련이있다. 또한대사질환은비알코올성지방간질환과의연관성이알려져있다. 저자들은비알코올성지방간질환에서지방간정도에따른혈청 adipokine 농도변화와혈청 adipokine 농도변화에영향을미치는독립적위험인자를알아보고자하였다. 방법 : 한국정상성인남자 65명을대상으로하였으 며, 지방간정도는초음파에서관찰되는소견에따라 Group I: 정상간 (27명), Group II: 경도지방간 (24명), Group III: 중등도이상의지방간 (14명) 세군으로분류하였다. 모든대상자로부터신체계측지표와 leptin, adiponectin 그리고 resistin의공복혈청농도를측정하였다. 인슐린저항성은 를사용하여평가하였다. 결과 : 혈청 leptin 농도는세군간에유의한차이가 있었다 ( 평균 ± 표준편차 : Group I (2.052±1.071), Group II (2.879±1.016), Group III (4.457±1.965 ng/ml), p<0.001). 혈청 adiponectin 과 resistin 농도는세군간에유의한차이가없었다 ( 각각 p=0.184, p=0.649). 체질량지수와 은혈청 leptin 농도변화에대한독립적위험인자이었으나 ( 각각 p=0.026, p=0.001), 혈청 adiponectin 과 resistin 농도변화에대한독립적위험인자는관찰할수없었다. 결론 : 본연구에서 leptin은비알코올성지방간질환의발생기전에대사장애를유도함으로써간접적으로관여함을알수있었다. 그러나 adiponectin과 resistin은비알코올성지방간질환의발생기전에관련성이있는지알수없었다. 체질량지수와 만이혈청 leptin 농도변화에대한독립적위험인자이었다. 중심단어 : 지방간, Leptin, Adiponectin, Resistin REFERENCES 1) Angulo P, Alba LM, Petrovic LM, Adams LA, Lindor KD, Jensen MD. Leptin, insulin resistance, and liver fibrosis in human nonalcoholic fatty liver disease. J Hepatol 41: , ) Nakao K, Nakata K, Ohtsubo N, Maeda M, Moriuchi T, Ichikawa T, Hamasaki K, Kato Y, Eguchi K, Yukawa K, Ishii N. Association between nonalcoholic fatty liver, markers of obesity, and serum leptin level in young adults. Am J Gastroenterol 97: , ) Hui JM, Hodge A, Farrell GC, Kench JG, Kriketos A, George J. Beyond insulin resistance in NASH: TNF-α or adiponectin? Hepatology 40:46-54, ) Vuppalanchi R, Marri S, Kolwankar D, Considine RV, Chalasani N. Is adiponectin involved in the pathogenesis of nonalcoholic steatohepatitis?: a preliminary human study. J Clin Gastroenterol 39: , ) Serin E, Ozer B, Gumurdulu Y, Kayaselcuk F, Kul K,

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Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract