Anti-islet autoantibodies in Japanese type 1 diabetes

Transcription

1 15 th Korea Japan Symposium on Diabetes Anti-islet autoantibodies in Japanese type 1 diabetes Eiji Kawasaki, Katsumi Eguchi Nagasaki University Hospital, Nagasaki, Japan November 20 21, Cheju Islend

2 Atiilt Anti-islet autoantibodies tibdi in Japanese type 1 diabetes 1.Humoral autoimmune response to ZnT8 2.Type 1 diabetes and autoimmune thyroid disease (AITD) 3.Prediction of the disease progression in GADA + NIDDM (LADA)

3 Atiilt Anti-islet autoantibodies tibdi in Japanese type 1 diabetes 1.Humoral autoimmune response to ZnT8 2.Type 1 diabetes and autoimmune thyroid disease (AITD) 3.Prediction of the disease progression in GADA + NIDDM (LADA)

4 Clinical subtypes of type 1 diabetes in Japan Child onset Adult onset 10% <1% 6% 27% 90% 67% Fulminant Acute onset Slow onset (E Kawasaki et al. Diabetologia 49: , 2006)

5 Multiple causes of insulin-deficient diabetes Disorder Genetic Abnormality Extra-Pancreatic Disease Manifestations Type 1A diabetes MHC and non-mhc genes Type 1B diabetes? No MODY-1 HNF-4α gene No Organ-specific autoimmune disease MODY-3 HNF-1α gene No MODY-6 NeuroD1 gene No Wolfram Syndrome WFS1 gene Neuronal Kearns-Sayre mit DNA deletion Neuronal MELAS mit DNA mutation Hearing Loss (Ichinose K, Kawasaki E, Eguchi K. Am J Nephrol 27: , 2007)

6 Anti-islet Anti islet autoantibodies in type 1 diabetes GADA IA-2A (1990) ZnT8A (1994) ((2007)) IAA (1983) ICA Islet cell antibody GADA Glutamic acid decarboxylase IA 2A Insulinoma associated antigen 2 ZnT8A Zinc transporter 8 l autoantibody b d IAA Insulin Diagnosis/Prediction

7 Zinc Transporter 8 (ZnT8) Structure and functional role in beta cells Insulin secretory granule Cytoplasm of βcell N His rich loop SNP for type 2 diabetes SLC30A8 R325W C Epitope for ZnT8A ZnT8 Insulin monomer Zn Lumen of Insulin secretory granule aa 369 Insulin hexamer (E Kawasaki et al. Diabetologia 51: , 2008)

8 ZnT8A in Japanese type 1 diabetes Prevalence 58% 0% 21% 2% (47/81) (0/85) (10/47) (6/302) index) ZnT8A ( Acute-onset Fulminant GADA + NIDDM GADA - Type 2DM Cut off

9 Prevalence of ZnT8A associated with age-of-onset (Acute-onset n=81) (%) *P<0.05 vs. > 10yrs 77%* 51%

10 Combinatorial analysis of anti-islet autoantibodies in acute-onset t type 1 diabetes ZnT8A(58%) 1% (n=81, < 2wks after disease onset) GADA+ZnT8A 3% 1% IA-2A+IAA IAA 3% All negative 9% 3% 3% IA 2A 4% 20% 24% 5% 1% IAA (65%) (54%) ZnT8A 4% 9% 5% - + 0Ab 10% 9% 5% 1Abs 90% 91% 2Abs 73% 79% GADA(77%)

11 Combinatorial analysis of anti-islet autoantibodies in fulminant type 1 diabetes 0% ZnT8A(0%) (n=85, < 2wks after disease onset) GADA+ZnT8A 0% 0% IA-2A+IAA IAA 0% All negative 80% 0% 0% IA 2A 4% 0% 0% 0% 6% IAA (4%) (7%) 0% 0% 1% 10% GADA(11%) Most Abs + patients are single antibody- positive.

12 Atiilt Anti-islet autoantibodies tibdi in Japanese type 1 diabetes 1.Humoral autoimmune response to ZnT8 2.Type 1 diabetes and autoimmune thyroid disease (AITD) 3.Prediction of the disease progression in GADA + NIDDM (LADA)

13 Organ-specific autoimmune disease coexisting with type 1 diabetes in Japan Mimura et al. # Our Cases Combined n n n (%) Graves disease (53.3) Hashimoto's thyroiditis (34.8) Rheumatoid arthritis (5.4) Pernicious anemia (2.2) Myasthenia gravis (1.1) 1) Addison's disease (1.1) Sjögren syndrome (1.1) Autoimmune uveitis (1.1) 1) AITD # Diabetes Res Clin Pract 8: , 1990

14 GAD DA (Un nits) High titer and persistence of GADA in patients with type 1 diabetes and AITD ** ** ** ** * * p< **p< *p<0.01 vs. type 1 without AITD Type 1 diabetes with AITD Type 1 diabetes without AITD Negative Duration of diabetes (yrs) (E.Kawasaki et al. Diabetes 43:80 86, 1994)

15 GADA epitope p recognition in type 1 diabetic patients with and without AITD N E1 E3 E2 GAD65 AITD (+) AITD ( ) P value (n=23) (n=23) E1+E2 8 (35%) 19 (83%) N+E1+E2 11 (48%) 2 (9%) E1 only 2 (9%) 1 (4%) E2 only 1 (4%) 1 (4%) E3 only 1 (4%) 0 (0%)

16 GADA IgG isotype in type 1 diabetic patients with and without AITD AITD (+) AITD ( ) P value (n=23) (n=23) IgG1 23 (100%) 23 (100%) IgG2 13 (57%) 2 (9%) IgG3 12 (52%) 4 (18%) IgG4 1 (4%) 1 (4%)

17 Atiilt Anti-islet autoantibodies tibdi in Japanese type 1 diabetes 1.Humoral autoimmune response to ZnT8 2.Type 1 diabetes and autoimmune thyroid disease (AITD) 3.Prediction of the disease progression in GADA + NIDDM (LADA)

18 Islet autoantibodies in Japanese patients initially diagnosed as type 2 diabetes Autoantibodies tib Total Diet/OHA Insulin (n=648) (n=357) (n=291) GADA 31 (4.8%) 7 (2.0%) 24 (8.2%) IA-2A 7(11%) (1.1%) 1(03%) (0.3%) 6(21%) (2.1%) IAA/ IA 101 (15.6%) 12 (3.4%) 89 (30.6%) GADA and/or IA-2A 34 (5.2%) 8 (2.2%) 25 (8.6%) IAA, insulin autoantibodies; IA, insulin antibodies (E.Kawasaki et al. Ann NY Acad Sci 1005: , 2003 )

19 To identify the predictive markers for disease progression in GADA + diabetes.. Non-insulin treated type 2 diabetes n=~3,000 GADA screening GADA positive n= 47 Follow up (~ 9yrs) Started insulin therapy for glycemic control (n=17) Treated by diet and/or OHA (n=30)

20 Proportion of GADA + patients requiring insulin therapy classified according to the GADA titer Non-ins sulin tr reatme ent (%) Low GADA(<20U/ml, n=17) High GADA ( 20U/ml, n=30) Follow up period (yrs) P = (Log-rank test)

21 Proportion of GADA + patients requiring insulin therapy classified according to the GADA epitope (%) Non n-insul lin trea atment NH2 Middle (E1) Middle epitope (+) COOH (E2) Middle epitope (-) Follow up period (yrs) GAD65 P = (Log-rank test)

22 The frequencies of IA-2A ZnT8A and IAA in GADA + NIDDM GADA + NIDDM (n=47) IAA IA 2A Multiple islet Abs 17 (36%) 2 5 (4%) 1 GADA (11%) (2%) single 4 1 (9%) positive 0 (2%) (0%) 30 (64%) 4 (9%) ZnT8A 30 (64%) IAA + 12 (26%) ZnT8A + 9 (19%) IA 2A + 7 (15%)

23 Proportion of GADA + patients requiring insulin therapy classified according to the simultaneous presence of other autoantibodies 100 P=0.002 (log-rank test) Non-ins sulin tre eatmen nt (%) GADA single positive IAA/IA-2A/ZnT8A (+) Follow up period (yrs)

24 Risk factors for the progression of GADA + NIDDM GADA titer GADA epitope Insulin dependent d Other anti-islet islet autoantibodies

25 Multivariate logistic regression analysis for the association of islet autoantibody status with early insulin requirement among GADA + NIDDM Insulin requirement Variable OR 95% CI P value High GADA titer Middle GADA epitope (+) Multiple islet autoantibody (+) All variables were entered simultaneously into the model. High GADA titer, GADA 20U/ml Multiple islet autoantibody (+), positive for one or more of IAA, IA-2A, or ZnT8A

26 Collaborators Nagasaki University sty Hirofumi Takino Norio Abiru Masakazu Kobayashi Tsuyoshi Soto Genpei Kuriya Kan Nakamura Shigenobu Nagataki ki(emeritus professor) Seitoku University Nobuo Matsuura Tokyo Women s Medical University School of Medicine Junnosuke Miura Yasuko Uchigata Barbara Davis Center for Childhood Diabetes, USA John Hutton

27 Thank you for your attention! World lddiabetes Day Spectacle Bridge, Nagasaki