<30392EB1E8BCD2BFB52E687770>

Size: px

Start display at page:

Download "<30392EB1E8BCD2BFB52E687770>"

소민 봉
5 years ago
Views:

1 대한내과학회지 : 제 74 권제 3 호 2008 제 2 형당뇨병환자에서혈청 C-reactive protein 과인슐린저항성과의관계 전북대학교의과대학내분비대사내과학교실 1, 부천세종병원 2 김소영 1 정수진 1 진흥용 1 김종화 2 백홍선 1 박태선 1 박지현 1 Relationship between the serum c-reactive protein concentration and insulin resistance in type 2 diabetic patients So-Young Kim, M.D. 1, Su-Jin Jeong, M.D. 1, Heung-Yong Jin, M.D. 1, Chong-Hwa Kim, M.D. 2, Hong-Sun Baek, M.D. 1, Tae-Sun Park, M.D. 1 and Ji-Hyun Park, M.D. 1 Division of Endocrinology and Metabolism, Department of Internal Medicine, Chonbuk National University Medical School, Chonju, Korea 1 ; Sejong general hospital, Bucheon, Korea 2 Background/Aims : Low grade inflammation has been suggested to be a risk factor for development of atherosclerosis. C-reactive protein (CRP) is very sensitive acute phase reactant, and it is considered as an important marker of atherosclerosis and related disorder. Insulin resistance is also known to be associated with atherosclerosis. However, the relationship between insulin resistance and CRP has not been thoroughly studied in patients with type 2 diabetes. This study aimed to determine whether insulin resistance in type 2 diabetes is related with CRP. Methods : 102 subjects with type 2 diabetes were included in the study. Fasting blood samples were taken for measurement for CRP, insulin and glucose. To estimate insulin resistance, the HOMA (homeostasis model assessment)-ir (insulin resistance) was calculated by the standard formula. We divided the subjects into two groups depending on their CRP levels (Group A: <1 mg/l, Group B: 1 mg/l), and analyzed indexes in each group. Results : There was significant correlation between CRP and (r=0.4, p<0.01). and fasting insulin levels in group B were higher than that of group A on the univariate analysis. On the multivariate analysis, among several variables such as fasting insulin,, total cholesterol, and triglyceride, were significantly related with CRP level independently. Conclusions : The serum CRP level, even if existed in normal range, was positively correlated with in type 2 diabetes. Further studies are needed to determine the CRP level considered as clinically significant, and relating HOMA -IR. (Korean J Med 74: , 2008) Key Words : Insulin resistance; C-Reactive protein; Atherosclerosis 서론. 제2형당뇨병의발생기전에근간이되는인슐린저항성 은내당능장애뿐만아니라심혈관질환의주된위험요인이되는복부비만, 지질대사이상, 고혈압, 고요산혈증, 혈액응고장애등에공통적인병인으로작용한다 1). Received : Accepted : Correspondence to : Ji-Hyun Park, M.D., Division of Endocninology and Metabolism, Department of Internal medicine, Chonbuk National University Medical School, , Keumam-dong, Dukjin-gu, Jeonju , Korea parkjh@chonbuk.ac.kr

2 - The Korean Journal of Medicine : Vol. 74, No. 3, 인슐린저항성은인슐린분비에대한체내감수성의저하로인해표적세포에서의인슐린반응도를감소시키고, 탄수화물과지질대사에변화를일으킴으로써고혈당을유발하게된다 2). 고혈당은지방세포로부터 Interleukin-6 (IL-6) 나 Tumor necrosis factor-α (TNF-α) 와같은 pro-inflammatory cytokine을분비하게하여 fibrinogen, plasminogen activator inhibitor-1 (PAI-1), 백혈구, CRP (C-reactive protein) 와같은여러급성기반응물질을자극하게되고, 이러한염증반응의일환으로죽상동맥경화증을유발한다고알려져있다 3). 따라서인슐린저항성에의해유발된고혈당은증가된염증반응과관련이될것으로여겨진다 4). 그러나고혈당이염증반응을유도한다고할지라도포도당항상성 (glucose homeostasis) 의조절과잠재성염증 (subcl -inical inflammation) 과의연관성은확립되어있지않으며, 일부보고에서정상인과대사증후군환자를대상으로 CRP 와인슐린저항성과의관련성을언급하였다 5, 6). CRP는대표적인급성기반응물질로서염증반응에따라상승하게되며, 염증반응을근본적인병인으로하는죽상경화증과내피세포기능이상과관련이있다 7). 정상범위내에서도일정농도이상을심혈관질환의위험인자로간주하자는보고들이있는데, 심혈관질환에대하여 CRP > 3 mg/l을고위험군, 1 3 mg/l를중등도위험군, < 1 mg/l을저위험군으로분류하여죽상경화증과관련한질병에대한예견인자로사용하자는의견들이있다 8, 9). 뿐만아니라 CRP가대사증후군각각의요소들과상관관계를보인다는보고도있다 6). 인슐린저항성을알아보는방법으로몇가지가제시되고있으나그중 Homeostasis model assessment of insulin resistance () 은공복인슐린과공복혈당을이용한계산식으로도출해낼수있다. 은인슐린저항성과췌장베타세포의기능을비교적간편하게평가할수있으면서도 gold standard 방법인 hyperinsulinemic euglycemic clamp와의재현성이우수하여대규모연구에이용되고있는유용한방법이다 10). 그러나인슐린을사용중인환자의경우에는 을적용하여인슐린저항성과베타세포의기능을평가하는것에논란의여지가있다 11). 따라서본연구에서는인슐린을사용하고있지않은제2 형당뇨병환자를대상으로, 인슐린저항성을나타내는 값과죽상경화증발생에독립적역할을갖는것으로알려진혈청 CRP값과의상관관계를알아보고, 중등도이상의위험군으로분류되는 CRP값을갖는경우의 HOMA -IR값에대해분석해보고자하였다. 대상및방법 1. 대상지난 2년동안전북대학교병원내분비대사내과에서미국당뇨병학회기준에따라제2형당뇨병으로진단받은환자들중인슐린을사용하고있지않으며 3개월간치료방법의변화가없는 102명을대상으로하였다. 공복시 C-peptide 가 0.3 nmol/l 미만, 케톤산증의과거력, 항 GAD (glutamic acid decarboxylase) 항체양성등으로제1형당뇨병이의심되는경우, 임신성당뇨병및 CRP 10 mg/l 이상의급성염증반응이동반된환자는제외하였으며, 75세이상이면서, 협조가되지않거나정신질환또는심각한타질환 ( 악성종양, 간부전, 심부정맥, 심부전 ) 이있는환자도대상에서제외하였다. 2. 방법체지방측정기 (InBody 2.0, Biospace Co, Korea) 로신장과체중을측정하여대상환자들의체질량지수 (body mass index, kg/m²) 를계산하였다. 혈액채취는 12시간이상의충분한금식후전주와정맥 (antecubital vein) 에서시행하였으며, 혈당치및인슐린, CRP, 총콜레스테롤, 중성지방등을측정하였다. 혈청 CRP는 Hitachi (Hitachi, Tokyo, Japan) 를이용하여면역비탁법으로측정하였는데, 측정범위는 0 15 mg/l이었다. 혈장인슐린은상품화된 Kit (DiaSorin, Inc., Reutlinger, Germany) 를이용하여면역방사능법으로측정하였다. 저밀도콜레스테롤은 homogenous method based on an innovative detergent technology를이용한 Hitachi (Hitachi, Tokyo, Japan) automatic analyzer로측정하였다. 인슐린저항성의지표인 은 Mattews 등 10,11) 이제안한다음의공식으로계산하였으며, 이를혈청 CRP 값과비교분석하였다. = insulin (µiu/ml) glucose (mmol/l) / 22.5 또한, 전체환자를 CRP값에따라두그룹으로분류하여 (Group A: <1 mg/l, Group B: 1 mg/l) 값을분석하였고, 이를바탕으로 CRP와 값의관련성을식으로규명하였으며, 그외다른대사위험요소들과의상관관계를알아보았다. 3. 통계분석

3 - So-Young Kim, et al : CRP and insulin resistance in type 2 DM - Table 1. Clinical characteristics according to C-reactive protein Group A (N=64) Group B (N=38) p value Age (years) 56.68± ±10.36 Body mass index (kg/m 2 ) 25.02± ±3.30 DM duration (years) 8.02± ±7.08 Hypertension frequency 66% 34% Glucose (mmol/l) Insulin (pmol/l) 7.35± ± ± ±3.19 * ± ±1.35 * Total cholesterol (mmol/l) 4.45± ±1.04 Triglyceride (mmol/l) 1.44± ±0.87 HDL-cholesterol (mmol/l) 1.18± ±0.26 LDL-cholesterol (mmol/l) 2.71± ±0.81 The data is express as Means±S.Ds. * p<0.05 N, Number of patients;, Non-significant. CRP, C-reactive protein, Homeostasis model assessment of insulin resistance Group A: population with a CRP level < 1 mg/l, Group B: population with a CRP level 1 mg/l. Table 2. Pearson s correlation coefficient between the variables of interest Glucose (mmol/l) Insulin (pmol/l) BMI CRP (mg/l) Total cholesterol (mmol/l) Triglyceride (mmol/l) * : Correlation is significant at the : Correlation is significant at the CRP (mg/l) * * * * * 연구대상자들의특성은평균값과표준편차로표시하였다. 통계분석은 SPSS (version 12.0, SPSS Inc., Chicago, IL, USA) 를이용하여 Independent samples t-test 및 Pearson's correlation, X 2 test, 선형회귀분석을시행하였으며 p-value 가 0.05 미만인경우를통계학적으로유의한것으로하였다. 결과 1. CRP 수치에따른임상특징및대사위험인자들의비교대상환자들의평균연령은 57.05±9.81세, 당뇨병유병기간은 8.47년이었고, 평균 CRP는 0.88 mg/l, 값은 2.28이었다. CRP 값 1을기준으로 <1 mg/l 인군을 A, 1 mg/l 인군을 B로분류하였을때, B군의 값과공복인슐린값이각각 2.79±1.35 (p<0.01), 7.77±3.19 pmol/l (p=0.021) 로 A군에비하여유의하게높았다. BMI 의경우 A 군은 25.02±3.54 kg/m², B군은 25.65±3.30 kg/m² 로큰차이를보이지않았으며, A군의경우고혈압의동반율이 64% 로 B 군에비하여높았으나통계학적으로유의하지않았다 ( 표 1). 2. CRP 및 값과대사위험인자들의상관관계 Pearson s correlation 방법으로분석하였을때 CRP는공복인슐린 (r=0.319, p=0.001), 값 (r=0.4, p<0.01), 총콜레스테롤 (r=0.199, p=0.045), 중성지방 (r=0.25, p=0.012) 과유의한양의상관관계를보였다. 값은 CRP외에중

4 - 대한내과학회지 : 제 74 권제 3 호통권제 571 호 Table 3. Stepwise multiple linear regression analysis for the serum C-reactive protein concentration in type 2 diabetic patients beta Standard Error p fasting insulin,, total cholesterol and triglyceride were analyzed as independent variables. Only variables that had a p 0.05 were considered in the final fitted model. R 2 for the model=23.6% ( 표 2). 이러한결과를토대로선형회귀분석을이용하여양의상관관계 (r=0.140, p<0.05) 를갖는 과 CRP의관련성에대하여다음의공식을도출할수있었다 ( 그림 1). = CRP 이러한양의상관관계를갖는 CRP와 에대하여혈압, BMI, 총콜레스테롤, 중성지방을보정한뒤관련성을분석하여보았을때에도통계학적으로유의성이지속되었다 (r=0.403, p<0.01) ( 표 4) 고 찰 CRP CRP(mg/L) (mg/l) Figure 1. The relationship between and C-reactive protein (CRP). = CRP (r=0.197, p<0.01) Table 4. Partial correlation coefficient of the serum C-reactive protein concentration after adjustment for the BMI, total cholesterol and triglyceridemia with and without hypertension <0.01 r 성지방과양의상관관계를보였다 (r=0.338, p=0.001)( 표 2). 뿐만아니라 CRP와상관성이관찰된공복시인슐린,, 총콜레스테롤, 중성지방중 CRP 농도에영향을주는독립적인변수를확인하기위해다중회귀분석을시행하였을때, 값이독립적으로 CRP와관련된유의한인자임이확인되었다 ( 표 3). 3. 값과 CRP 와의관계 전체환자군을대상으로 Pearson 상관분석을하였을때 CRP와 은양의상관관계를가졌다 (r=0.4, p<0.01) p 본연구에서는제2형당뇨병환자를대상으로 CRP값 1 mg/l를기준으로두군으로분류하여 값과의관련성을분석하였고, 이러한상관관계로부터 = CRP+0.453의공식을도출해볼수있었다. 고혈압이나비만도, 콜레스테롤과같은위험인자들을보정한후에도 CRP와 값은유의한관련성을보여주었다. 본연구의대상환자들에서는심혈관질환의고위험군 8, 9) 으로분류되는 CRP가 3 mg/l 이상인환자들이없었으며, CRP값 1 mg/l을기준으로전체환자를두군으로분류하였을때, 두군사이에서의 값이유의하게차이가있어 (Group A: r=0.252, p=0.02, Group B: r=0.375, p=0.02), 경도의 CRP 상승에따라 값이상승하는양의상관관계를나타내었다. 이전보고에서도 CRP를 0.25 mg/l 미만, 0.25~ 0.59 mg/l, 0.60 mg/l 이상인그룹으로분류하여유의한 값의차이를보여준바가있다 12). 본연구결과와함께임상적예후와관련되는 CRP 값이얼마인지에대해서는추가적인대규모연구가필요할것으로보인다. CRP와인슐린저항성의병인에대하여최근 L 6 myotube 를통한연구가보고된바있다. 이연구에서저자들은 CRP 가 c-jun N-terminal kinase (JNK) 와 extracellular signal-regul -ated kinase (ERK)1/2의자극을통해 Ser 307 과 Ser 612 에서인슐린수용체기질 (insulin receptor substrate, IRS) 의인산화를증가시켜인슐린저항성을유발하게되고이에따라인슐린자극성포도당섭취장애및포도당수송체 (glucose transporter-4,

5 - 김소영외 6 인 : 2 형당뇨환자의 CRP 값과인슐린저항성 - GLUT-4) 의전위와 IRS-1/PI-3K (phosphatidylin -ositol-3 kinase) / Akt(protein kinase B) / GSK-3 (glycogen synthase kinase-3) 에의해조절되는글라이코겐합성에손상을유발하게된다고제시하였다 13). 이러한결과는내장지방에서분비되는 IL-6, TNF-α와같은 proinflammatory cytokine이 CRP 를자극함으로써인슐린저항성에영향을미친다는이전의연구결과와도일치하는소견이다 14). IL-6 는식후에피하지방의간질액에서상승하는포도당및인슐린농도와유사한양상을보이며 15), TNF-α 와다른염증성 cytokine 및 leptin은인슐린수용체에영향을주어인슐린수용체의자가인산화 (autophosphorylation) 및인슐린수용체기질의인산화감소와인슐린자극성포도당섭취를억제하며비에스테르화지방산생산에대한베타세포의기능을바꾼다 16, 17). 한편, TNF-α는비만증에서증가된지방조직으로부터유출되어주변의지방조직과근육조직에 autocrine 또는 paracrine 형식으로작용함으로써비만증과연관된인슐린저항성의요인으로관여하는것으로알려져있다. 복강내지방축적으로혈액내지방산농도가증가하고, 문맥내지방산증가로인해인슐린저항성이유발되는것으로비만과인슐린저항성의연관성이설명되고있어 16, 19), 본연구에서보여진 CRP와 의연관성이비만과의상호작용으로인한결과로생각될수도있다. 그러나 BMI와 CRP, 은각각에서연관성을보이지않았으며, BMI 를보정한후에도 CRP와 의양의상관관계는유지되었다. CRP의분비를자극하는 proinflammatory cytokine은지방세포에서주로생성되어, 당뇨병환자에서 CRP가지방증정도를반영하며, 체중의감량이 CRP감소효과를보인다는등비만도와 CRP과의관련성이알려져있다 20-22). 그러나앞서언급했듯이본연구에서비만도를나타내는 BMI와 CRP 는연관성을보이지않았는데, 이는 30 이상의 BMI를보였던이전의연구에 20) 비하여 BMI가 25로상대적으로낮았고, 허리둘레가아닌 BMI로비만도를평가하였기때문으로생각된다. 같은 BMI를가지더라도피하지방과내장지방의분포에따라다양한염증반응정도를보이며허리둘레측정이중심성비만과좀더연관성을가질것으로보고되고있기는하지만, 대부분의임상에서허리둘레의측정이이루어지지못하며또한인종에따라차이를보인다는한계점을가지고있다 23, 24). 경도의염증반응은동맥경화의병태생리와관련하여중요한위험인자로알려져있다 7-9). 이전연구들에서 CRP는대식세포에서생산된조직인자를자극하며, 보체계를활성 화시키고, 백혈구의동원에작용하는유착물질의발현및 LDL (low density lipoprotein) 과 VLDL (very low density lipoprotein) 같은지단백의결합과응집을유도함으로써죽상경화성병변의발생과진행에직접적인역할을하는것으로알려져있다 25, 26). 당뇨병환자에서 값이이러한염증반응유발과관련된다면유의한 CRP상승이있는경우인슐린저항성의감소를통한치료적접근법이보다구체화될수있으리라보인다. 은인슐린저항성을나타내는지표로서 Matthew 등이제안한이후인슐린저항성및췌장베타세포의기능을평가하는데사용되고있다 10, 11). 하지만제2형당뇨병의경우오랜시간이경과되면췌장베타세포가파괴되고인슐린의분비량이감소하여인슐린저항성이높다하더라도인슐린값은낮게측정되어, 본연구에서처럼평균유병기간이약 8.5년인비교적진행된제2형당뇨병환자에서는실제보다 값이낮게측정될수있겠다. 즉 CRP와인슐린저항성의상관관계는초기당뇨병환자인경우본연구에서의결과보다도더높을수있음을추정해볼수있다. 고려해보아야할또다른사항으로서, 한국인에서당뇨병의발병에있어서는인슐린저항성보다인슐린분비능의감소가더큰역할을할것으로생각되어왔다는점이다. 따라서, 서구인에비하여덜비만하고낮은인슐린분비능을가지는한국인에서 을통한인슐린저항성의평가는한계를가진다고여겨질수있으나 27), 최근한국인에서도비만형당뇨병의빈도가증가하고있고, 본연구에서는평균 BMI가약 25.3으로한국인의평균 BMI에비해비교적높았다. 이러한제한점에도불구하고본연구는건강한성인이나내 5, 12, 28, 29) 당능장애의환자군을대상으로한대부분의연구에비하여, 한국인당뇨병환자를대상으로하여염증반응과인슐린저항성의직접적인연관관계를알아본연구이며, 일부당뇨병환자를대상으로한연구에 28, 30) 비해 CRP가상대적으로낮은대상군이었다는점에서좀더의미를가질수있다. 더불어당뇨병으로인해이미약물치료를받고있는환자들에서 CRP가높게측정되었다면인슐린저항성을의미할수있으며, 이들에서인슐린저항성개선을위한약제나추가적인생활양식의변경이도움이될지는추후연구가필요하다. 결론적으로, 제2형당뇨병환자에서정상범위라할지라도상대적으로증가되어있는 CRP는 값의증가와

6 - The Korean Journal of Medicine : Vol. 74, No. 3, 관련이있으며, 이는인슐린저항성과잠재성염증반응의관련성을시사한다. 이러한관련성을바탕으로인슐린저항성을조기평가하는것은죽상경화증의예방에중요한인자일수있다. 향후임상적인예후와관련된의미있는 CRP 값의규명과이와관련된 값의도출을위한추가적인연구들이필요하다. 요 목적 : 염증반응은죽상경화증의주요병인이다. 제2형당뇨병환자를대상으로염증반응의표지자로알려진 CRP 와인슐린저항성과의상관관계를살펴보고자하였다. 방법 : 평균유병기간이 8.5년인제 2형당뇨병환자 102 명을대상으로하였다. CRP와 HOMA IR과의상관관계및대사위험요소들간의연관성을분석하였다. 결과 : CRP값은 값과양의상관관계를보였으며 (r=0.4, p<0.01), 특히공복시인슐린과밀접한상관관계를보였다 (r=0.319, p=0.001). 대상군을 CRP 값 1 mg/l를기준으로구분하였을때 1 mg/l이상인군에서 1 mg/l미만인군에비하여유의하게높은 값의분포양상을보였다 (p=0.001). 공복시인슐린, 지질, 고혈압유무로보정을한후에도이러한상관관계는지속되었다. 결론 : 본연구에서는제2형당뇨병환자에있어 CRP가정상범위내에있을지라도, 정상범위내에서 값과양의상관관계를가진다는것을알수있었다. 향후예후와관련된의미있는 CRP 상승의정도규명및이러한 CRP 상승을일으키는 값에대한추가적인연구들이필요하다. 중심단어 : 인슐린저항 ; C- 반응성단백 ; 죽상경화증 약 REFERENCES 1) DeFronzo RA. Pathogenesis of type 2 diabetes mellitus. Med Clin North Am 88: , ) Folsom AR, Kushi LH, Anderson KE, Mink PJ, Olson JE, Hong CP, Sellers TA, Lazovich D, Prineas RJ. Associations of general and abdominal obesity with multiple health outcomes in older women. Arch Intern Med 160: , ) Morohoshi M, Fujisawa K, Uchimura I, Numano F. Glucose-dependent interleukin 6 and tumor necrosis factor production by human peripheral blood monocytes in vitro. Diabetes 45: , ) Pickup JC, Mattock MB, Chusney GD, Burt D. NIDDM as a disease of the innate immune system: association of acute phase reactants and interleukin-6 with metabolic syndrome X. Diabetologia 40: , ) Aronson D, Bartha P, Zinder O, Kerner A, Shitman E, Markiewicz W, Brook GJ, Levy Y. Association between fasting glucose and C-reactive protein in middle-aged subjects. Diabet Med 21:39 44, ) Lee WY, Park JS, Noh SY, Rhee EJ, Sung KC, Kim BS, Kang JH, Kim SW, Lee MH, Park JR. C-reactive protein concentrations are related to insulin resistance and metabolic syndrome as defined by the ATP III report. Int J Cardiol 97: , ) Ridker PM, Hennekens CH, Buring JE, Rifai N. C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women. N Engl J Med 342: , ) Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome and risk of incident cardiovascular event: an 8-year follow-up of initially healthy American women. Circulation 107: , ) van Ree RM, de Vries AP, Oterdoom LH, The TH, Gansevoort RT, Homan van der Heide JJ, van Son WJ, Ploeg RJ, de Jong PE, Gans RO, Bakker SJ. Abdominal obesity and smoking are important determinants of C-reactive protein in renal transplant recipients. Nephrol Dial Transplant 20: , ) Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia 28: , ) 장현아, 김진우, 류미숙, 박철영, 오승준, 우정택, 김성운, 김영설, 최영길. 한국인제 2 형당뇨병환자에서의 Homeostasis model assessment. 당뇨병 26: , ) Najanishi N, Shiraishi T, Wada M. Association between C-reactive protein and insulin resistance in Japanese population. Intern Med 44: , ) D'Alessandris C, Lauro R, Presta I, Sesti G. C-reactive protein induces phosphorylation of insulin receptor substrate-1 on Ser 307 and Ser 612 in L 6 myocytes, thereby impairing the insulin signaling pathyway that promotes glucose transport. Diabetologia 50: , ) Krogh-Madsen R, Plomgaard P, Moller K, Mittendorfer B, Pedersen BK. Influence of TNF-alpha and IL-6 infusions on insulin sensitivity and expression of IL-18 in humans. Am J Physiol Endocrinol Metab 291:E108-E114, ) Krogh-Madsen R, Plomgaard P, Keller P, Keller C, Pedersen BK. Insulin stimulates interleukin-6 and tumor necrosis factoralpha gene expression in human subcutaneous adipose tissue. Am J Physiol Endocrinol Metab 286:E234 E238, ) Orban Z, Remaley AT, Sampson M, Trajanoski Z, Chrousos

7 - So-Young Kim, et al : CRP and insulin resistance in type 2 DM - GP. The differential effect of food intake and beta-adrenergic stimulation on adiopose-derived hormones and cytokines in man. J Clin Endocrinol Metab 84: , ) Valverde AM, Benito M, Lorenzo M. The brown adipose cell: a model for understanding the molecular mechanisms of insulin resistance. Acta Physiol Scand 183:59-73, ) Shen BJ, Todaro JF, Niaura R, McCaffery JM, Zhang J, Spiro A 3 rd, Ward KD. Are metabolic risk factors one unified syndrome?: modeling the structure of the metabolic syndrome X. Am J Epidemiol 157: , ) Hotamisligil SG, Spiegelman BM. Tumor necrosis factor alpha: a key component of the obesity-diabetes link. Diabetes 43: , ) Kahn SE, Zinman B, Haffner SM, O'neill MC, Kravitz BG, Yu D, Freed MI, Herman WH, Holman RR, Jones NP, Lachin JM, Viberti GC. Obesity is a major determinant of the association of C-reactive protein levels and the metabolic syndrome in type 2 diabetes. Diabetes 55: , ) Timpson NJ, Lawlor DA, Harbord RM, Gaunt TR, Day IN, Palmer LJ, Hattersley AT, Ebrahim S, Lowe GD, Rumley A, Davey Smith G. C-reactive protein and its role in metabolic syndrome: mendelian randomization study. Lancet 366: , ) Pereira MA, Swain J, Goldfine AB, Rifai N, Ludwig DS. Effects of a low-glycemic load diet on resting energy expenditure and heart disease risk factors during weight loss. JAMA 292: , ) Krotkiewski M, Bjorntorp P, Sjostrom L, Smith U. Impact of obesity on metabolism in men and women: importance of regional adipose tissue distribution. J Clin Invest 72: , ) Cnop M, Landchild MJ, Vidal J, Havel PJ, Knowles NG, Carr DR, Wang F, Hull RL, Retzlaff BM, Walden CE, Knopp RH, Kahn SE. The concurrent accumulation of intra-abdominal and subcutaneous fat explains the association between insulin resistance and plasma leptin concentrations: distinct metabolic effects of two fat compartments. Diabetes 51: , ) Singh U, Jialal I. Oxidative stress and atherosclerosis. Pathophysiology 13: , ) Stegenga ME, van der Crabben SN, Levi M, de Vos AF, Tanck MW, Sauerwein HP, van der Poll T. Hyperglycemia stimulates coagulation, whereas hyperinsulinemia impairs fibrinolysis in healthy humans. Diabetes 55: , ) Kang ES, Yun YS, Park SW, Kim HJ, Ahn CW, Song YD, Cha BS, Lim SK, Kim KR, Lee HC. Limitation of the validity of the homeostasis model assessment as an index of insulin resistance in Korea. Metabolism 54: , ) Temelkova-Kurktschiev T, Siegert G, Bergmann S, Henkel E, Koehler C, Jaross W, Hanefeld M. Subclinical inflammation is strongly related to insulin resistance but not to impaired insulin secretion in a high risk population for diabetes. Metabolism 51: , ) Festa A, D'Agostino R Jr, Howard G, Hykkanen L, Tracy RP, Haffner SM. Chronic subclinical inflammation as part of the insulin resistance syndrome. Circulation 102:42-47, ) Leinonen E, Hurt-Camejo E, wiklund O, Hulten LM, Hiukka A, Taskinen MR. Insulin resistance and adiposity correlate with acute-phase reaction and soluble cell adhesion molecules in type 2 diabetes. Atherosclerosis 166: ,

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