Korean Diabetes J 33:124~133, 2009 DOI : 10.4093/kdj.2009.33.2.124 ORIGINAL ARTICLES 성인당뇨병환자에서 GAD 자가항체유무와만성합병증과의관계 전남대학교의과대학내과학교실 정진욱 조동혁 정동진 정민영 Chronic Complications in Adult Diabetic Patients with and without GAD Antibody Jin Ook Chung, Dong Hyeok Cho, Dong Jin Chung, Min Young Chung Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea Abstract Background: Although the majority of diabetes mellitus (DM) patients diagnosed as adults have non-autoimmune forms of the disease, islet autoimmunity is encountered in some patients initially thought to have type 2 DM. The phenotype of DM patients with glutamic acid decarboxylase (GAD) antibodies is different from that of patients with GAD antibody-negative type 2 DM, with features such as relative leanness and hyperglycemia which may influence the development of complications. We sought to compare the prevalence of chronic complications in patients with and without the GAD antibody. Methods: We recruited 427 patients (M: 218, F: 209) that were clinically diagnosed with type 2 DM after the age of 35 years. We measured GAD antibody and assessed the factors associated with chronic microvascular and macrovascular complications. Results: Of these patients, 26 were GAD antibody-positive. The patients with GAD antibody had lower systolic blood pressure, higher high-density lipoprotein cholesterol value, and lower level of fasting and stimulated C-peptide than patients without GAD antibody (P < 0.05). Also, the patients with GAD antibody had lower prevalence of retinopathy compared with the patients without GAD antibody (19.2 vs. 47.9%; P < 0.05). The prevalence of nephropathy, peripheral neuropathy and cardiovascular autonomic neuropathy did not differ between the groups. In addition, the prevalence of coronary heart disease, cerebrovascular disease and peripheral arterial disease did not differ between the two groups. Conclusion: This study suggests that diabetic patients with GAD antibody have a lower risk for the development of retinopathy compared with patients without GAD antibody. (Korean Diabetes J 33:124-133, 2009) Key words: Diabetes Complications, Diabetes Mellitus, Glutamate decarboxylase 서론제2형당뇨병환자에서인슐린저항성과베타세포기능부전은당뇨병발생의주된요인이며, 자가면역기전에의한베타세포의선택적파괴는제1형당뇨병에서당뇨병발생의주된요인으로알려져있다. Islet cell cytoplasmic antigen (ICA) 나 Glutamic acid decarboxylase (GAD) 에대한자가항체는자가면역기전에의한베타세포파괴를나타내는면역표지자로서질병초기에제1형당뇨병을가지는환자의대부분에서발견된다 1). 이에반해성인에서진단되는제2형당뇨병환자의대부분은비면역학적기전에의해발생하며, 초기에제2형당뇨병으로진단되었던일부환자에서 GAD 접수일자 : 2009 2 월 02 일, 통과일자 : 2009 년 4 월 06 일교신저자 : 정민영, 전남대학교의과대학내과학교실, E-mail: mychung@chonnam.ac.kr 124
정진욱외 3 인 : 성인당뇨병환자에서 GAD 자가항체유무와만성합병증과의관계 에대한항체를가지고있다 2). 이러한항체가발견되는환자는경구혈당강하제로혈당조절이가능한전형적인제2형당뇨병환자와는달리인슐린결핍으로인해조기에인슐린치료를필요로하거나혈당강하제의효과가상대적으로낮은것으로알려져있다 2-4). 당뇨병환자에서만성적인고혈당은당뇨병성미세혈관합병증의발생위험을증가시키며, 고혈당이외에도당뇨병유병기간, 고혈압, 고지혈증, 체질량지수등여러요인들이미세혈관합병증의발생에영향을미칠수있다 5). 또한당뇨병환자에서심혈관합병증의발생위험이증가함이알려져있다 6). 제2형당뇨병환자에서인슐린저항성이심혈관질환의위험성을증가시킬수있다고보고되었으며 7), Lehto 등은인슐린치료를받지않고있는제2형당뇨병환자를대상으로한연구에서공복고인슐린혈증이심혈관계질환으로인한사망의위험을증가시킨다고보고하였다 8). 또한임상적으로제2형당뇨병으로진단되는환자들을대상으로 GAD 자가항체유무에따른특성을비교한기존의연구들에의하면, GAD 자가항체양성환자에서는자가항체음성환자에비해베타세포기능감소가더현저하며마른체형및고혈당의빈도가더높다고하였으며 9) Zinman 등은공복인슐린과 Homeostasis model assessment insulin resistance (HOMA-IR) 를토대로 GAD 자가항체를가진환자에서자가항체음성환자에비해인슐린저항성이더낮았다고보고하였다 10). 따라서이러한점들은임상적으로제2형당뇨병으로진단되는 GAD 자가항체양성환자는만성미세혈관합병증이나대혈관합병증의발생에있어서 GAD 자가항체음성을보이는제2형당뇨병환자와는다른양상을보일수있을것으로생각된다. GAD 자가항체를가지는제2형당뇨병환자에서만성미세혈관합병증과대혈관합병증에관한외국의일부연구가있으나서로다른결과들이보고되고있고 11-13), 국내에서는제2형당뇨병으로진단된환자에서 GAD 자가항체를가진환자의유병률이나인슐린결핍으로인한치료의차이점등에관한보고가있었으나 14,15) GAD 자가항체를가진성인당뇨병환자에서미세혈관합병증과대혈관합병증에관련된국내연구는아직부족한실정이다. 이에본연구는임상적으로제2형당뇨병으로진단되는성인당뇨병환자에서 GAD 자가항체유무와당뇨병성만성미세혈관합병증및대혈관합병증의발생과의관련성을알아보고자하였다. 대상및방법 1. 연구대상 2007년 1월부터 2008년 1월사이에전남대학교병원내분비대사내과에방문하여임상적으로제2형당뇨병으로진단되어치료중인환자들중에서 GAD 자가항체측정과당뇨병성합병증에관한평가가이루어진환자 427명을대상으로단면적분석을실시하였다. 분석을위해제2형당뇨병으로임상적진단을받고치료중인환자들을 GAD 자가항체유무에따라두군으로나누어분류하였다. 또한제1형당뇨병을배제하기위해당뇨병진단당시연령이 35세이상인환자를대상으로하였고당대사에영향을미칠수있는심한전신질환이나스테로이드등의약물을복용하고있는환자들은제외하였다. 2. 신체계측및생화학적검사환자의신체지표로신장, 체중, 체질량지수 (kg/m 2 ) 및허리둘레를측정하였다. 혈압은 5분이상안정을취한후앉은상태에서우측상완동맥에서수축기혈압과이완기혈압을측정하였으며 2회측정하여두값의평균값을사용하였다. 고혈압의진단은각각다른날에 2회이상측정한수축기혈압이 140 mm Hg 이상인경우와이완기혈압평균이 90 mm Hg 이상인경우로하였고본원에방문하기전에이미고혈압을진단받고항고혈압제를복용중인환자를고혈압환자로간주하였다. 대상환자를 10시간이상금식시킨후아침공복시에채혈하여혈장혈당, C-펩티드 (RIA법: Biosource Europe S.A., Nivelles, Belgium), GAD 자가항체 (IRMA법: RSR, Cardiff, United Kingdom), 인슐린농도 (IRMA 법 : DAINABOT, Japan), 당화혈색소, 총콜레스테롤, 중성지방, 고밀도지단백콜레스테롤, 저밀도지단백콜레스테롤, 유리지방산 (ACS -ACOD법: Wako Pure Chemical Industries Ltd., Japan) 을측정하였다. GAD 자가항체의측정은영국 RSR사의 125 I- labelled human GAD kit를사용하였으며정상치의상한선인평균 +2 표준편차인 0.9 U/mL를초과하는경우 GAD 자가항체양성으로정의하였다. 이측정키트는 2005 Diabetes Antibody Standardization Programme (DASP) antibody workshop에서특이도 95%, 민감도 84% 를보였다. 베타세포의기능평가를위해공복 C-펩티드측정과표준당뇨식이 2시간후채혈을하여식후 C-펩티드를측정하였다. 3. 당뇨병성합병증검사 당뇨병성미세혈관합병증에대한평가를위해서안저촬 125
Korean Diabetes J 33:124~133, 2009 영, 진동감각역치검사, 신경전도검사및미세알부민뇨검사를실시하였다. 당뇨병성망막증의평가를위해안저검사를하였으며혈관투과성, 미세동맥류, 미세경색, 점상출혈, 면화반, 신생혈관, 망막박리등의소견이있는경우당뇨병성망막병증으로진단하였으며비증식성망막증과증식성망막증의분류는하지않았다. 당뇨병성신경병증유무는신경전도검사와진동감각역치검사를통하여실시하였으며신경전도검사는양측정중, 척골, 장딴지및종아리신경에서시행하여말초신경병증의증거가나타나거나양측족부의무지 (hallus) 에서 biothesiometer (Biomedical Instrument, Newbury, OH) 를이용하여 2회측정한진동감각역치의평균값이 25 V 이상인경우를신경병증이있는것으로정하였다. 심혈관계자율신경병증의평가를위해 Monitor one ndx (QMed, Inc. Entontown, NJ) 기계를이용하여반복적인심호흡호기와흡기시 (E/I 비 ), 체위변화시 (30: 15 비 ), 발살바수기시심박동수변화를측정하였다. E/I 비는연령과관련된참고치를이용하였고, 30:15 비는 1.03 미만, 발살바비는 1.2 미만일때를비정상으로정의하였으며각세가지항목중 2가지이상이비정상인경우심혈관계자율신경병증으로정의하였다. 당뇨병성신증의평가를위해수시뇨 (spot urine) 에서미세알부민뇨를측정하였고미세알부민뇨는아침에기상후배뇨한요에서알부민과크레아티닌을측정하여요에서알부민대크레아티닌비 [urinary albumin-tocreatinine ratio: UAE (mg/g of creatinine)] 를구하였다. UAE가 30 mg/gcr를넘는경우를당뇨병성신증으로정의하였다. 대혈관합병증의유무를확인하기위해관상동맥질환, 허혈성뇌혈관질환및말초동맥혈관질환을평가하였다. 관상동맥질환은안정시심전도, 운동심부하검사, 64-다편절심장전산화단층촬영이나관상동맥혈관조영술에서관상동맥질환이증명된경우로하였다. 허혈성뇌혈관질환은뇌경색의병력을가지고있거나뇌전산화단층촬영, 뇌자기공명영상촬영에서뇌경색이있거나대뇌동맥의협착이있는경우로하였다. 말초동맥혈관질환은 VaSera VS-1000 (Fukuda Denshi, Co. Ltd, Tokyo, Japan) 을이용한진동법 (oscillometric method) 으로상하지혈압을측정하여 ankle-brachial pressure index (ABPI) 를구하였으며 ABPI가 0.9 미만인경우로하였다. 4. 통계분석통계분석은 SPSS version 12.0 (SPSS Inc., Chicago, IL) 을이용하였고, 측정값은평균 ± 표준편차로표시하였다. 두군사이에연속변수의비교는 Student's T-test 또는 Mann-Whitney test를이용하였고, 범주형변수의비교는카이제곱검정또는피셔의정확성검정을이용하였다. P < 0.05인경우에통계적으로유의성이있는것으로판정하였다. 결과 1. GAD 자가항체유무에따른임상및생화학적특성총 427명의환자중 GAD 자가항체양성인환자는 26명이었으며 GAD 자가항체음성인환자는 401명이었다. GAD 자가항체양성환자의평균나이는 53.8 ± 13.1세, GAD 자가항체음성환자의평균나이는 59.6 ± 12.5세로두군사이에유의한차이는없었다. GAD 자가항체양성환자의평균허리둘레가남자 85.9 ± 11.1 cm, 여자 82.8 ± 8.2 cm, 평균체질량지수 21.5 ± 2.8 kg/m 2 로 GAD 자가항체음성환자의평균허리둘레남자 90.2 ± 8.7 cm, 여자 89.9 ± 14.2 cm, 평균체질량지수 25.1 ± 20.6 kg/m 2 에비해낮은경향을보였으나두환자사이에유의한차이는없었다 (Table 1). 수축기및이완기혈압을각각비교하였을때 GAD 자가항체양성환자에서 GAD 자가항체음성환자에비해수축기혈압 (121.8 ± 27.5 mm Hg vs. 131.8 ± 19.0 mm Hg, P = 0.014) 이유의하게낮았으나이완기혈압은차이를보이지않았다. GAD 자가항체양성환자에서 GAD 자가항체음성환자에비해고밀도지단백콜레스테롤 (53.5 ± 15.1 vs. 45.3 ± 15.9 mg/dl, P = 0.011) 이유의하게높았으나총콜레스테롤, 중성지방및저밀도지단백콜레스테롤수치에서는유의한차이가없었다. GAD 자가항체양성환자에서공복 C-펩티드 1.30 ± 1.20 ng/ml, 식후 C-펩티드 1.66 ± 1.58 ng/ml였고, GAD 자가항체음성환자에서공복 C-펩티드 2.99 ± 3.17 ng/ml, 식후 C-펩티드 5.06 ± 4.28 ng/ml 로공복및식후 C-펩티드모두 GAD 자가항체양성환자에서음성환자에비해유의하게낮았다 (P < 0.001). 두군사이에혈당조절방법을비교하였을때 GAD 자가항체양성환자에서경구혈당강하제 38.5%, 인슐린단독요법이나경구혈당강하제와인슐린의병합요법 61.5% 였으며 GAD 자가항체음성환자에서는식이요법 8.0%, 경구혈당강하제 63.6%, 인슐린단독요법이나경구혈당강하제와인슐린의병합요법 28.4% 로 GAD 자가항체양성환자에서인슐린치료비율이높았다 (P = 0.001). 그외당뇨병가족력, 당뇨병유병기간, 당화혈색소, 유리지방산, 공복혈당수치, 고지혈증치료및고혈압치료여부는 GAD 자가항체양성환자와음성환자사이에유의한차이는없었다 (Table 1). 126
정진욱외 3 인 : 성인당뇨병환자에서 GAD 자가항체유무와만성합병증과의관계 Table 1. Clinical characteristics of the subjects GAD antibody-negative GAD antibody-positive P-value Number 401 26 - Age (years) 59.6 ± 12.5 53.8 ± 13.1 0.58 Family history (n) 217 (54.1) 12 (46.2) 0.43 * DM duration (years) 9.6 ± 7.8 7.8 ± 7.1 0.23 WC (cm) 0.39 Male 90.2 ± 8.7 85.9 ± 11.1 0.212 Female 89.9 ± 14.2 82.8 ± 8.2 0.24 BMI (kg/m 2 ) 25.1 ± 20.6 21.5 ± 2.8 0.398 SBP (mm Hg) 131.8 ± 19.0 121.8 ± 27.5 0.014 DBP (mm Hg) 82.7 ± 11.4 83.1 ± 14.6 0.862 HbA 1c (%) 9.2 ± 11.0 9.7 ± 2.8 0.819 TC (mg/dl) 181.9 ± 54.9 183.0 ± 52.3 0.913 HDL-C (mg/dl) 45.3 ± 15.9 53.5 ± 15.1 0.011 LDL-C (mg/dl) 115.7 ± 47.6 109.2 ± 44.7 0.483 TG (mg/dl) 161.7 ± 126.3 156.2 ± 111.0 0.816 FFA (μeq/l) 707.7 ± 406.3 709.1 ± 257.6 0.989 FBS (mg/dl) 164.4 ± 91.7 171.7 ± 101.4 0.715 Fasting C-peptide (ng/ml) 2.99 ± 3.17 1.30 ± 1.20 < 0.001 Stimulated C-peptide (ng/ml) 5.06 ± 4.28 1.66 ± 1.58 < 0.001 Treatment (n) Diet/OHA/insulin-based 32 (8.0) / 255 (63.6) / 114 (28.4) 0 (0) / 10 (38.5) / 16 (61.5) 0.001 * No/antihyperlipidemic 301 (75.1) / 100 (24.9) 18 (62.9) / 8 (30.8) 0.507 * No/antihypertensive 290 (72.3) / 111 (27.7) 21 (80.8) / 5 (19.2) 0.348 * Data are mean ± standard deviation. Number in parenthesis is percentage. * Analyzed by Student s T-test or by χ 2 test. BMI, body mass index; DBP, diastolic blood pressure, DM, diabetes mellitus; FBS, fasting blood glucose; FFA, free fatty acid; GAD, glutamic acid decarboxylase; GAD antibody-negative, patients without GAD antibody; GAD antibody-positive, patients with GAD antibody; HDL-C, high-density lipoprotein cholesterol; insulin-based, insulin based treatment including insulin treatment and the combination treatment of insulin and OHA; LDL-C, low-density lipoprotein cholesterol; OHA, oral hypoglycemic agent; SBP, systolic blood pressure; TC, total cholesterol; TG, triglyceride; WC, waist circumference. Table 2. The prevalence of chronic complications in diabetic patients with or without GAD antibody GAD antibody-negative GAD antibody-negative (n = 401) (n = 401) P-value Retinopathy Present 192 (47.9) 5 (19.2) 0.005 Nephropathy Present 190 (47.4) 11 (42.3) 0.615 Polyneuropathy Present 245 (61.1) 13 (50.0) 0.262 Autonomic neuropathy Present 128 (31.9) 10 (38.5) 0.489 CHD Present 45 (11.2) 2 (7.7) 0.755 * CVD Present 33 (8.2) 3 (11.5) 0.472 * PAD Present 25 (6.2) 3 (11.5) 0.238 * Number in parenthesis is percentage. * Analyzed by χ 2 test or by Fisher s exact test. CHD, coronary heart disease; CVD, cerebrovascular disease; GAD, glutamic acid decarboxylase; GAD antibody-negative, patients without GAD antibody; GAD antibody-positive, patients with GAD antibody; PAD, peripheral arterial disease. 2. GAD 자가항체유무에따른만성합병증과의관계 당뇨병성미세혈관합병증의유병률을비교하였을때당뇨병성망막병증은 GAD 자가항체양성환자가 19.2% (5/26), GAD 자가항체음성환자가 47.9% (192/401) 로 GAD 자가항체양성환자에서유의하게낮았다 (P = 0.005, Table 2). 당뇨병성신증의유병률은 GAD 자가항체양성환자에서 42.3% (11/26), GAD 자가항체음성환자에서 47.4% (190/401) 127
Korean Diabetes J 33:124~133, 2009 로두군사이에유의성은없었다. 당뇨병성말초신경병증은 GAD 자가항체양성환자에서 50% (13/26), GAD 자가항체음성환자에서 61.1% (245/401) 로두군사이에유의성은없었으며, 심혈관계자율신경병증또한 GAD 자가항체양성환자에서 38.4% (10/26), GAD 자가항체음성환자에서 31.9% (128/401) 로두군사이에유의한차이를보이지않았다. 대혈관합병증의유병률을비교하였을때관상동맥질환의유병률은 GAD 자가항체양성환자에서 7.7% (2/26), GAD 자가항체음성환자에서 11.2% (45/401) 로두군사이에유의한차이는없었다. 허혈성뇌혈관질환의유병률도 GAD 자가항체양성환자에서 11.5% (3/26), GAD 자가항체음성환자에서 8% (33/401) 로두군사이에유의성은없었으며, 말초동맥혈관질환의유병률을비교했을때또한 GAD 자가항체양성환자에서 11.5% (3/26), GAD 자가항체음성환자에서 6% (25/401) 로두군사이에유의한차이는관찰되지않았다. 3. GAD 자가항체유무에따른만성합병증과임상및생화학적특성과의관계 GAD 자가항체양성환자에서당뇨병성망막병증유무에따라비교하였을때망막병증이없는환자에비해망막병증이동반된환자에서당뇨병유병기간이더길었으며, GAD 자가항체음성환자에서는망막병증이동반될수록당뇨병유병기간, 총콜레스테롤및저밀도지단백콜레스테롤수치가더높았다 (Table 3). GAD 자가항체양성환자에서당뇨병성신증유무에따라비교하였을때신증이없는환자에비해신증이동반된환자에서식후 C-펩티드가더높았으며 (0.8 ± 0.5 vs. 2.5 ± 1.9 ng/ml, P = 0.02), GAD 자가항체음성환자에서는당뇨병성신증이동반될수록당뇨병유병기간 (7.2 ± 6.4 vs. 12.4 ± 8.5 years, P = 0.001), 수축기혈압 (129.9 ± 14.5 vs. 139.9 ± 22.6 mm Hg, P = 0.046), 총콜레스테롤 (176.5 ± 44.1 vs. 188.6 ± 65.1 mg/dl, P = 0.036) 이더높았다. GAD 자가항체음성환자에서당뇨병성말초신경병증유무에따라비교하였을때말초신경병증이없는환자에비해신경병증이동반될수록당뇨병유병기간 (6.6 ± 6.9 vs. 11.6 ± 7.9 years, P = 0.001), 수축기혈압 (128.3 ± 15.8 vs. 134.6 ± 18.7 mm Hg, P = 0.002), 이완기혈압 (81.2 9.9 vs. 83.8 ± 10.6 mm Hg, P = 0.024) 이더높았으며, GAD 자가항체양성환자에서는말초신경병증유무에따른당뇨병유병기간, 당화혈색소, 수축기혈압, 이완기혈압, 지질수치, 공복혈당및 C-펩티드등에유의한차이는없었다. 1명의 GAD 자가항체양성환자에서관상동맥질환과말초동맥혈관질환을함께가지고있었으며 GAD 자가항체음성환자에서는 3명이관상동맥질환과말초동맥혈관질환, 3 Table 3. Comparison of clinical characteristics according to the presence of retinopathy in patients with or without GAD antibody GAD antibody-negative GAD antibody-positive Retinopathy (-) (n = 209) Retinopathy (+) (n = 192) Retinopathy (-) (n= 21) Retinopathy (+) (n = 5) Age (years) 58.2 ± 13.2 59.2 ± 11.9 53.1 ± 13.4 54.6 ± 15.8 DM duration (years) 6.6 ± 7.0 13.5 ± 7.8 * 7.4 ± 6.5 16.7 ± 4.7 HbA 1c (%) 10.0 ± 6.4 8.8 ± 2.0 9.8 ± 3.1 8.8 ± 2.2 SBP (mm Hg) 130.5 ± 15.9 134.6 ± 20.6 117.3 ± 32.5 125.0 ± 10.0 DBP (mm Hg) 81.7 ± 10.9 83.8 ± 10.8 83.0 ± 16.9 77.5 ± 5.0 TC (mg/dl) 171.9 ± 46.1 192.3 ± 63.7 * 183.1 ± 49.7 199.2 ± 36.3 HDL-C (mg/dl) 44.5 ± 12.4 47.2 ± 18.9 57.3 ± 14.6 48.5 ± 15.3 LDL-C (mg/dl) 108.4 ± 39.2 122.3 ± 58.5 * 106.4 ± 46.0 128.5 ± 32.7 TG (mg/dl) 161.7 ± 129.5 170.0 ± 146.3 133.1 ± 83.6 213.5 ± 146.4 FBS (mg/dl) 178.2 ± 121.3 163.8 ± 71.4 172.4 ± 120.2 178.0 ± 45.1 Fasting C-peptide (ng/ml) 3.03 ± 2.38 2.93 ± 4.29 1.37 ± 1.41 1.12 ± 0.58 Stimulated C-peptide (ng/ml) 5.50 ± 4.65 4.51 ± 4.38 1.90 ± 1.88 1.37 ± 0.66 Data are mean ± standard deviation. * P < 0.05 for retinopathy (-) vs. retinopathy (+) in patients without GAD antibody. P < 0.05 for retinopathy (-) vs. retinopathy (+) in patients with GAD antibody. Analyzed by Student s T-test or by Mann-Whitney test. DM, diabetes mellitus; FBS, fasting blood glucose; GAD, glutamic acid decarboxylase; GAD antibody-negative, patients without GAD antibody; GAD antibody-positive, patients with GAD antibody; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; TC, total cholesterol; TG, triglyceride. 128
정진욱외 3 인 : 성인당뇨병환자에서 GAD 자가항체유무와만성합병증과의관계 Table 4. Comparison of clinical characteristics according to the presence of macrovascular complications in patients with or without GAD antibody GAD antibody-negative GAD antibody-positive Macrovascular (-) (n = 310) Macrovascular (+) (n = 91) Macrovascular (-) (n = 19) Macrovascular (+) (n = 7) Age (years) 57.9 ± 12.7 65.2 ± 10.2 * 48.2 ± 12.1 61.6 ± 11.1 DM duration (years) 8.7 ± 7.4 12.6 ± 8.5 * 6.5 ± 6.4 11.4 ± 8.3 BMI (kg/m 2 ) 25.6 ± 23.5 23.7 ± 3.5 21.5 ± 3.0 21.4 ± 2.4 HbA 1c (%) 9.5 ± 2.5 8.3 ± 1.8 10.1 ± 3.1 8.7 ± 1.7 SBP (mm Hg) 131.4 ± 18.7 133.2 ± 19.9 123.8 ± 13.7 116.7 ± 49.5 DBP (mm Hg) 82.5 ± 11.7 83.0 ± 10.4 80.5 ± 9.3 89.7 ± 23.1 TC (mg/dl) 184.9 ± 57.4 171.5 ± 44.5 * 172.9 ± 53.1 210.5 ± 41.5 HDL-C (mg/dl) 45.6 ± 16.4 44.1 ± 14.2 52.3 ± 14.3 56.7 ± 17.7 LDL-C (mg/dl) 118.1 ± 48.7 107.5 ± 42.8 104.2 ± 43.7 122.8 ± 47.8 TG (mg/dl) 167.0 ± 133.1 144.0 ± 98.9 148.4 ± 109.0 176.4 ± 122.3 FBS (mg/dl) 166.0 ± 97.6 159.3 ± 69.8 173.3 ± 116.9 168.2 ± 59.3 Fasting C-peptide (ng/ml) 2.95 ± 3.35 3.12 ± 2.49 0.93 ± 0.64 2.30 ± 1.78 Stimulated C-peptide (ng/ml) 5.11 ± 4.52 4.87 ± 3.43 1.28 ± 1.05 2.73 ± 2.37 Data are mean ± standard deviation. Macrovascular complications include coronary heart disease, cerebrovascular disease and peripheral arterial disease. * P < 0.05 for macrovascular (-) vs. macrovascular (+) in patients without GAD antibody. P< 0.05 for macrovascular (-) vs. macrovascular (+) in patients with GAD antibody. Analyzed by Student s T-test or by Mann-Whitney test. BMI, body mass index; DM, diabetes mellitus; FBS, fasting blood glucose; GAD, glutamic acid decaroxylase; GAD antibody-negative, patients without GAD antibody; GAD antibody-positive, patients with GAD antibody; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; macrovascular (-), patients without macrovascular complications; macrovascular (+), patients with macrovascular complications; TC, total cholesterol; TG, triglyceride. 명이관상동맥질환과허혈성뇌혈관질환, 4명이허혈성뇌혈관질환과말초동맥혈관질환을함께가지고있었고 1명은관상동맥질환, 허혈성뇌혈관질환및말초동맥혈관질환을모두가지고있었다. GAD 자가항체양성환자에서대혈관합병증유무에따라비교하였을때대혈관합병증이동반된환자에서연령과공복 C-펩티드가높았으며, GAD 자가항체음성환자에서는대혈관합병증이동반된환자에서연령, 당뇨병유병기간이높았고총콜레스테롤은낮았다 (Table 4). 고찰본연구에서 GAD 자가항체음성환자와비교하여 GAD 자가항체양성인환자에서고밀도지단백콜레스테롤이더높았으며수축기혈압, 공복및식후 C-펩티드는더낮았고, 만성합병증중당뇨병성망막증의유병률이더낮았다. 하지만그외다른만성미세혈관합병증과대혈관합병증의유병률의차이는없었다. GAD 자가항체는췌장소도세포의질량 64,000의단백에반응하는자가항체로새로진단되는제1형당뇨병환자의 약 50~80% 에서관찰되는것으로알려져있다 16). 국내보고에의하면초기에제2형당뇨병으로진단된환자에서도약 3~13% 에서 GAD 자가항체가발견된다 14,17). 자가면역기전에의해당뇨병이급속히진행되는제1형당뇨병과는달리제2형당뇨병환자에서 GAD 자가항체가양성인경우자가면역기전에의한베타세포의파괴가서서히일어나서초기에는제2형당뇨병의양상을보이지만시간이경과하면서인슐린의존형으로되며이러한환자들을 latent autoimmune diabetes in adults (LADA) 로정의하기도한다 2). 본연구에서 GAD 자가항체양성환자에서 GAD 자가항체음성환자보다공복및식후 C-펩티드가더낮아 GAD 자가항체를가지고있는환자의경우베타세포의기능감소가더현저함을알수있었다. 이러한결과는 GAD 자가항체양성인환자는상대적인인슐린결핍을보였다는다른연구들과비슷한결과를보였다 18,19). Littorin 등은제2형당뇨병으로진단된환자에서진단당시에 GAD 자가항체의존재는향후인슐린치료에대한필요성을예측할수있다고보고하였으며 20), Niskanen 등은새로진단된 GAD 자가항체양성당뇨병환자는약 50% 에서글루카곤자극시 C-펩티드가 0.7 nmol/l를보였으며 GAD 자가항체음성인환자에서는약 129
Korean Diabetes J 33:124~133, 2009 3% 에서 C-펩티드가 0.7 nmol/l 미만을보였다고보고하였다 21). 따라서이러한결과들은 GAD 자가항체를가지고있는환자에서는자가항체음성인제2형당뇨병과달리인슐린저항성보다인슐린결핍이당뇨병발병의더주된요인이될수있음을시사한다. GAD 자가항체음성인환자보다 GAD 자가항체양성인환자에서더마른체형을보였다는 Tuomi 등의보고 9) 와는달리본연구에서는 GAD 자가항체양성환자에서 GAD 자가항체음성환자보다허리둘레와체질량지수가더낮은경향은보였으나유의한차이를보이지않았다. 이는서구환자들에서제2형당뇨병이국내의환자보다비만한경우가많으며국내환자들의경우는비만하지않은환자에서도당뇨병이환율이높다는것과관련될것으로생각된다 22). GAD 자가항체를가진당뇨병환자에서당뇨병성미세혈관합병증에관한몇개의연구결과들이보고되고있다. Owen 등은 45세이하의비교적젊은제2형당뇨병환자를대상으로비교하였을때 GAD 자가항체양성과음성환자에서망막병증과미세알부민뇨의유병률은차이가없었다고보고하였다 23). Baum 등은 5년이내의비교적짧은당뇨병유병기간을가진제2형당뇨병환자를대상으로한연구에서 GAD 자가항체양성환자가 GAD 자가항체음성인환자에비해말초신경병증과자율신경병증의발생이더적다고보고하였으나 24), Vinik 등은 GAD 자가항체역가와당뇨병성신경병증의정도와는관련성이없다고하였다 25). 본연구에서만성미세혈관합병증을비교하였을때말초신경병증, 심혈관계자율신경병증및신증의유병률은두군사이에유의한차이가없었지만 GAD 자가항체양성환자에서망막병증의유병률은 19.2% 로 GAD 자가항체음성환자의 47.9% 에비해유의하게낮았다. 또한당뇨병유병기간이길수록당뇨병성망막병증의위험이증가하는경향을보였다. 본연구결과와유사하게문등은제1형당뇨병과 LADA 환자를대상으로한연구에서 GAD 자가항체양성인환자에서 GAD 자가항체음성인환자에비해당뇨병성망막병증의유병률이낮음을보고하여 GAD 자가항체가당뇨병성망막병증의발생에있어예방적역할을할수있을것으로제안하였다 26). 이에반하여본연구결과와다르게 Balme 등은제2형당뇨병환자에서 GAD 자가항체음성환자보다 GAD 자가항체양성환자에서당뇨병성망막병증의유병률이더높다고보고하였다 12). 하지만이러한결과는두군사이에혈당조절상태에차이가없었던본연구와달리 GAD 자가항체음성환자보다양성환자에서더높았던혈당상태가영향을미쳤을것으로생각된다. 인슐린저항성에의해발생하는고혈당, 고혈압, 고지혈증, 비만의각인자들이한개체에서동시에군집해서발생하여심혈관계발생위험을증가시키는것을대사증후군이라명명하며인슐린저항성이중심적역할을하는것으로알려져있다 27). 대사증후군은제2형당뇨병에서흔히관찰되며, 대사증후군이동반되지않은경우보다당뇨병과대사증후군이동반되는경우심혈관질환발생의위험이더증가한다고보고되었다 28). 따라서본연구에서는 GAD 자가항체양성환자와 GAD 자가항체음성환자에서의대혈관합병증의유병율을비교하였다. 대혈관합병증의발생과관련하여 Myhill 등은 1,294명을대상으로한전향적연구에서 GAD 자가항체양성인환자와음성인환자에서관상동맥질환과뇌혈관질환의발생에서차이가없었다고보고하였다 13). 본연구에서도관상동맥질환, 허혈성뇌혈관질환및말초동맥혈관질환의유병률을비교하였을때 GAD 자가항체유무에따른차이는관찰되지않았다. 수축기고혈압과고밀도지단백콜레스테롤이외에도통계학적유의성은없었으나대사증후군의관련인자들인허리둘레, 체질량지수, 중성지방이 GAD 자가항체양성환자에서더좋은경향을보였으나심혈관질환의유병률은차이가없었다. 따라서본연구결과는 GAD 자가항체양성환자에서대사증후군에관련된인자이외에도심혈관질환을예방하기위해서다양한심혈관질환의위험인자에대한집중적인관리가필요함을시사한다. 본연구에서 GAD 자가항체양성인환자에서 GAD 자가항체음성인환자에비해당뇨병성망막병증의유병률이더낮았으나그외미세혈관합병증및대혈관합병증의유병률은차이를보이지않았다. 이는 GAD 자가항체양성인환자에서당뇨병성망막병증의발생위험이더낮다는것을시사한다. 그러나단면적연구였다는점과 GAD 자가항체음성환자군에비해상대적으로 GAD 자가항체양성환자군이적었다는점을본연구의한계점으로들수있다. 따라서 GAD 자가항체양성환자에서자가항체음성환자에비해망막병증이더낮게발생하는요인에대해서더많은환자군을대상으로한전향적연구가필요할것으로사료된다. 요약연구배경 : 제2형당뇨병환자의대부분은비면역학적기전에의해발생하지만초기에제2형당뇨병으로진단되었던일부환자에서는 GAD에대한항체를지니고있다. 이러한환자에서는베타세포기능감소가더현저하며마른체형및고혈당의빈도가더높다고보고된다. 따라서이러한점 130
정진욱외 3 인 : 성인당뇨병환자에서 GAD 자가항체유무와만성합병증과의관계 들은만성미세혈관합병증이나대혈관합병증의발생에있어서인슐린저항성을특징으로하는전형적인제2형당뇨병과는다른양상을보일수있을것으로생각된다. 본연구는성인당뇨병환자에서 GAD 자가항체유무와당뇨병성만성미세혈관합병증및대혈관합병증발생과의관련성을알아보고자하였다. 방법 : 35세이후에임상적으로제2형당뇨병으로진단된환자들중 GAD 자가항체측정과당뇨병성합병증에대한평가가이루어진환자들을대상으로단면적분석을실시하였다. 신장, 체중, 체질량지수및허리둘레를측정하였고, 혈장혈당, C-펩티드, GAD 자가항체, 인슐린농도, 당화혈색소, 총콜레스테롤, 중성지방, 고밀도지단백콜레스테롤, 저밀도지단백콜레스테롤, 유리지방산을측정하였다. GAD 자가항체는 0.9 U/mL를초과하는경우 GAD 자가항체양성으로정의하였다. 당뇨병성미세혈관합병증에대한평가를위해서안저촬영, 진동감각역치검사, 신경전도검사및미세알부민뇨검사를실시하였다. 대혈관합병증의유무를확인하기위해관상동맥질환, 허혈성뇌혈관질환및말초동맥혈관질환을평가하였다. 결과 : 총 427명의환자중 GAD 자가항체양성인환자는 26명이었으며 GAD 자가항체음성인환자는 401명이었다. GAD 자가항체양성환자에서수축기혈압이낮았으며고밀도지단백콜레스테롤은높았다 (P < 0.05). 또한 GAD 자가항체양성환자에서공복 C-펩티드와식후 C-펩티드모두유의하게낮았다 (P < 0.001). 당뇨병성미세혈관합병증의유병률을비교하였을때당뇨병성망막병증은 GAD 자가항체양성환자가 19.2%, GAD 자가항체음성환자가 47.9% 로 GAD 자가항체양성환자에서유의하게낮았다 (P < 0.05). 그외신증, 말초신경병증및심혈관계자율신경병증은두군사이에유의한차이를보이지않았다. 대혈관합병증의유병률을비교하였을때관상동맥질환의유병률은 GAD 자가항체양성환자에서 7.7%, GAD 자가항체음성환자에서 11.2% 로두군사이에유의한차이는없었다 (P = 0.755). 또한허혈성뇌혈관질환및말초동맥혈관질환의유병률을비교했을때두군사이에유의한차이는관찰되지않았다. 결론 : GAD 자가항체양성인환자에서자가항체음성환자에비해당뇨병성망막병증의유병률이더낮았으나그외미세혈관합병증과대혈관합병증의유병률의차이는없었다. 따라서 GAD 자가항체양성환자에서자가항체음성환자에비해망막병증이더낮게발생하는요인에대해서더많은환자군을대상으로한전향적연구가필요할것으 로사료된다. 참고문헌 1. Landin-Olsson M, Palmer JP, Lernmark A, Blom L, Sundkvist G, Nyström L, Dahlquist G: Predictive value of islet cell and insulin autoantibodies for type 1 (insulin-dependent) diabetes mellitus in a population-based study of newly-diagnosed diabetic and matched control children. Diabetologia 35:1068-73, 1992 2. Tuomi T, Groop LC, Zimmet PZ, Rowley MJ, Knowles W, Mackay IR: Antibodies to glutamic acid decarboxylase reveal latent autoimmune diabetes mellitus in adults with a non-insulin-dependent onset of disease. Diabetes 42:359-62,1993 3. UK Prospective Diabetes Study Group: UKPDS 25: autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. Lancet 350:1288-93, 1997 4. Zimmet PZ, Tuomi T, Mackay IR, Rowley MJ, Knowles W, Cohen M, Lang DA: Latent autoimmune diabetes mellitus in adults (LADA): the role of antibodies to glutamic acid decarboxylase in diagnosis and prediction of insulin dependency. Diabet Med 11:299-303, 1994 5. Skyler JS: Diabetic complications. The importance of glucose control. Endocrinol Metab Clin North Am 25:243-54, 1996 6. Wagenknecht LE, D'Agostino RB Jr, Haffner SM, Savage PJ, Rewers M: Impaired glucose tolerance, type 2 diabetes, and carotid wall thickness: the Insulin Resistance Atherosclerosis Study. Diabetes Care 21:1812-8, 1998 7. Birkeland KI, Kilhovd B, Thorsby P, Torjesen PA, Ganss R, Vaaler S, Hanssen KF: Heterogeneity of non-insulin-dependent diabetes expressed as variability in insulin sensitivity, beta-cell function and cardiovascular risk profile. Diabet Med 20:37-45, 2003 8. Lehto S, Rönnemaa T, Pyörälä K, Laakso M: Cardiovascular risk factors clustering with endogenous 131
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