HLA Distribution in Korean Patients with Insulin-Dependent Diabetes Mellitus

Huh, Kap Bum,Lee, Hyun Chul,Park, Kiil,Lee, Sang Yong Yonsei University, College of Medicine 1986 Yonsei medical journal Vol.27 No.1

한국인 성인에서 발생하는 인슐린 의존형 당뇨병의 임상 및 면역 유전학적 특성

임승길(Sung Kil Lim),이현철(Hyun Chul Lee),송민경(Min Kyung Song),차봉수(Bong Soo Cha),송영득(Young Duk Song),김경래(Kyung Rae Kim),허갑범(Kap Bum Huh),김덕희(Duck Hi Kim) 대한내과학회 1999 대한내과학회지 Vol.56 No.1

Insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease occurring among genetically susceptible individuals. Although the HLA class II genes and immunological abnormalities are clearly associated with IDDM in all racial groups, there are considerable variations in associated genotypes and prevalence of autoantibodies. Especially, it seems that adult-onset IDDM is somewhat different from childhood- onset IDDM in clinical and immunogenetic aspect. In order to determine the characteristics of the immunogenetic patterns and to use these results as an early diagnostic tool and a guideline of the therapeutic plan in Korean adult- onset IDDM, we investigated the clinical and immunogenetic characteristics in adult-onset IDDM patients. Methods : We investigated the clinical and biochemical characteristics, and measured anti-GAD antibody by immunoradiometric assay or immunoprecipitation after in vitro translation of human GAD cDNA and IA-2 antibody by immunoprecipitaion after in vitro translation of human IA-2cDNA. The distribution of HLA-DR serotypes by lymphocyte microcytotoxicity method, HLA-DQA1 genotypes by restriction fragment length polymorphism and HLA-DQB1 genotypes by dot-blotting analysis using sequence specific oligonucleotide probe were analysed in 233 IDDM patients and controls. Results : 1) Adult-onset patients had more preserved beta cell functions and slowly evolving form of clinical pattern rather than childhood-onset cases. 2) Each prevalences of anti-GAD and IA-2 antibody were 64% and 14.4% in adult-onset patients. Among them, the group with DR9-DQ9 had higher prevalence of antiGAD antibody rather than DR4-DQ4 group. 3) There were increased frequencies of HLA-DR4 and -DR9 in adult-onset patients. Considering the frequency of HLA-DQA1 and -DQB1 and the distribution of DQ heterodimers, they had no significantly increased genotypes or haplotypes. But childhood-onset cases had high frequencies in HLA DR3, -DR4, -DR9 serotypes and DQA1*0301, DQA1*0501, DQB1*0201 genotypes. Conclusion : Korean adult-onset IDDM patients have relatively higher prevalence of anti-GAD antibody implicating autoimmune pathogenesis. HLA genetic markers in adult-onset IDDM were somewhat different from those in childhood-onset cases. This pathogenetic heterogenesity according to age of onset may be due to the influences of other genetic markers and environmental factors involved in the etiology of Korean IDDM.

혈청 C - peptide 치로 정의한 한국인 인슐린 의존형 당뇨병 환자의 임상상

김상욱(Sang Wook Kim),이기업(Ki Up Lee),정상식(Sang Sik Cheong),김형호(Hyeong Ho Kim),박중열(Joong Yeol Park),김기수(Ghi Su Kim),이문호(Mun Ho Lee) 대한내과학회 1993 대한내과학회지 Vol.45 No.6

Background: Diabetes mellitus is one of the major health problems in Korea. It has been suggested that there are quite many atypical IDDM patients who initially manifest as NIDDM, but require insulin eventually. However, little is known about the clinical characteristics of this type of diabetics in Korea. This study was undertaken to find out how many current IDDM patients bad a history of noninsulin requiring phase. Methods: We obtained medical histories retrospectively from 2300 patients who visited Asan Medical Center from June 1989 to July 1992. Fifty nine patients were classified as IDDM because their fasting plasma C-peptide levels were below 0. 13fmol/L (0.4ng/ml). The patients were classified further into the two groups: group A who required isulin within 1year after diagnosis or presented as debut DKA, and group B who had nonisulin requiring phase at least for 1year after the diagnosis. Results: Twenty six patients (44%) were classified as group A, and 27patients (46%) as group B. Median age of onset was 26years in group A, (range; 10-50) and 45 (range; 23-73) in group B. As a whole, 24patients (41percent) were diagnosed as diabetes over the age of 40. Two groups had similiar values in body mass index. History of DKA was found in 58percent in group A and 7percent in group B. All patients of group A were using insulin at the time of the study, while only 56percent of group B were using insulin. Conclusion: Our study showed: first, forty percent of IDDM patients developed their diabetes at the age over 40: second, about half of the patients had a non-insulin- requiring phase at least for one year, The lack of DKA, old age of onset, and the initial non-insulin-requiring phase suggest that these patients are different from the typical IDDM. This subclass of IDDM in Korea may be classified as slowly progressive IDDM.

자연과학 : 유산소 운동프로그램 참여가 소아,청소년 IDDM 환자의 항산화 유전자 발현과 지질, DNA 손상에 미치는 영향

우진희 ( Jin Hee Woo ),여남회 ( Nam Hwoeh Yeo ),강성훈 ( Sung Hwun Kang ) 한국스포츠정책과학원(구 한국스포츠개발원) 2008 체육과학연구 Vol.19 No.3

본 연구는 소아ㆍ청소년 IDDM 남자 환자(DM군, n=10)와 건강한 남자 어린이(HT군, n=10)를 대상으로 12주간 유산소 운동프로그램 참여 전과 후의 지질 profiles, 항산화효소 유전자 발현, 그리고 산화물 생성의 차이를 비교하는데 그 목적이 있었다. 측정 시기는 훈련 전과 훈련 후 하였으며, 신장, 체중, 체지방, WHR, 혈압, 최대산소섭취량을 측정하였고, 혈중 지질 profiles, HbA1c, ox-LDL, DNA damage, total RNA를 분석하였다. 연구결과, 체질량지수(BMI), 체지방률, 최대산소섭취량은 그룹 간, 시기 간 차이가 없었다. 이완기 혈압은 HT군에 비해 DM군이 높게 나타났으며(p<.05), TC와 HDL-c, ox-LDL은 그룹 간, 시기 간 차이가 없었다. HbA1c는 DM군이 HT군에 비해 높았지만(p<.05), 트레이닝에 의한 변화는 나타나지 않았다. 항산화 효소 유전자 발현은 방어 기전에 따라 다른 양상을 보였으며, 조직손상과의 관계도 일관성을 보여주지 않았다. DNA damage는 트레이닝 후 DM군에서 유의한 증가가 나타났다(p<.05). 따라서, 항산화 방어역량이 약한 IDDM 환자에게 운동은 일시적인 DNA damage를 수반한다고 보지만, 트레이닝에 의해 일부 항산화 효소 유전자 발현이 증대될 수 있으며, 당화 Hb 개선을 위해선 역치수준 이상의 운동강도와 더불어 무산소성 트레이닝이 필요할 것으로 사료된다. The purpose of this study was to compare the differences between before and after 12 week aerobic training on lipid profiles, antioxidant enzyme gene expressions, and oxidative products in children with IDDM. We therefore studied 20 children (age, 11.9±1.85 years; 10 boys) with IDDM and 10 age-matched healthy controls during 12 week of moderate intense running exercise. Blood samples for lipid profiles, HbA1c, ox-LDL, 8-OHdG, and total RNA were drawn before, and after training. There were no differences of BMI, body fat, and VO2 max between groups and periods. Also, there were no differences of TC, HDL-c, and ox-LDL between groups and periods. In IDDM, baseline DBP, and HbA1c was higher than that of controls(p<.05). And exercise-induced DNA damage peak occurred greater than control(p<.05). Antioxidant enzyme gene expression displayed different aspect according to antioxidant defense mechanism, and there was no consistency that related to tissue damages. Therefore, during or immediately after intense exercise, temporary alterations in the tissue damage occurred in children with IDDM who are at weakened antioxidant defence capacity. However, some kinds of antioxidant enzyme gene expressions magnitude by long term training, and anaerobic exercise include in training may help to improve the normalization of glycated Hb.

레트로바이러스의 표면단백질 : 인슐린의존형 당뇨병의 동물모델인 NOD 쥐의 혈청과 반응하는 새로운 자가항원 A New Autoantigen Reactive with Non Obese Diabetic (NOD) Mice Sera

김경수,김기환,김현만,윤지원,강엽 아주대학교 1997 아주의학 Vol.2 No.2

IDDM (Insulin dependent diabetes mellitus) is believed to be an autoimmune disease and characterized by the immune activation against insulin-producing pancreatic beta cell. The identification and characterization of new autoantigens reactive with an activated immune System would heip to elucidate the pathogenic mechanism of this disease. Several autoantigens are trying to apply for diagnosis and prevention of IDDM. The NOD (non obese diabetic) mice have been the best model for studying the pathogenesis of human IDDM. To identify new autoantigens reactive with activated humoral immunity of NOD mice, the lambda gt11 cDNA library was constructed from NOD-derived pancreatic beta cell (MIN6N8a: mouse insulinoma cell) and screened with prediabetic NOD sera. Mine positive dones were selected from 2x10^(5) phage plaques. The 5'-end sequencing and homology searching showed that six clones from nine clones had over 98% sequence homolgy with the retroviral envelope gene. Full sequendng reveated that the cloned gene was a fragment of ecotropic retrovirus (emv-3) envelope gene. To confirm the immunoreactivity of doned retroviral envelope protein, the cloned gene fragment was expressed in an E.coli expression vector System. Western blotting showed that the recombinant envelope protein fragment also reacted with prediabetic NOD sera.

성인에서 발생하는 인슐린의존성 당뇨병 유병율 추정

박용수(Y . S . Park),이경진(K . J . Lee),김태화(T . W . Kim),김목현(M . H . Kim),이홍규(H . K . Lee),김성연(S . Y . Kim),고창순(C . S . Hoh),민헌기(H . K . Min) 대한내과학회 1997 대한내과학회지 Vol.52 No.5

Objective: IDDM is an autoimmune disease, which occurs among genetically susceptible individuals. In the Asian populations, it is not uncommon for adult patients with NIDDM to eventually lose beta cell function and develop IDDM. These individuals may be characterized by autoantibodies to GAD and high risk HLA-DQ alleles, which are unlikely to be prevalent among true NIDDM cases or in the general population. The objective of the present study was to evaluate and compare the prevalence of these immunogenetic markers in NIDDM patients and healthy non-diabetic individuals from Korea. Methods: The prevalence of anti-GAD antibodies and HLA-DQA1 and DQB1 alleles among 121 newly diagnosed NIDDM cases identified from a population-based study in Yonchon, Korea and 100 matohed healthy control subjects were evaluated and compared. Results: The overall prevalence of anti-GAD antibodies was 1.7% (2 of 121) in patients with previously undiagnosed NIDDM, whereas 1 of 100 controls had positive antibodies. Among those who were positive, their titer of antibodies to GAD were not high. No statistically significant differences in the distributions of either mean levels of anti-GAD or DQA1 and DQB1 alleles were found comparing NIDDM patients to controls. Conclusion: The low prevalence of anti-GAD antibodies and HLA-DQA1 and DQB1 susceptibility alleles among recent-onset NIDDM patients, which was similar to observations in controls, suggests that diabetes in Korean adults is unlikely to have an autoimmune component to its pathogenesis.

한국인 성인 당뇨병의 병인론적 이형성 및 임상적 특성

이병두 인제대학교 1991 仁濟醫學 Vol.12 No.4 sup

수유기 NOD 마우스에서 BCG 투여 시기에 따른 당뇨병 발생 및 인슐린염 억제효과

황태선,강호석,김영욱,정춘희 대한해부학회 2000 Anatomy & Cell Biology Vol.33 No.1

당뇨병의 임상형에 따른 임상적 특성과 인슐린 분비능

고경수,이병두,김관엽 인제대학교 1995 仁濟醫學 Vol.16 No.1

우리 나라 성인 당뇨병의 임상형에 따른 임상적 특성 및 인슐린 분비능을 알아보기 위하여, 전형적인 인슐린 의존성 당뇨병(19명) 및 인슐린 비의존성 당뇨병(인슐린 필요군 48명과 불필요군 20명) 환자를 대상으로 혈철 C-peptide농도를 측정하고, 임상적 특성을 알아 본 후 각 군간의 비교를 하였다. 1) Objective : To clarify the clinical characteristics and serum C-peptide levels of insulin dependent diabetes mellitus(IDDM) and non-insulin dependent diabetes mellitus(NIDDM). 2) Methods and Materials: 19 IDDM and 68 NIDDM(48 insulin requiring and 20 non insulin requiring NIDDM), of whom serum C-peptide levels were measured, were included. Patients were classified as typical IDDM in the presence of the following criteria : 1) body mass index(BMI) less than 25kg/m2, 2) positive sedum or urine ketone bodies, 3) insulin treatment started within one Year after diagnosis. Various clinical parameters including glucagon -stimulated serum C-peptide levels were compared among the clinical class of diabetic patients. 3) Results: In IDDM patients, onset age was younger than that of NIDDM(29±2 vs. 51±2 years, p〈 0.01), and histories of weight loss(74%) and ketosis-proneness(74%) were more prevalent than those of NIDDM(25%, p<0.05, 15%, p<0.01). BMI(18.9±0.8, 23.3±0.4kg/m2, p<0.01). Waist to hip girth ratio(WHR) (0.82±0.03, 0.93±0.01cm/cm, p<0.01), lasting serum C-peptide levels(0.7±0.2, 1.3±0.1ng/mL, p<0.05), and glucagon-stimulated serum C-peptide levels(0.9±0.2, 2.7±0.3ng/mL, p<0.01) were lower in IDDM patients. HbAlc levels were higher in IDDM(11.3±0.7, 9.6±0.3%, p<0.05) than those of NIDDM patients. In NIDDM patients group, durations of diabetes were longer in insulin requiring group than those of non insulin requiring group(8±1.4±2 years, p<0.05). Other clinical parameters were not different between these two groups. Onset age, history of weight loss, history of ketosis-proneness, BMI. WHR, and HbAlc levels were different between insulin requiring patients including IDDM and NIDDM and non insulin requiring NIDDM patients. Differences of fasting serum C-peptide levels were observed between IDDM and non insulin requiring NIDDM as well as between insulin requiring NIDDM and non insulin requiring NIDDM patients. Stimulated serum C-peptide levels were different between all of these groups. Correlation coefficients between fasting and stimulated sedum C-peptide levels were 0.54(p<0.05) in IDDM, 0.85(p<0.01) in NIDDM patients, respectively. In IDDM patients, serum triglyceride levels were correlated with fasting serum C-peptide levels(r = 0.49, p<0.05). Postprandial serum glucose levels showed negative correlation wish stimulated serum C - pep - tide levels(r= -0.43, p<0.05) . In NIDDM patients, BMI and fasting C-peptide, BMI and stimulated C-peptide levels, fasting serum glucose and lasting C-peptlde levels showed significant correlation. On the other hand, HbAlc levels showed negative correlation with serum C-peptide levels. Fasting serum glucose levels were positively(r=0.36, p<0.01) and serum HDL-cholesterol levels were negatively (r = -0.27, p<0.05) correlated with fasting serum C-peptide levels in insulin requiring NIDDM patients. In non insulin requiring NIDDM patients, BMI were correlated with fasting and stimulated C-peptide bevels(r=0.71, p<0.01, r=0.69, p<0.01), and HbAlc levels were negatively correlated with fasting and stimulated serum C-peptide levels(r=-0.51, p<0.05, r=-0.44, p<0.05), respectively. 4) Conclusion : In Korean adult-onset diabetic patients, no single clinical parameter is decisive to classify the clinical diabetes mellitus because of the heterogeneity and atypical clinical course of the disease. To make the clinical characterisitcs of Korean adult-onset diabetic patients clear, a large-scaled, prospective study targeting recent-onset diabetes is needed.

혈청 C-peptide치와 비만도에 의한 한국인 당뇨병의 병형 분류

이기업 ( Lee Gi Eob ),류진숙 ( Lyu Jin Sug ),김용태 ( Kim Yong Tae ),송영기 ( Song Yeong Gi ),김기수 ( Kim Gi Su ),이문호 ( Lee Mun Ho ),박성우 ( Park Seong U ) 대한내과학회 1992 대한내과학회지 Vol.42 No.3

Background : Despite many previous studies, clinical characteristics of Korean diabetic patients have not been precisely defined yes. Although it is generally assumed that typical IDDM and obese NIDDM patients are relatively rare in Korean diabetics, the actual prevalence of those subpopulations among diabetic patients have not been properly evaluated, because of the lack of a definite clinical critria to distinguish IDDM from NIDDM, and the scarcity of the information about previous and present degree of obesity in Korean diabetic patients. Recently, we reported that fasting plasma C-peptide level gives a good distinction between IDDM and NIDDM. Method : Two hundred fifty seven patients with diabetes mellitus who visited Diabetes Clinics of Asan Medical Center and Hankang Sacred Hospital during the period from May 1989 to June 1990 were included in this study. By a premade protocol, inquiry was made about family history, onset age, present weight and maximum previous weight before the disease onset. Patients were classified into IDDM and NIDDM by their fasting plasma C-peptide levels (IDDM if the C-peptide level is less than 0.6 ng/㎖; NIDDM if the C-peptide level is higher than 1.0 ng/㎖), Body mass index (wt/ht¹; ㎏/㎡) greater than 25 was defined as overweight. 1)Ratients classified as IDDM were 27 cases. Age(yr) of onset was less than 25 in 8 cases, 26∼40 in 9 cases, and more than 40 in 10 cases. Most of the adult-onset IDDM patients have not required insulin for more than l year. 2) Seventy three percent of the NIDDM patients were overweight previously, but only 37% remained persistently overweight. 3) There was a strong family history in NIDDM patients who were diagnosesd at young ages. Our data show that obesity is one of the mojor determinants of diabetes in most Korean NIDDM patients, but only 1/3 of the patients remain persistently overweight after the onset of disease. The data also show that there are some atypical NIDDM patients who develop diabetes early in life and have a strong family history. From these data, we suggest that most Korean diabetic patients have limited insulin secretory capacity and thus cannot maintain their obesity after the onset of disease. It is also suggested that there are subgroups of patients who can be classified as slowly progressive IDDM and MODY.