Korean Diabetes J 33:16~23, 2009 DOI : 10.4093/kdj.2009.33.1.16 ORIGINAL ARTICLES 한국인성인당뇨병환자에서항 GAD 항체양성률 울산대학교의과대학서울아산병원내분비내과 이상아ㆍ김의영ㆍ김은희ㆍ정지윤ㆍ정은희ㆍ김동우ㆍ조은희ㆍ고은희ㆍ김민선ㆍ박중열ㆍ이기업 Anti-GAD Antibody in Patients with Adult-Onset Diabetes in Korea Sang Ah Lee, Eui Young Kim, Eun Hee Kim, Ji Yun Jeong, Eun Heui Jeong, Dong Woo Kim, Eun Hee Cho, Eun Hee Koh, Min Seon Kim, Joong Yeol Park, Ki-Up Lee Department of Internal Medicine, University of Ulsan College of Medicine, Seoul, Korea Abstract Background: It is well known that the clinical characteristics of diabetes mellitus in Korean people are different from those of Western people. The purpose of this study was to investigate the prevalence of the anti-gad antibody (GADA) in a large number of Korean patients with adult-onset diabetes. Methods: The GADA was measured by radioimmunoassay for 11,472 adult-onset diabetic patients who visited the Asan Medical Center from 1998 to 2007. According to the fasting C-peptide levels, we classified the patients into an insulin dependent diabetes mellitus group (IDDM; C-peptide < 0.6 ng/ml) and non-insulin dependent diabetes mellitus group (NIDDM; C-peptide 1.0 ng/ml). Other clinical and laboratory data were obtained from medical records. Results: Among the 11,147 diabetic patients, 9,250 patients were classified as NIDDM, 922 patients were classified as IDDM and 975 patients excluded. Within the latter group 472 patients were to absolute insulin deficient (C-peptide < 0.1 ng/ml). The prevalence of GADA was 22.0% in the IDDM group and 4.7% in the NIDDM group. GADA was more prevalent in younger-onset NIDDM patients (25~40 years of age; 12.4%) than in older-onset NIDDM patients ( 40 years of age; 3.8%). The GADA-positive NIDDM patients had lower C-peptide and BMI levels, and higher rates of typical diabetic symptoms and insulin treatment. Conclusion: The prevalence of GADA in Korean patients with IDDM and NIDDM was lower than that reported in Western populations. It is thus suggested that autoimmunity is a rarer cause of diabetes in Korean people. However, since over 10% of younger-onset NIDDM patients were positive for GADA, routine GADA measurement in such patients is recommended. (Korean Diabetes J 33:16-23, 2009) Key words: Diabetes mellitus, Glutamic acid decarboxylase, Korea, Prevalence 서론 1997년미국당뇨병학회는베타세포파괴로인한당뇨병을제1형당뇨병으로, 인슐린저항성과상대적인슐린분비의감소를특징으로하는당뇨병을제2형당뇨병으로명명 하였다 1). 제1형당뇨병은다시면역학적병인에의한것 (type 1A) 과비면역학적병인에의한것 (type 1B) 으로나누는데면역학적병인과관련된자가항체로는췌도세포질항체 (islet cell autoantibody, ICA) 2), 항인슐린자가항체 (insulin auto-antibody, IAA) 3), 항 GAD (glutamic acid 접수일자 : 2008 년 6 월 16 일, 통과일자 : 2008 년 8 월 19 일교신저자 : 이기업, 울산대학교의과대학내과학교실, E-mail: kulee@amc.seoul.kr 16
이상아외 10 인 : 한국인성인당뇨병환자에서항 GAD 항체양성률 decarboxylase) 항제 4) 등이알려져있다. 이중췌도세포질항체는췌장베타세포의파괴가진행되어인슐린분비능이감소할수록양성률이낮아지지만항 GAD 항체는인슐린분비능과관계없이비교적오랜기간지속적인양성률을보이는것으로보고되었다 5). 한편임상상이나혈액내 C-peptide 농도로판단할때인슐린결핍을보이지않는인슐린비의존형당뇨병환자중에도자가면역기전에의한소위지진형인슐린의존형 (slowly progressive insulin dependent diabetes mellitus, SPIDDM) 6) 이나 latent autoimmune diabetes in adults (LADA) 7) 에속하는당뇨병이일부있다는것이알려졌고, 특히항 GAD 항체가있는환자에서는인슐린의존형당뇨병으로의진행이유의하게증가한다고보고되었다 8,9). 서구인에서와는달리한국인에서의인슐린비의존형당뇨병환자들중비만형보다비비만형이더많다는것은잘알려진사실이다 10-12). 이와같은사실에근거하여한국인인슐린비의존형당뇨병환자특히비비만환자중에서지진형인슐린의존형당뇨병 (SPIDDM) 이흔하지않을까하는생각에베타세포자가항체를측정하는연구가수행되었다. 그렇지만이제까지발표된대부분의국내연구에따르면인슐린비의존형당뇨병에서의자가면역항체양성률은 1.7~5% 정도로서구인에비해낮은경향을보인다 13-17). 한편본교실에서는한국인의경우인슐린의존형당뇨병환자의경우에도베타세포자가항체양성률이서구인에비해매우낮음을보고한바있다 18). 즉한국인에서는제1형당뇨병중에자가면역기전에의한 1A형이외에비자가면역기전의 1B형이다수있으며, 특히미토콘드리아 DNA 3,243점돌연변이가최소한 1년이상인슐린치료가필요하지않았던비전형적인슐린의존형당뇨병환자중 10% 정도에서발견되었다 18). 그러나이연구에서는소아연령에서발병한환자까지포함된인슐린의존형환자를대상으로하였기때문에성인에서발생하는인슐린의존형당뇨병에서자가면역학적요인에의한당뇨병이얼마나되는지는정확히알수없었다. 본연구에서는이제까지국내보고중가장많은환자를대상으로성인당뇨병환자들에서임상형에따른항 GAD 항체발현율을조사하였다. 대상및방법 1. 연구대상 1998년 8월부터 2007년 8월까지 10년간울산의대서울아산병원내분비내과를방문한당뇨병환자를대상으로하였 다. 환자들은 25세이후에당뇨병을진단받은사람들로서이들중 Child-Pugh score C 이상의간질환, 만성신부전, 만성췌장염, 췌장적출술, 다른내분비질환에의해유발된당뇨, 암및장기이식이후에발생한경우등의 2차성원인에의한당뇨병환자는제외하였다. 인슐린비의존형당뇨병환자중항 GAD 항체양성인환자의임상적특징을알아보기위해양성환자 5명중 1명을엑셀의표본추출방법을이용하여임의선택하였고, 이환자들과나이와성별이같은인슐린비의존형당뇨병환자를항 GAD 항체음성군에서두배수로추출하였다 2. 연구방법 1) 병력및신체검사본연구의자료는의무기록검색을통하여얻어졌다. 처음내원당시인슐린과경구혈당강하제중어떤치료를하고있는지와, 당뇨병을진단받은시기, 진단당시다음, 다뇨, 다식과같은증상의유무, 발병당시 2 kg 이상의체중감소유무에대해조사하였다. 가벼운옷차림에신발을벗은상태에서체중과키를쟀고체질량지수 (body mass index, BMI) 는체중 (kg) 을키의제곱 (m 2 ) 으로나누어계산하였다. 2) 혈청학적검사환자들은밤 12시이전부터금식한후다음날아침에공복시 C-peptide와항 GAD 항체및다른화학적검사및당화혈색소를검사하였다. C-peptide는방사면역측정법 (RIA kit, TFB, Tokyo, Japan) 을이용하여측정하였다. 공복시 C-peptide가 1.0 ng/ml 이상인환자들은인슐린비의존형당뇨병으로, 0.6 ng/ml 미만인경우는인슐린의존형당뇨병으로정의하였고 19,20), 이중 0.1 ng/ml 미만인경우는절대적인슐린결핍이있는인슐린의존형당뇨병이라고정의하였다. C-peptide가 0.6 ng/ml 이상 1 ng/ml 미만인경우는분석에서제외하였다. 3) 항 GAD 항체의측정혈액내항 GAD 항체농도는 RSR사 (London, United Kingdom) 의항 GAD 항체키트를이용하여방사면역침전법으로측정하였다. 양성판정은 reference value에따라서 1 IU/mL 이상으로정의하였다. 3. 통계분석 SPSS (Version 15) 를이용하였으며, 항 GAD 항체유무에따른양군간의특징을비교하기위해두군간의특징비교는 Student's t test를사용하였다. 군간의비율의분석 17
Korean Diabetes J 33:16~23, 2009 은카이제곱검정을사용하였고, P value가 0.05 미만인경우를통계적으로유의하다고판정하였다. 결과 1. 항 GAD 항체양성률총 11,147명의환자들중 C-peptide가 1 ng/ml 이상으로인슐린비의존형당뇨병으로분류된환자는 9,250명이었고, C-peptide가 0.6 ng/ml 미만으로인슐린의존형당뇨병으로분류된경우는 922명이였다. 인슐린비의존형당뇨병환자중항 GAD 항체양성인환자들은 9,250명중 439명으로 4.7% 였고인슐린의존형당뇨병환자는 922명중 203명으로 22.0% 의양성률을보였다. C-peptide가 0.1 ng/ml 미만으로절대적인슐린결핍으로진단된환자에서의항 GAD 항체양성률은 26.9% 이었다 (Table 1). 성별에따른항 GAD 항체양성률의유의한차이는없었다. 하지만인슐린의존성유무에관계없이모든군에서항 GAD 항체양성인경우통계적으로유의하게환자의연령이낮았다. 또한인슐린비의존형당뇨병의경우항 GAD 항체양성군에서음성군에비해체질량지수가유의하게낮았다. 2. 발병연령에따른항 GAD 항체양성률인슐린의존형당뇨병의경우발병연령이 25세이상 40세 미만에서 35.2%, 40세이상에서 17.1% 로 40세미만군에서 40세이상군에비해유의하게항 GAD 항체양성률이높았다 (P < 0.05). 인슐린비의존형당뇨병의경우에도발병연령이 25세이상 40세미만에서 12.4%, 40세이상에서 3.8% 로 40세미만군에서 40세이상군에비해유의하게항 GAD 항체양성률이높았다 (P < 0.05) (Table 2). 한편 40세미만연령에서발생한인슐린비의존형당뇨병환자에서는로그변환을하여비교한평균항 GAD 항체역가가 40세이상군에비해유의하게높았다 (P < 0.05) (Fig. 1). 그러나인슐린의존형당뇨병환자에서는이와같은차이를보이지않았다. 3. 인슐린비의존형당뇨병중항 GAD 항체양성이었던환자들의임상적특징인슐린비의존형당뇨병환자중무작위로선택한항 GAD 항체양성환자 87명과음성환자중에서나이와성별을맞춰서선택한대조군환자 174명을대상으로임상적특성을비교하였다 (Table 3). 항 GAD 항체양성군에서혈액내 C-peptide 농도와체질량지수가대조군에비해유의하게낮았으며, 발견당시당뇨병의전형적인증상이나체중감소의병력이더많았고, 내원당시인슐린을사용하고있는경우가더많았다. Table 1. Demographic characteristics of study subjects according to the status of Anti-GAD antibody NIDDM IDDM Absolute insulin insufficiency GAD Ab Positive Negative Positive Negative Positive Negative Number (%) 439 (4.7%) 8,811 203 (22.0%) 719 127 (26.9%) 345 Sex (F/M) 197/243 3,533/5,278 85/118 299/490 62/65 145/200 Age (year) 49.3 ± 14.3 * 54.8 ± 11.8 45.6 ± 14.3 * 50.2 ± 13.8 44.1 ± 13.9 * 51.7 ± 14.0 BMI (kg/m 2 ) 22.5 ± 0.5 * 24.6 ± 0.5 22.4 ± 0.5 22.5 ± 0.4 22.4 ± 0.4 22.3 ± 0.3 The data represent the mean ± SEM. * P < 0.05 vs. GAD Ab negative patients. BMI, body mass index; F, female; GAD Ab, Anti-GAD (glutamic acid decarboxylase) antibody; IDDM, insulin dependent diabetes mellitus; M, male; NIDDM, non-insuiln dependent diabetes mellitus. Table 2. Prevalence of Anti-GAD antibody among patients with NIDDM and IDDM according to the onset-age 25 Onset age (year) < 40 Onset age (year) 40 NIDDM 121/976 (12.4%) * 318/8,274 (3.8%) IDDM 88/250 (35.2%) * 115/672 (17.1%) * P < 0.05 vs. onset-age 40. GAD, glutamic acid decarboxylase; IDDM, insulin dependent diabetes mellitus; NIDDM, non-insulin dependent diabetes mellitus. 18
이상아외 10 인 : 한국인성인당뇨병환자에서항 GAD 항체양성률 Table 3. Clinical characteristics of anti-gad antibody positive and negative NIDDM patients GAD Ab positive (n = 87) GAD Ab negative (n = 174) P value Age (years) 53.6 ± 12.6 53.6 ± 12.5 NS Sex (F) 37 (42%) 111 (42%) NS C-peptide (ng/ml) 2.0 ± 0.8 2.4 ± 1.5 0.003 HbA1 C (%) 9.5 ± 2.8 9.5 ± 2.8 NS BMI (kg/m 2 ) 24.1 ± 3.6 25.0 ± 3.2 0.027 Duration (years) 6.3 ± 7.2 7.2 ± 6.3 NS Typical symptoms of DM (Yes) 43 (49.4%) 75 (28.7%) < 0.001 Weight loss (Yes) 42 (46.2%) 68 (26.1%) < 0.001 Insulin use (%) 17 (19.5) 4 (6.3) 0.041 The data represent the mean ± SEM. Ab, antibody; BMI, body mass index; DM, diabetes mellitus F, female; GAD, glutamic acid decarboxylase; HbA1c, hemoglobin A1c; NS, not significant. Age (years) Fig. 1. Anti-GAD antibody titer in diabetic patients according to the onset-age. Among NIDDM patients, those who were diagnosed before 40 years of age had higher titer of Anti-GAD antibody than those diagnosed after 40 years of age. * P < 0.05. GAD, glutamic acid decarboxylase; IDDM, insulin dependent diabetes mellitus; NIDDM, non-insulin dependent diabetes mellitus. 고 본연구에서성인연령에발생한인슐린의존형당뇨병환자중항 GAD 항체양성률은 22.0% 였다. 본교실의이전연구에서는인슐린의존형당뇨병 56명중 16명 (28.5%) 이항 GAD 항체양성이라고보고한바있는데 18), 이연구의경우본연구와는달리소아연령의인슐린의존형당뇨병이포함되어있었고, 공복상태 C-peptide 농도 0.6 ng/ml 미만이면서 glucagon stimulation test 6분 C-peptide가 1.0 ng/ml 미만인군만을대상으로하였기때문에본연구보다는더엄격한진단기준을적용한경우였다. 실제본연구에참여한환자들의경우에도공복시 C-peptide 0.1 ng/ml 미 찰 만의절대적인슐린결핍환자들의경우항 GAD 항체양성률이 26.9% 로이전의연구와비슷한유병률을보인다. 한편국내의다른연구들의결과는인슐린의존형당뇨병환자에서의항 GAD 항체양성률을 17.6~75% 로보고하였는데이들논문대부분은소아연령의인슐린의존형당뇨병환자들을일부포함한집단을대상으로하였다 13,16,18,21-23). 그렇다고하여도이와같은결과들은서구인에서의 70~80% 양성률과비교한다면낮은경향을보이며, 특히본연구의결과와같이성인연령에서발병한인슐린의존형당뇨병에서항 GAD 항체가 22.0% 밖에발견되지않는다는것은특이한것이다. 실제우리나라사람을포함한동양인에서의인슐린의존형당뇨병의발생률 (incidence) 은서양인에비해매우낮음이알려져있는데 24,25), 이와같은현상은동양인에서인슐린의존형당뇨병의발생에는서구에서알려진자가항체이외의다른면역학적인자가관여하거나, 면역학적기전이외의다른기전이더중요하게작용할가능성을시사한다. 본연구에참여한인슐린비의존형당뇨병환자중항 GAD 항체양성률은 4.7% 로이전의보고 13-17) 와비슷한수치를보이고있다. 이제까지나온서구인에서의보고에의하면인슐린비의존형당뇨병환자에서 6~12% 정도까지항 GAD 항체가발견된다고하기때문에 9,26-29) 인슐린의존형당뇨병과마찬가지로인슐린비의존형당뇨병환자에서의자가면역항체양성률이서구에비해국내에서는낮다고추론할수있다. 한편일본인에서의항 GAD 항체양성률역시 3.8~4.3% 30,31) 로본연구결과와비교적비슷한결과를보였는데, 이와같은현상도본연구에서시사하는점, 즉동양인에서자가면역기전에의한당뇨병이드물다는것을지지하는소견이다. 그러나, 김등은한국인비비만형제2형당뇨병환자에서항 GAD 항체양성률은 12.6% 로기존의자 19
Korean Diabetes J 33:16~23, 2009 료에비해높게보고하고있다 32). 실제본연구의대상환자중에서도체질량지수 25 이하인환자의경우에는 8.2% 에서항 GAD 항체가검출되었는데 (data not shown), 서구인과한국인에서비만도에따라항 GAD 항체의빈도가어떻게나타날지는흥미로운과제가될수있을것이라생각된다. 본연구에서주목할점은임상적으로인슐린비의존형당뇨병으로생각되는환자라도발병연령이 40세미만인경우에는 12.4% 에서항 GAD 항체가양성이었다는점이다. 비록서구인에서의결과, 예를들어 UKPDS-25에서보고한 25세부터 34세까지발병한인슐린비의존형당뇨병환자에서의 35% 9) 보다는낮은수치이지만상당히많은수에서항 GAD 항체가검출됨을알수있다. 또한 40세미만에서발병한인슐린비의존형당뇨병환자에서는높은항 GAD 항체역가를보이는경우가많았다. 이와같은연령에따른차이가나타난이유는확실치않지만, 이전의연구들이항 GAD 항체역가가높을경우인슐린의존형으로의진행이빠름을보고하고있기때문에 8,33) 젊은연령에서발생한당뇨병환자의경우에는그임상형에관계없이항 GAD 항체검사가필요할것으로생각된다. 한편, 항 GAD 항체양성인인슐린비의존형당뇨병환자들의임상적특징을보면전형적인증상이더자주나타나고낮은체질량지수를보이며공복시 C-peptide 수치가낮은것으로보아간접적이기는하나췌장베타세포의파괴가병인에좀더깊게관여하고있음을시사하고있다. 본연구에서는미토콘드리아 DNA 돌연변이를측정하지않았다. 앞에서기술한바와같이본교실의이전연구에서비전형적인인슐린의존형당뇨병환자의일부에서미토콘드리아 DNA 3243 돌연변이가관찰됨을보고하였지만 18), 인슐린비의존형당뇨병환자들중에서는이의빈도가매우낮은것으로보고되었다 34). 따라서본연구에서미토콘드리아 DNA 돌연변이를지닌환자들을제외하지않았기때문에항 GAD 항체유병률이낮게나왔을가능성은크지않을것으로생각된다. 본연구는몇가지제한점을가진다. 첫번째는본연구가한대학병원을방문한환자들만을대상으로했기때문에우리나라의전체환자, 특히개인병원을다니는좀가벼운환자들을대변하지못한다는것이다. 두번째는본연구에서서울아산병원을방문한모든환자에서항 GAD 항체를잰것이아니라선택된사람에서만측정되어선택편견 (selection bias) 이있을것이라는점이다. 실제우리나라에서는인슐린의존형당뇨병이전체환자의 2~3% 미만일것으로생각하고있으나본연구에서는전체환자중약 10% 가인슐린의존형당뇨병으로분류된점으로보아임상적으로좀더심한환자들에서항 GAD 항체가재어졌을가능성이높다. 그러나본연구의결과가서구인보다우리나라환자에서항 GAD 항체양성률이낮다는것을주장하고있기때문에이와같은선택편견의한계는극복될수있으리라생각한다. 세번째는본연구에서공복시혈청 C-peptide 만으로인슐린의존형당뇨병환자와인슐린비의존형당뇨병환자를구분하였다는것이다. 체내인슐린분비능을측정하는가장일반적인방법은 glucagon을정맥주사한후혈액내 C-peptide를측정하는것이다 35). 그러나이전연구에서공복시 C-peptide와 glucagon-stimulated C-peptide 사이에좋은상관관계를보임이보고되었고 36,37), 특히본교실에서는공복시 C-peptide 0.6과 1.0을기준으로할때 glucagon-stimulated C-peptide와매우좋은상관성이있으며임상적으로인슐린의존형당뇨병환자와인슐린비의존형당뇨병환자를비교적명확히구분할수있음을보고한바있다 38). 다만이방법의경우중간군인공복 C-peptide 0.6~1.0군에서는인슐린의존형, 인슐린비의존형을명확히구분하기어렵다는단점이있고, 이에따라본연구에서는이중간군을배제하였다. 그러나이들중간군환자를제외함으로써항 GAD 항체양성률이다른논문들에비해낮아졌을가능성은있을것으로생각된다. 결론적으로한국인에서는인슐린의존형당뇨병과인슐린비의존형당뇨병모두에서항 GAD 항체양성률이서양에비해낮음을알수있었다. 특히성인에서발생한인슐린의존형당뇨병의경우에는면역학적기전보다다른원인에의한베타세포기능소실이더중요한역할을할것이라는것을추측할수있다. 그러나인슐린비의존형당뇨병의경우에도앞으로인슐린의존형당뇨병으로의진행을미리예측하기위해항 GAD 항체측정이더보편화되어야할것으로생각되며, 특히발병연령이 40세이전의환자이거나발병당시증상이현저했던환자의경우에는항 GAD 항체측정을일반화할필요가있을것이다. 한편항 GAD 항체양성인한국인인슐린비의존형당뇨병환자중어느정도가몇년안에인슐린의존형당뇨병으로진행하는지에대해서는앞으로더연구가필요할것으로생각된다. 요약연구배경 : 한국인에서의당뇨병환자들의임상적인특징이서구인과다르다는것은잘알려진사실이다. 본연구는성인연령에발생한당뇨병에서항 GAD 항체의양성률을 20
이상아외 10 인 : 한국인성인당뇨병환자에서항 GAD 항체양성률 알아보기위해시행되었다. 방법 : 1998년부터 2007년까지서울아산병원을방문한환자중성인연령에서발생한당뇨병환자 11,147명을대상으로항 GAD 항체를측정하였다. 공복시 C-peptide 결과에따라 C-peptide 0.6 ng/ml 미만인환자들은인슐린의존형당뇨병환자로구분하였고, 1.0 ng/ml 이상인환자들은인슐린비의존형당뇨병환자로분류하였다. 다른임상적자료와검사자료들은의무기록검색을통해얻어졌다. 결과 : 상기환자중인슐린비의존형당뇨병으로분류된환자는 9,250명이었고, 922명은인슐린의존형으로분류되었다. 항 GAD 항체양성률은인슐린의존형당뇨병환자에서 22.0%, 인슐린비의존형당뇨병환자에서 4.7% 를보였다. 인슐린비의존형당뇨병환자에서항 GAD 항체양성률은발병연령이어릴수록더높게나타났다 (40세미만에서 12.4%, 40세이상에서 3.8%). 항 GAD 항체양성인인슐린비의존형당뇨병환자는음성인환자에비해낮은 C-peptide 와체질량지수를보였으며, 전형적인당뇨병증상을더빈번하게경험하였다. 결론 : 우리나라인슐린의존형당뇨병환자및인슐린비의존형당뇨병환자모두에서항 GAD 항체양성률은서구인에비해낮음을알수있었다. 한국인에서인슐린의존형당뇨병발생률이서구인에비해낮다는사실과같이생각할때본연구결과는우리나라에서자가면역학적기전에의한당뇨병이드물다는것을시사한다. 그러나, 40세미만인젊은연령에서발생한인슐린비의존형당뇨병환자들중에서는항 GAD 항체가양성인환자가자주발견되기때문에이들환자들에서는항 GAD 항체측정을더보편화시킬필요가있을것이다. 참고문헌 1. The Expert Committee on the diagnosis and classification of diabetes mellitus: Report of the expert committee on the diagnosis and classification of diabetes mellitus. Diabetes Care 20:1183-97, 1997 2. Bottazzo GF, Florin-Christensen A, Doniach D: Islet-cell antibodies in diabetes mellitus with autoimmune polyendocrine deficiencies. Lancet 2:1279-83, 1974 3. Palmer JP, Asplin CM, Clemons P, Lyen K, Tatpati O, Raghu PK, Paquette TL: Insulin antibodies in insulin-dependent diabetics before insulin treatment. Science 222:1337-9, 1983 4. Baekkeskov S, Aanstoot HJ, Christgau S, Reetz A, Solimena M, Cascalho M, Folli F, Richter-Olesen H, De Camilli P: Identification of the 64k autoantigen in insulin-dependent diabetes as the GABA-synthesizing enzyme glutamic acid decarboxylase. Nature 347: 151-6, 1990 5. Borg H, Gottsater A, Fernlund P, Sundkvist G: A 12-year prospective study of the relationship between islet antibodies and beta-cell function at and after the diagnosis in patients with adult-onset diabetes. Diabetes 51:1754-62, 2002 6. Kobayashi T, Tamemoto K, Nakanishi K, Kato N, Okubo M, Kajio H, Sugimoto T, Murase T, Kosaka K: Immunogenetic and clinical characterization of slowly progressive IDDM. Diabetes Care 16:780-8, 1993 7. 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 8. Rosario PW, Reis JS, Fagundes TA, Calsolari MR, Amim R, Silva SC, Purisch S: Latent autoimmune diabetes in adults (LADA): Usefulness of anti-gad antibody titers and benefit of early insulinization. Arq Bras Endocrinol Metabol 51:52-8, 2007 9. Turner R, Stratton I, Horton V, Manley S, Zimmet P, Mackay IR, Shattock M, Bottazzo GF, Holman R: UKPDS 25: Autoantibodies to islet-cell cytoplasm and glutamic acid decarboxylase for prediction of insulin requirement in type 2 diabetes. UK prospective diabetes study group. Lancet 350:1288-93, 1997 10. Rhee BD: The etiological heterogeneity and clinical characteristics of adult-onset diabetes mellitus in Korea. Inje Medical Journal 12:69-79, 1990 11. Min HK: Clinical characteristics of diabetes in Korea. J Korean Diabetes Assoc 16:163-9, 1982 12. Lee KU, Lyu JS, Kim YT, Song YG, Kim GS, Lee MH, Park SU: Clinical characteristics of Korean diabetic patients classified by fasting plasma C-peptide level and degree of obesity. The Korean Journal of Internal Medicine 42:315-21, 1992 21
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