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1 Type 1 Diabetes Registry Yongsoo Park, MD Dept of Internal Medicine, College of Medicine; Dept of Bioengineering, College of Engineering, Hanyang University

2 T1DM = Diabetes in childhood Easy to diagnose Abrupt onset Requiring medical attention Requiring medication (insulin) the epidemiologist s dream

3 By the 1980 s.. * Few registries monitoring T1DM incidence * Limited information but geographical differences in incidence identified * However, lack of standardization: - different case definition - different ages - different degrees of ascertainment

4 Diabetes in Childhood: T1DM Registries Establishment of population-based registries around the world Monitor the global pattern of the disease Provide a basis for standardized studies of risk factors Karvonen M et al. Diabetes Care 2000

5 Worldwide Difference in the Incidence of T1DM 0 14 years DIAMOND Project Sardinia Finland Sweden U.S. Australia Germany France Tunisia Sudan Hong Kong Japan Korea Karvonen M et al. Diabetes Care 2000 /100,000

6 Definition of T1DM 1) 당뇨병발병이후 2 년이상계속적으로인슐린투여가요구, 2) 케톤산혈증의병력 3) 혈액내 c-peptide 농도가낮으며 ( 기저 0.6 미만, 자극후 90 분에 1.5 미만 ) 4) 췌도와인슐린등에대한자가항체가있는당뇨병 대한소아과학회

7 Approach to the determination of diabetes type in Asian adolescent New onset diabetes Blood Ketone (+) Consider MODY Positive Pancreatic autoantibodies Negative Likely Type 2 Type 1a Monitor course Insulin requirement No Type 2 Yes low c-peptide Normal/elevated Type 1b? Type 2 ᆞPoor adherence ᆞSevere resistance

8 Diabetes Registry Establishment of well defined populations of persons with diabetes T1D Registry Establishment of well defined populations of persons with T1D

9 제 1 형당뇨병관리와연구에있어서 Diabetes Registry 의필요성 전세계발병지역에따른발생율, 합병증발생율, 사망율등이차이가나며이의배경에는환경적인자이외에유전적감수성등이작용하고있음을시사함. Lifetime incidence of diabetes: 대략 10%, 반수정도는만성합병증이동반된이후진단됨 성인이되어야대부분발견 (T2DM 과감별요망 ) 유병상태및발병율의증가 1992 년미국에서사용되는의료비의 1/7 은당뇨병기인 등록연구를통해질병의예측및예방이가능

10 Diabetes Registries and Clinical Biology: Pivotal role in predictive and preventive strategies Risk stage Environment Genes Genetic susceptibility markers Islet-specific and nonspecific autoantibodies Latent Disease Defect or destruction of pancreatic B-cells Loss of 1 st phase of IVGTT Clinical Onset Hyperglycemia due to decreased insulin release and/or peripheral insulin resistance Decreased plasma c-peptide conc. 당뇨병발생율 INVALIDITY Chronic complications Markers for the complication development 당뇨병합병증발생율 Decreased quality of life decreased life expectancy QOL studies, Disabilities, Reimbursement 당뇨병사망율

11 Diabetes Registry 목적과선택 1. Why predict and prevent diabetes? - primary prevention vs. secondary prevention - study much larger subject groups within the framework of vast (inter)national collaboration - studies conducted on representative populations recruited through diabetes registries 2. Why concentrate on T1D first? - disproportionately large part of the chronic complications derives from T1D patients - findings in (pre)t1d patients may be of relevance for at least part of the more numerous (pre)t2d subjects - more expertise has been accumulated regarding the early biological markers of T1D 3. Why use diabetes registries? - registry-based association studies 의가능성 (age- and sex-matched ) 4. Why study first-degree relatives of T1D patients first? - 고위험군 - familial vs. sporadic

12 외국선진국의제 1 형당뇨병관리 유럽및일본 미국및 WHO 미국 - 일부지역중심제 1 형당뇨병코호트운영 : 각국가별제1형당뇨병코호트구축 영국, 덴마제1 크형, 독일당뇨병, 오스트리아발생률, 발생원인, 핀, 합병증 Allegheny, 사망률 county 데이터제1형분석란드, 일본당뇨병등록사업새로운치료방법의효과판정 DCCT 연구국가적으로대표적인만성질환 효율적 Diabetes 관리 Control 방안마련 and Complication Trial 제1 유럽중심다국적제1형형당뇨병환자치료효과당뇨병코호트 모니터링 EURODIAB populationbased cohort project for T1D WHO multinational (DiaMond) project

13 Registry Average population at risk 0-14 yrs ( 천명 ) Number of cases Source of data Primary Validation Canada Montreal hospitals summer camp 94% Canada Prince Edward Island Basic Characteristics of the T1DM registries (Data are presented for the years ) drug registry pharmacies 99% Finland drug registry hospitals 99% France Rhone Endocrinology general clinics >90% ( ) clinics/wards and hospitals Japan Hokkaido 1, university hospitals: health 100% hospitals department: summer camp Japan , major hospitals Hospitals (Tokyo 60% National survey survey) New Zealand hospitals/ clinic -? Auckland Norway hospitals National insurance 92% Poland Wielkopolska Hospitals/ clinic Sanatoria: social support 95% Sweden 1,642 1,124 Hospitals Independent hospital survey 93% Germany ( ) 3, Central registry Death certificate? Netheland 3, Physicians and Dutch Diabetes 90% hospitals Association 미 국 Allegheny hospitals pediatricians 95% County 미국 Colorado physicians hospitals >95% Completeness rate

Registries in the Pittsburgh Research 1979 Beginning of the registry 1981 Initial incidence data from Allegheny County 1982 First famillial incidence from Allegheny County 1985 Collaboration of

Famillial Epidemiology of IDDM, Arthritis and Thyroid ds 1993년 1996년 Famillial Autoimmune and Diabetes Study Allegheny County Registry: a population-based registry - developed through retrospective

14 Registries in the Pittsburgh Research 1979 Beginning of the registry 1981 Initial incidence data from Allegheny County 1982 First famillial incidence from Allegheny County 1985 Collaboration of registries 1986 DERI 1990 WHO DiaMond Project Pittsburgh T1DM registry의변화 1981년 656 T1DM proband survey: mortality study 위해 define 1990년 survey for the self-report history of autoimmune disease --- Famillial Epidemiology of IDDM, Arthritis and Thyroid ds 1993년 1996년 Famillial Autoimmune and Diabetes Study Allegheny County Registry: a population-based registry - developed through retrospective record review of all hospitals in the County - to identify all children who fulfill a standardized criteria Children s Hosp. Registry: a hospital-based registry at the Children s Hosp.of Pittsburgh - identify all children who were diagnosed at Children s Hosp

15 European T1D Diabetes Registry 실례 1) The Swedish Registry 1970 년부터 7 개병원에서 ascertain 시작, register 는않음 당뇨병이의심되는모든환자들을소아과로 refer, 이들을등록하여추적 (central register), 93% ascertainement 2) The Norwegian Registry Hospital record 를이용한 retrospective study 를통한 prevalence 조사, 이들을등록 central insurance register 를이용하여 ascertain 3) The Finnish Registry 년 National drug recipient register 로출발 모든당뇨병환자는 Sickness Insurance Act 에따라무료로약을나눠줌, 이들을등록하여 register, Hospital record 로 ascertain 4) The Danish Registry case finding 을 National Service conscript registry 로, 또 death certificate 를이용 hospital record 로 incidence 추적 1973 ascertain 방법은 insulin prescription 으로

16 한국제 1 형당뇨병의현황 연간발생률인구 10 만명당 1.36 명? 수만명의환자? 발생률이증가추세, 비전형적인유형이많을것으로추정 기존통계의저조한응답률을보인단면적연구 제 1 형당뇨병으로인한사망률과사망원인은? 환자등록사업없이는표준화사망률을구할수없음

17 Fig. 1. Annual Incidence Rate I Fig. 2. Annual Incidence Rate II Incidence Rate(/ 100,000 ㆍ y r) Year Incidence Rate(/ 100,000 ㆍ y r) Year 대상 제 1형당뇨병 진단시기 : 나이 : 진단시만 15세미만 방법 질문지발송소아과 113병원, 내과 170병원, 보건소 8곳 회신 : 총 70곳

18 Incidence Rate of T1DM in Korea Incidence Rate per 100,000 Children Year

19 Annual Incidence of T1DM in Japan Age group (yrs) Hokkaido Tokyo Kagoshima Japan IDDM Epidemiology Study Group. Diabetes Care 16:796, 1993

20 Relative increase in incidence of T1DM Children 0-14 years Increase in the incidence (%/year) Increase confined to the patients with onset age yrs Yearly change: 2.5 % per year ( ) United Kingdom Hungary Hawaii China Japan Norway Finland USA Allegheny Sweden Lithuania Estonia Adapted from Onkamo P et al, Diabetologia 1999

21 제 1 형당뇨병환자등록사업의필요성 인구기반제 1 형당뇨병환자등록사업 우리나라제 1 형당뇨병의정확한실태파악 적극적인인슐린요법에의한혈당조절유도 표준화사망률분석, 보건정책수립에이용 합병증발생으로인한사회적비용감소

22 Putative Environmental Trigger?? Intact islets and β cells STAGE 1: STAGE 2: STAGE 3: Genetic Predisposition Susceptibility Genes Autoimmunity Humoral Autoantibodies STAGE 4: Glucose Impairment Metabolic Defect Glucose Loss of 1st PhaseIntolerance Insulin(IVGTT) (OGTT) Clinical Onset STAGE 5: Clinical Diabetes STAGE 6: Total Diabetes Time

23 Recombinant Anti-islet Autoantibody Assays Antigen Sensitivity (Specificity) Comment Insulin 40-95% (99%) Inversely Age of Diabetes Onset Related GAD65 70% (99%) Predominantly Age Independent IA-2 Zinc Transporter 60% (99%) 48% (99%) Islet Protein Tyrosine Phosphatase Zinc Transporter (Zn T8) Phogrin/IA-2β 45% (99%) Autoantibodies Predominantly Subset of IA-2 Autoantibodies Carboxypeptidase H 10% (99%) Low Sensitivity

24 Autoradiography of in vitro translated Ag ICA512 IA-2/GAD ZnT8 Marker GAD65 fia-2 (bdc) (combi)

25 DASP 2009 GAD antibody Standardization Reported Sensitivity and Specificity % Sensitivity Our Lab Sensitivity : 71% Specificity : 93% % Specificity

26 DASP 2009 IA-2 antibody Standardization Reported Sensitivity and Specificity % Sensitivity Our Lab Sensitivity : 71% Specificity : 97% % Specificity

27 DASP 2009 IAA Standardization Reported Sensitivity and Specificity % Sensitivity Our Lab Sensitivity : 78% Specificity : 97% % Specificity

28 Genotype + Environment = Phenotype Insulin Deficiency β-cell Autoimmunity Virus Infection Milk Feeding Stress Type 1 Diabetes

29 Hypothesis To Prove The High Risk haplotypes/genotypes are independent determinants of diabetes in the 1st degree relatives of individuals with type 1 diabetes, particularly in the presence of islet-specific antibodies. Incidence Seoul IDDM Registry Seoul Type 1 Diabetes Genetic Consortium Familial Risk of each Genetic Markers AutoAb(-) T1DM AutoAb(+) Simplex Families Simplex Families Diabetes development Stored samples

30 Difference in the Relative Proportion of T1DM by Age of Onset Number of Cases Percentage Japanese (Kuzuya et al.) Finnish (Laakso et al.) Age of Onset (yrs)

31 Atypical diabetes (Winter et al. 1987) :12 young obese African Americans spontaneous DKA anti-islet cell Ab(ICA) was negative strong family Hx of type 2 diabetes Idiopathic type 1 diabetes (Type 1 B ) ( phenotype characteristics of type 2 diabetes + clinical picture of type 1 diabetes by having unprovoked DKA )

32 Fulminant type 1 diabetes 11 Japanese individuals Presented with DKA and a low HbA1c level (diabetes was of very short duration.) severe hyperglycemia associated with DKA lacked the usual diabetes related antibodies. different than most of the North American patients with idiopathic Type 1 diabetes all thin, a lower HbA1c. Mild elevations of serum exocrine pancreatic enz.

33 Insulin secretory defect or increased susceptibility of desensitization to hyperglycemia may be an important factor in the pathogenesis of T1 B DM. IGI NGT NGT Rapid decrease in insulin secretory defect may predm in MS resemble T1DM T2DM in NoMS predm in NoMS T2DM in MS HOMA-IR

34 Latent Autoimmune Diabetes in Adults (LADA) LADA: type 1 diabetes presenting as non-insulin dependent diabetes The diagnosis of LADA according to Immunology of Diabetes Society 1) age over 35 years, 2) the presence at least one of four circulating autoantibodies to pancreatic islet cell antigens (ICA, GAD, IA-2, insulin) 3) lack of requirement for insulin at least 6 month after diagnosis

35 The Low Prevalence of Immunogenetic Markers in Korean Adult-onset IDDM Patients Study Design The prevalence of GAD Ab and high-risk HLA DQ alleles among 121 patients with newly diagnosed NIDDM identified from a population-based survey and 100 matched controls Results The overall prevalence of GAD Ab was 1.7% (2 of 121) in patients with previously undiagnosed NIDDM, whereas 1 of 100 control subjects had GAD Ab. Titers of GAD Abs were not high. Low prevalence of HLA DQB1 susceptibility alleles among recent-onset NIDDM patients was noted. Conclusions Diabetes in Korean adults is unlikely to have an autoimmune components to its pathogenesis. Park Y. et al. Diabetes Care 19: , 1996

36 The progression to insulin dependency after 36 months Park Y. et al. Diabetes Metab Res Rev 27:975, 2011

37 The mean titers of islets specific antibodies GAD ZnT8 IA-2 Insulin dependency (n=3) 0.071± ± ±0.031 Insulin independency (n=36) 0.029± ± ±0.025 p-value Park Y. et al. Diabetes Metab Res Rev 27:975, 2011

38 At present * Type 1 and type 2 diabetes defined * Type 2 diabetes in children described * Reports of double, hybrid, atypical diabetes (mixed phenotype) * Changes in the phenotype of typical T1DM

39 Diabetes in childhood T1DM Easy to diagnose Abrupt onset X Requiring medical attention Requiring medication (insulin) the epidemiologist s challenge

40 New T1DM Registry 의지향점 Serum Separation DNA Extraction EDTA 4 ml Plain 4 ml Vacuum DNA Fragment Analyses Autoantibody Detection

41 Construction of T1D Blood Bank Blood Sampling Blood Bank at Hanyang University center IRB inspection Barcode management Blood Bank DB system Cold room

42 Approach to the treatment of the Asian adolescent with diabetes New onset diabetes in an Asian adolescent Asymptomatic A1c < 9% No acidosis Symptomatic A1c > 9% No acidosis acidosis ᆞmetformin ᆞTitrate as tolerated ᆞInitiate education with focus on lifestyle change ᆞbasal insulin ᆞmetformin ᆞtitrate as tolerated ᆞInitiate education with focus on lifestyle change ᆞWean insulin as tolerated Pancreatic autoantibodies?t2d ᆞInsulin as in T1D until acidosis resolved ᆞWean insulin as tolerated?t1d ᆞInitiate MDI insulin therapy ᆞInitiate T1D education negative positive Continue metformin wean insulin Continue or initiate MDI insulin therapy Failure to maintain target A1c > % Initiate add-on insulin therapy basal insulin to max 1 unit/kg/day Failure to maintain target A1c > 6.5 7%

43 Underascertainment in diabetes epidemiology Incidence & pervalence data ascertained by Capture-Recapture method Source of Case Identification Traditional Aggregated Method Hospitals M. D. Pharmacies Schools Capture - Recapture Crude Counts Ascertainment - Corrected Counts

44 제 1 형당뇨병환자등록사업 동국의대 김경아 44

45 개요 사업추진배경및필요성 2011 년건강보험보장성확대계획으로 2011 년 7. 1 부터제 1 형당뇨병환자를위한혈당측정지보험시행규정으로건강보험공단에제 1 형당뇨병환자등록이시행됨. 자료분석 ; ~ 까지의등록 6059 명데이터를분석함 45

46 건강보험제 1 형당뇨병환자등록신청서 46

47 등록된진단명 ( 상병명 ) 상병별등록인원 상병코드상병명 인원 E10 인슐린-의존당뇨병 753 E100 혼수를동반한인슐린의존당뇨병 29 E1000 고삼투압성혼수를동반한인슐린-의존당뇨병 14 E1001 혼수와케토산증을동반한인슐린-의존당뇨병 47 E1002 혼수와젖산증을동반한인슐린-의존당뇨병 6 E1003 혼수와케토산증및젖산증을동반한인슐린-의존당뇨병 5 E1008 기타및상세불명의혼수를동반한인슐린-의존당뇨병 36 E101 케토산혈증을동반한인슐린의존당뇨병 35 E1010 케토산증을동반한인슐린-의존당뇨병 193 E1011 젖산증을동반한인슐린-의존당뇨병 2 E1012 케토산증및젖산증을동반한인슐린-의존당뇨병 4 E1018 기타및상세불명의산증을동반한인슐린-의존당뇨병 41 E102 콩팥 ( 신장 ) 합병증을동반한인슐린의존당뇨병 37 E1020 초기당뇨병신장병증을동반한인슐린-의존당뇨병 100 E1021 확정된당뇨병신장병증을동반한인슐린-의존당뇨병 53 E1022 말기신장병을동반한인슐린-의존당뇨병 56 E1028 기타및상세불명의신장합병증을동반한인슐린-의존당뇨병 39 E103 눈합병증을동반한인슐린의존당뇨병 13 E1030 배경성망막병증을동반한인슐린-의존당뇨병 28 E1031 당뇨병성전증식성망막병증을동반한인슐린-의존당뇨병 15 E1032 당뇨병성증식성망막병증을동반한인슐린-의존당뇨병 9 E1033 기타망막병증을동반한인슐린-의존당뇨병 18 E1034 당뇨병성백내장을동반한인슐린-의존당뇨병 4 E1038 기타및상세불명의눈합병증을동반한인슐린-의존당뇨병 23 E104 신경학적합병증을동반한인슐린의존당뇨병 36 E1040 당뇨병성단일신경병증을동반한인슐린-의존당뇨병 36 E1041 당뇨병성다발성신경병증을동반한인슐린-의존당뇨병 104 E1042 당뇨병성자율신경병증을동반한인슐린-의존당뇨병 14 E1048 기타및상세불명의신경학적합병증을동반한인슐린-의존당뇨병 63 상병별등록인원 상병코드상병명 인원 E105 말초순환장애합병증을동반한인슐린의존당뇨병 8 E1050 당뇨병성말초혈관병증을동반한 ~ 동반하지않는인슐린- 의존당뇨병 48 E1051 당뇨병성말초혈관병증을동반한, 괴저를동반한인슐린-의존당뇨병 1 E1058 기타및상세불명의순환기계합병증을동반한인슐린-의존당뇨병 11 E106 기타명시된합병증을동반한인슐린의존당뇨병 9 E1060 근골격및결합조직의합병증을동반한인슐린-의존당뇨병 1 E1061 피부및피하조직의합병증을동반한인슐린-의존당뇨병 2 E1062 치주합병증을동반한인슐린-의존당뇨병 0 E1063 저혈당을동반한인슐린-의존당뇨병 22 E1068 달리분류되지않은기타명시된합병증을동반한인슐린-의존당뇨병 62 E107 다발성합병증을동반한인슐린의존당뇨병 38 E1070 궤양을동반한 ( 하지 )( 혈관 ~ 성합병증을동반한인슐린-의존당뇨병 12 E1071 궤양과괴저를동반한 ( 하지 ) ~ 성합병증을동반한인슐린- 의존당뇨병 2 E1078 기타및상세불명의다발성합병증을동반한인슐린-의존당뇨병 211 E108 상세불명의합병증을동반한인슐린의존당뇨병 501 E109 합병증이없는인슐린의존당뇨병 3,318 총계 6,059 Data from 보험공단

48 연령분포 Data from 공단 소모성재료등록환자현황 인원총계 10대이하등록시연령별 6,059 1,628 1,172 1, 진단시연령별 20 대 30 대 40 대 50 대 60 대 70 대이상 6,059 2, 등록시연령별 2% 진단시연령별 7% 4% 6% 11% 12% 19% 27% 19% 10대이하 20대 30대 40대 50대 60대 70대이상 11% 9% 16% 16% 40% 10대이하 20대 30대 40대 50대 60대 70대 48

49 진단기준별제 1 형당뇨병등록현황 인슐린투여 공복 C-peptide 0.6 ng/ml 이하 자극 c-peptide 1.8 ng/ml 이하 24 시간소변 c-peptide 최초진단시당뇨병성케톤산증 자가항체 인원 6,059 4, ,294 1,386 % 100% 72% 8% 10% 21% 23% 각항목별로중복체크된경우도모두값에포함. Data from 보험공단

50 진단연령별상세증상별제 1 형당뇨등록현황 (i) 0~10 세군 11~20 세군 100% 100% 80% 80% 60% 60% 40% 40% 20% 20% 0% C-pep<0.6 GST Urine C-pep DKA Ab+ 0% C-pep<0.6 GST Urine C-pep DKA Ab+ 21~30 세군 31~40 세군 100% 100% 80% 80% 60% 60% 40% 40% 20% 20% 0% C-pep<0.6 GST Urine C-pep DKA Ab+ 0% C-pep<0.6 GST Urine C-pep DKA Ab+ 50

51 진단연령별상세증상별제 1 형당뇨등록현황 (ii) 41~50 세군 51~60 세군 100% 100% 80% 80% 60% 60% 40% 40% 20% 20% 0% 100% 80% 60% C-pep<0.6 GST Urine C-pep DKA Ab+ 61~70 세군 0% C-pep<0.6 GST Urine C-pep DKA Ab+ 71~84세군 100% 80% 60% 40% 40% 20% 20% 0% C-pep<0.6 GST Urine C-pep DKA Ab+ 0% C-pep<0.6 GST Urine C-pep DKA Ab+ 51

52 한국인제 1 형당뇨병환자등록사업및 제 1 형당뇨병환자의국가기반전향적 표준화전산데이터베이스구축

53 관리프로그램개발필요사유 현재 10 여개의연동케이블제공업체제품을검토한결과, 각제품별연동케이블을일원화하기는어려움 ( 통신프로토콜이혈당측정기자체에내장되어있거나연동케이블내에있는경우로나뉠수있고, 통신프로토콜방식이다양함 ) 각업체별관리프로그램이차별화되어존재하고, PC 기반및온라인기반의프로그램등으로구별됨. 프로그램별운영 DB 방식도다양하고보험관리 DB 양식으로부족한부분이있음. 하나의 DB 로운영할수있는건강보험관리공단에서관리할수있는표준화된프로그램필요함 독일 / 오스트리아 DPV-Wiss database 형태모방 건강보험관리공단프로그램과연동, 효율적시험지관리 시험지보험효과의 cost-effectiveness 평가 환자등록, 병원치료성적평가, 연구목적이용가능 53

54 혈당측정장비및소모품지급및 측정치의데이터베이스화 환자의경제적부담감소 성공적인등록사업 자가혈당측정을더많이하도록유도 혈당조절개선에따른합병증감소 소모품암시장생성의방지 전국규모의전향적다기관표준화전산데이터베이스구성

55 제 1 형당뇨병환자의국가기반전향적 표준화전산데이터베이스 소프트웨어표준화 자료의무기명화 인터넷기반당뇨병관리의전국적보급 이미혈당조절의개선효과가증명되어있으나도시지역에만보급 전국적보급으로취약계층지원 심한혈당변동성을보이는환자에대한연구 심한혈당변동성과합병증발생및사망률과의관계규명 중증도환자군선별및국가차원의체계적관리

56 Acknowledgment Park LJ, Park HW, Lim MS, Nam JW, Min DS, Shin GW (Hanyang U) Kim YH, Lee YM, Kim HJ, Cho AR, Sung KH (Hanyang U Hosp) Chung HY, Chun TH, Hwang KW (Hanyang & Chungang U) Yang SW, Kim DH (T1DGC) Choi DS, Choi SK, Park HY (T1DGC) LaPorte RE, Dorman J, Libman I (Pittsburgh U) Eisenbarth GS, Hutton J (UCHSC) Kawasaki E, Abiru N (Nagasaki U) Ikegami H (Osaka Kinki U) She JX, Wang CY (Med C Georgia) Tait B, Colman P (WEHI, U Melbourne) Zimmet P, Rowley M, Mackay I (Monash U) Sonderstrup G (Stanford U)

A 617

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