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1 원저 GAD 자가항체양성인당뇨병환자에게서당뇨병성망막병증의유병률 영남대학교의과대학내과학교실, 핵의학교실 1 문선중 이찬희 문준성 문희정 이지은 천경아 1 윤지성 조인호 1 원규장 이형우 Prevalence of Diabetic Retinopathy in Diabetics Who are Positive for GAD Autoantibody Seon Joong Moon, Chan Hee Lee, Jun Sung Moon, Hee Jung Moon, Ji Eun Lee, Kyung Ah Chun 1, Ji Sung Yoon, Ihn Ho Cho 1, Kyu Chang Won, Hyoung Woo Lee Department of Internal Medicine, Department of Nuclear Medicine 1, College of Medicine, Yeungnam University Abstract Background: Diabetic retinopathy is a leading cause of adult blindness. Some patients show early development and progression of diabetic retinopathy despite of apparently good glycemic control. This is suggesting the involvement of other contributing factors. Recent studies have shown that retinopathy and GAD autoantibody (GADA) show an inverse relationship immunologically. This study is designed to investigate the clinical manifestation of diabetes who are positive for GADA and the relationship between GADA and diabetic retinopathy. Methods: Type 1 diabetic patients & LADA patients who had visited Yeungnam university Medical Center from 1988 to 2005 were involved. We reviewed the pathologic and laboratory records of these patients and investigated the development of diabetic microvascular complications. Results: Compared with patients who had GADA negative diabetes, patients with GADA positive diabetes had lower prevalence of diabetic retinopathy (GADA negative subject: 25.8% vs. GADA positive subject: 9.6%, P < 0.05). Conclusion: We confirmed that diabetic retinopathy and GADA showed an inverse relationship. It seems quite probable that GADA may contribute to the prevention of retinopathy. Further research should be needed concerning the effect of GADA on diabetic retinopathy. (J Kor Diabetes Assoc 31:429~434, 2007) Key Words: Diabetic retinopathy, GAD autoantibody, Late autoimmune diabetes in adults (LADA), Type 1 diabetes 서론당뇨병성망막병증은당뇨병의미세혈관합병증으로성인실명의가장흔한원인이며 1), 이의발생기전, 치료및예방등에대한많은연구가보고되고있다 2). 당뇨병환자에서망막병증의발생위험인자들로는다른미세혈관합병증과같이만성적인고혈당과당뇨병의유병기간등이잘알려져있으나 3), 혈당조절이잘되는환자들에서당뇨병초기에당뇨병성망막병증이발생할수있고, 혈당조절이불량한환자에서도오랜기간동안당뇨병성망막병증이발생되지않는경우도보고되고있다 4). 제1형당뇨병의발생기전에매우중요한역할을하는것으로알려져있는췌도항원에대한혈청자가항체들중하나인 glutamic acid decarboxylase (GAD) 자가항체 5) 와당뇨병성미세혈관합병증과의연관성에대한연구도최근보고되고있다 4). 당뇨병쥐를대상으로시행한연구에따르면망막이허혈상태로변하게되면망막의 muller 세포내에 γ-aminobutyric acid (GABA) 가축적되며, GABA의축적이당뇨병성망막병증의발생과진행에영향을미칠것이라보고하였다 6,7). 당뇨병성망막병증은대부분허혈성망막에서발생하고 GAD는 glutamate를 GABA로전환시키는효소로서 8) GAD 자가항체와당뇨병성망막병증은역의상 접수일자 : 2007 년 6 월 1 일, 통과일자 : 2007 년 8 월 21 일, 책임저자 : 이형우, 영남대학교의과대학내과학교실 429

2 Table 1. Clinical characteristics of subjects GADA Positive Negative Number Age (years) ± ± 1.57 Sex (M/F) 23/29 19/15 Hypertension (-/+) 40/11 27/4 diastolic BP (mmhg) ± ± 1.93 systolic BP (mmhg) ± ± 2.83 BMI (kg/m 2 ) ± ± 0.77 smoking (-/+) 37/15 17/15 ESR (mm/h) ± ± 6.66 GGT (U/L) ± ± 3.06 FBS (mg/dl) 221 ± ± PPBS (mg/dl) ± ± Fasting C-peptide (ng/ml) 1.15 ± ± pp C-peptide (ng/ml) 2.30 ± ± 0.09 HbA1c (%) ± ± 0.70 Total cholesterol (mg/dl) ± ± TG (mg/dl) ± ± 8.70 HDL (mg/dl) ± ± 3.15 DM duration (years) 4.02 ± ± 0.84 M, male; F, female; BP, blood pressure; BMI, body mass index; FBS, fasting blood sugar; 2PP, 2hours post prandial; GADA, GAD autoantibody. P < 관관계를가진다는보고가있다 4,9,10). 이에저자등은 GAD의활동성을감소시킬수있는 GAD 자가항체와당뇨병성망막병증과의연관성에대해알아보고자본연구를시행하였다. 대상및방법 1. 연구대상및방법 1988년부터 2005년까지영남대학교병원에서치료를받은당뇨병환자들중 GAD 자가항체양성인제1형당뇨병및 latent autoimmune diabetes in adults (LADA) 환자 52 명과 GAD 자가항체음성인제1형당뇨병환자 34명을대상으로내원당시신체계수, 혈압, 체질량지수, 지질농도, 간기능, HbA1c, 공복및식후혈당, 공복및식후 insulin/cpeptide 측정치, 고혈압, 및당뇨병성합병증유무등을단면적연구를통해조사하였다. 제1형당뇨병은절대적인인슐린분비장애 (C-peptide < 1.2 ng/ml) 가있으면서췌도항원에대한혈청자가항체들인 GAD 11) 또는 insulin 12) 에대한자가항체가양성인환자로정의하였으며, LADA는 immunology of Diabetes Society의기준에따라 30세이상이면서제1형당뇨병에서발견되는췌도항원에대한자가항체가최소 1개이상양성이고진단초기에 insulin 치료가 필요없었던환자들로정의하였으며 13), 대상환자들은모두인슐린으로혈당을조절중이였다. GAD 자가항체의측정에는영국 RSR사의 125 I-labelled human GAD kit를사용하였다. 혈청 20 μl와 eukaryocytic recombinant production system을이용하여만든 125 I-labelled GAD 50 μl를혼합하여실온 (20~25 ) 에서 2시간배양후 solid phase protein A 50 μl를추가하여실온에서 1시간더배양하였다. 2~8 사이의 assay buffer 1 ml를첨가한후 4 에서 1500 g로 30분간원심분리하여상층액을제거하고감마카운터로 1 분정도 123 I를측정하여, 1.45 U/mL 초과한경우를 GAD 자가항체양성으로정의하였다. 모든대상환자들에서안저검사를시행하였으며안저검사상증가된혈관투과성, 미세동맥류, 유리체출혈, 미세경색, 점상출혈, 면화반, 신생혈관, 망막박리, 및확장된정맥등의소견중한가지이상의소견이있는환자를당뇨병성망막병증으로진단하였으며비증식성당뇨병성망막병증과증식성망막병증의구분은시행하지않았다. 당뇨병성신병증은 spot 소변에서알부민이 30 μg/mg creatinine 이상으로소변으로배출되는환자에서미세단백뇨와현성단백뇨를구분하지않고정의하였으며, 당뇨병환자에서신경전도속도검사에서명확한신경병증의소견이있으면서손발저림, 통증, 감각이상등의증상이있을때당뇨병성신경병증으로진단하였다. 고 430

문선중외 9 인 : GAD 자가항체양성인당뇨병환자에게서당뇨병성망막병증의유병률 Diabetic nephropathy Table 2. Relationship between GADA and diabetic nephropathy & neuropathy GADA Positive Negative P-value Present 20 (38.5) 15 (48.4) 0.

3 문선중외 9 인 : GAD 자가항체양성인당뇨병환자에게서당뇨병성망막병증의유병률 Diabetic nephropathy Table 2. Relationship between GADA and diabetic nephropathy & neuropathy GADA Positive Negative P-value Present 20 (38.5) 15 (48.4) Absent 32 (61.5) 16 (51.6) - Total Diabetic Present 17 (32.7) 15 (48.4) neuropathy Absent 35 (67.3) 16 (51.6) - Total Number in parentheses are percentage. GADA, GAD autoantibody. Fig. 1. Prevalence of diabetic retinopathy according to GADA. The prevalence of diabetic retinopathy is significantly lower in GADA positive patients group compared with GADA negative patients group. 혈압은 2003 ESH/ESC Hypertension Guidelines 14) 에서제시한진단기준에의해수축기혈압 140 mmhg 이상또는이완기혈압 90 mmhg 이상이거나, 현재고혈압약제를복용중인환자로정의하였다. 2. 통계분석 모든통계처리에는 SPSS 13.0 for Windows를사용하였으며모든자료는평균 ± 표준오차로표시하였다. 연속변수분석은 Leven's test를사용하였으며명목변수분석은 Chi-square test를사용하였고통계의유의수준은 95%, 신뢰구간은 P값 0.05 미만으로정의하였다. 결 GAD 자가항체양성환자군의평균나이는 ± 2.59 세, GAD 자가항체음성환자군의평균나이는 ± 1.57세로두환자군사이에유의한차이가있었으며 (P < 0.01), GAD 자가항체양성환자군은남성이 44% ( 남자 23 과 명, 여자 29명 ), GAD 자가항체음성환자군은남성이 56% ( 남자 19명, 여자 15명 ) 로두군사이에유의한차이가없었다 (Table 1). GAD 자가항체양성환자군과음성환자군의공복혈당은 ± mg/dl와 ± mg/dl로 GAD 자가항체양성환자군에서음성환자군에비해유의하게낮았다 (P < 0.05). GAD 자가항체양성환자군의공복 C-peptide와식후 C-peptide는 1.15 ± 0.23 ng/ml 및 2.30 ± 0.45 ng/ml였고, GAD 자가항체음성환자군의공복 C-peptide와식후 c-peptide는 0.29 ± 0.05 ng/ml 및 0.50 ± 0.09 ng/ml로두가지모두 GAD 자가항체양성환자군에서음성환자군에비해유의하게높았다 (P < 0.05, Table 1). 당뇨병유병기간, 이완기및수축기혈압, 체질량지수, 흡연력, 식후혈당, HbA1c, GGT, total-cholesterol, triglyceride, HDL-cholesterol, 및 LDL-cholesterol 측정치는 GAD 자가항체양성환자군과음성환자군사이에서유의한차이가없었다 (Table 1). 당뇨병성망막병증의유병률은 GAD 자가항체양성환자군에서 52명중 5명인 9.6%, GAD 자가항체음성환자군에서 31명중 8명인 25.8% 로 GAD 자가항체양성환자군에서유의하게낮았다 (P < 0.05, Fig. 1). 당뇨병성신병증의유병률은 GAD 자가항체양성환자군에서 52명중 20명인 38.5%, GAD 자가항체음성환자군에서 31명중 15명인 48.4% 로 GAD 자가항체양성환자군에서낮았으나유의성은없었으며, 당뇨병성신경병증의유병률도 GAD 자가항체양성환자군에서 52명중 17명인 32.7%, GAD 자가항체음성환자군에서 31명중 15명인 48.4% 로 GAD 자가항체양성환자군에서낮았으나유의성은없었다 (Table 2). 고혈압의유병률은 GAD 자가항체양성환자군에서 52 명중 11명인 21.6%, GAD 자가항체음성환자군에서 31 명중 4명인 14.8% 로 GAD 자가항체양성환자군에서유의하게높았다 (P < 0.05, Table 3). 431

4 Table 3. Relationship between GADA and hypertension GADA Positive Negative P-value Hypertension Present 11 (21.6) 4 (14.8) Absent 40 (78.4) 27 (85.2) - Total Number in parentheses are percentage. GADA, GAD autoantibody. 고찰 Sarah 등은전세계적으로당뇨병의유병률이 2000년 2.8% 에서 2030년 4.4% 로꾸준히증가할것이라보고하였으며 15), 최근서구에선당뇨병이성인실명의주요원인으로알려져있다 1). 당뇨병은녹내장, 백내장, 각막손상및홍채의신생혈관생성등의안과적합병증과연관성이있으며그중실명의주된원인이되는합병증은당뇨병성망막병증이다 16). 일부연구에서당뇨병성망막병증중증도와 GAD 자가항체사이에역의상관관계가있으며당뇨병성망막병증이없는환자들에게서 GAD 자가항체의비율이더높다는보고가있다 4,9,10,17). 이에저자는제1형당뇨병환자에서당뇨병성망막병증의발생과 GAD 자가항체의연관성에대해조사하였다. Mimura 등은 80명의제1형당뇨병환자들을대상으로 GAD 자가항체와당뇨병성망막병증과의연관성에대해알아본연구에서증식성당뇨병성망막병증을가진 22명의환자중 GAD 자가항체양성환자가 4명 (18.2%), GAD 자가항체음성환자는 18명 (81.8%) 이였으며, 비증식성당뇨병성망막병증을가진 26명의환자중 GAD 자가항체양성환자가 8명 (30.8%), GAD 자가항체음성환자는 18명 (69.2%) 으로 GAD 자가항체양성환자에서당뇨병성망막병증의유병률이낮았다고보고하였다 4). 당뇨병쥐의망막에서신경전도물질을포함한자유아미노산의여러변화가발생하며, 특히초기당뇨병쥐의망막에서 Glycine과 GABA가증가되어있다는보고가있다 17,18). Perry 등은허혈상태와같은산성화환경에서 GAD 활성도는지속적으로유지된다고하였으며 20), Hall 등은허혈상태와같은산성환경의망막에서 GABA transaminase 활성도는감소된다고보고하였다 21). 허혈상태의망막에서 GAD 활성도는상대적으로증가되고 GABA transaminase의활성도는감소되어 GABA가망막의 Mϋller 세포에축적되게된다 7,19). 따라서, 장기간의고혈당및허혈로인해망막이산성화환경으로변하게되면 GAD 자가항체는 GAD 활성도를억제하여망막의 Mϋller 세포에 GABA 축적을감소시키고당뇨병성망막병증발생을억제시키는역할을할수있을것으로생각된다. 본연구에서도당뇨병성망박병증의유병률은 GAD 자가항체양성환자군에서음성환자군보다유의하게낮음을알수있었으나 (9.6% vs. 25.8%, P < 0.05), 당뇨병성신병증과신경병증의유병률은 GAD 자가항체양성환자군과음성환자군사이에유의한차이가없었다. Hermitte 등은 GAD 자가항체와 IA-2 자가항체가당뇨병성미세혈관합병증과연관성이없다고보고하였으며 22) Viktoria 등은제1형당뇨병환자를대상으로시행한연구에서자율신경병증과연관성이있는자율신경자가항체 (autonomic nerve autoantibody, ANabs) 양성인군에서 GAD 자가항체는오히려낮음을보고하였다 23). HLA 표현형중 HLA-DR3, -DR4, -DR9는제1형당뇨병의병인과연관성이있는것으로알려져있다 24-26). HLA -DQ4는증식성당뇨병성망막병증을동반한젊은제1형당뇨병과연관성이있으며, 당뇨병성망막병증환자에서비당뇨병성망막병증환자군에비해유의하게더높다는보고가있다 27). HLA-DR4 및 HLA-DR3/4, HLA- DR4/9는제1형당뇨병발생과는연관성이있지만당뇨병성망막병증의발생과는연관성이없는것으로보고되고있다 10). 제1 형당뇨병환자에서 GAD 자가항체는 HLA-DR4 및 HLA- DR3/4, DLA-DR4/9와밀접한연관성이있고, HLA-DR4/-DQ4 halotype 을가지는환자에게서 GAD 자가항체의비율이더낮다는보고가있으며 27), Mimura등은 GAD 자가항체와 HLA-DR4, /HLA-DQ4사이에역의상관관계가있다는보고하였다 10). 본연구에서당뇨병성망막병증발생과연관성이있다고알려져있는나이 28), 고혈압의유병률은 29) 오히려 GAD 자가항체양성환자군이음성환자군에비해더높았으며공복혈당은 GAD 자가항체음성환자군이양성환자군에비해높았으나이는내원당시 1회측정값으로환자의평균혈당조절을나타내는 HbA1c는유의한차이가없었다. 본연구는소규모의환자를대상으로실행되어졌으며, 당뇨병의만성합병증발생에중요한요소중하나인당뇨병의유병기간이 30) 두환자군모두 4~5년정도로짧지만, 두군사이에유의한차이가없었기때문에 GAD 자가항체유무에따른망막병증유병률을비교할때결과에큰영향은없을것으로생각된다. GAD 자가항체양성환자군에서음성환자군에비해공복및식후 C-peptide가높았으며이는 GAD 자가항체양성환자군내에 LADA 환자가포함되어있 432

5 문선중외 9 인 : GAD 자가항체양성인당뇨병환자에게서당뇨병성망막병증의유병률 기때문이라생각된다. LADA는제1 형당뇨병과상당한이질적인부분이있지만췌도항원에대한자가항체와 T-cell 반응등유사한부분또한많다고보고되고있으며 13), C-peptide와당뇨병성망막병증유병률및중증도는유의한연관성이없다는보고도있다 31). Biesenbach 등의연구에따르면제1형당뇨병과 LADA 사이에당뇨병성미세혈관합병증 ( 망막병증, 신경병증, 신병증 ) 의유병률은유의한차이가없었다 32). 이상의결과로당뇨병환자들에서 GAD 자가항체는당뇨병성망막병증발생에예방적인역할을할수도있을것으로생각되며, 이의기전에대해서향후더많은수의전향적연구가필요할것으로생각된다. 요약연구배경 : 당뇨병환자에서망막병증을비롯한미세혈관합병증발생에영향을주는주요한요소로는만성적인고혈당과당뇨병의유병기간등이알려져있으나, 혈당조절이잘되는환자들에서당뇨병초기에당뇨병성망막병증이발생하고, 혈당조절이불량한환자에서비교적오랜기간망막병증의발생이되지않는경우를관찰할수있다. Glutamic acid decarboxylase antibody (GADA) 와허혈성망막병증의발생사이에연관성이있다는보고들이있어저자등은 GADA 양성인제1형당뇨병및 LADA 환자와음성인제1 형당뇨병환자에게서당뇨병성망막병증의유병률을조사하여 GADA 와당뇨병성망막병증의연관성에대해알아보고자본연구를시행하였다. 방법 : 1988년부터 2005년까지영남대학교병원을방문한 GAD 자가항체양성인제1형당뇨병및 LADA 환자군 52 명 ( 남자 23, 여자 29) 과 GAD 자가항체음성인제1형당뇨병환자 34명 ( 남자 19, 여자 15) 을대상으로문진및신체계수, 혈압, HbA1c, 지질농도, 간기능검사등을측정하였으며당뇨병성망막병증을비롯한당뇨병성미세혈관합병증및고혈압의유병률을조사하였다. GAD 자가항체는영국 RSR사의 125 I-labelled human GAD kit를사용하여측정하였으며 1.45 U/L 초과인경우를양성으로정의하였다. 결과 : GAD 자가항체양성환자군과음성환자군의평균나이는각각 ± 2.59세와 ± 1.57세였으며두군사이의당뇨병유병기간은유의한차이가없었으며, 공복혈당은 GAD 자가항체양성환자군이음성환자군보다유의하게낮았고 ( ± vs ± mg/dl, P < 0.05), 공복 C-Peptide는 GAD 자가항체양성환자군이음성환자군에비해유의하게높았다 (1.15 ± 0.23 vs ± 0.05 ng/ml, P < 0.05). 당뇨병성망박병증의유병률은 GAD 자가항체양성환자군이음성환자군보다유의하게낮았으며 (9.6% vs. 25.8%, P < 0.05), 당뇨병성신경병증및신병증의유병률은두군사이에유의한차이가없었다. 그외지질농도와간기능검사, HbA1c는두군사이에서유의한차이가없었다. 결론 : 이상의결과에서 GAD 자가항체가당뇨병성망막병증발생에예방적인역할을할수도있을것으로생각되며이에기전에대해서는더많은연구가필요할것으로생각된다. 참고문헌 1. Alaim M, Tim G, Desmond K, Michael O: Cause of blindness in the adult population of the republic of Ireland. Bre J Ophthalmol 82:630-3, Kuiper EJ, de Smet MD, Van Meurs JS, Tan HS, Tanck MW, Oliver N, Van Nieuwenhoven FA, Goldschmeding R, Schlingemann RO: Association of connective tissue growth factor with fibrosis in vitreoretinal disorders in the human eye. Arch Ophthalmol 10: , Sato T, Iwaki M, Shimogaito N, Wu X, Yamagishi S, Takeuchi M: TAGE(toxic AGEs) theory in diabetic complications. Curr Mol Med 6(3):351-8, Mimura T, Funatsu H, Uchigata Y, Kitano S: Development and progression of diabetic retinopathy in patients with Type 1 diabetes who are positive for GAD autoantibody. Diabet Med 21:559-62, Wasserfall CH, Atkinson MA: Autoantibody markers for the diagnosis and prediction of type 1 diabetes. Autoimmun Rev 5:424-8, Lizasoain I, Cardenas A, Hurtado O, Romera C, Mallolas J, Lorenzo P, Castillo J, Moro MA: Targets of Cytoprotection in Acute Ischemic Stroke: Present and Future. Cerebrovascular Disease 21:1-8, Ishikawa A, Ishiguro S, Tamai M: Changes in GABA metabolism in streptozotocin-induced diabetic rat retinas. Curr Eye Res 15:63-71, Connaughton VP, Behar TN, Massey SC: Immunocytochemical localization of excitatory and inhibitory neurotransmitters in the Zebrafish retina. Visual Neuroscience 16:483-90, Mimura T, Funatsu H, Uchigata Y, Kitano S: Relationship between human leukocyte antigen status and proliferative diabetic retinopathy in patients with younger-onset type 1 diabetes mellitus. Am J Ophthalmol 135:844-8, Mimura T, Funatsu H, Uchigata Y, Kitano S: Glutamic Acid Decarboxylase Autoantibody Prevalence 433

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A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R