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Do we understand the development of type 1 diabetes? Approaches to future therapy

Do we understand the development of type 1 diabetes? Approaches to future therapy. Anette-G. Ziegler Institut für Diabetesforschung and Krankenhaus München-Schwabing. Natural history of type 1 diabetes. Genetic susceptibility. Islet autoimmunity single multiple. Clinical diabetes.

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Do we understand the development of type 1 diabetes? Approaches to future therapy

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  1. Do we understand the development of type 1 diabetes? Approaches to future therapy Anette-G. Ziegler Institut für Diabetesforschung and Krankenhaus München-Schwabing

  2. Natural history of type 1 diabetes Genetic susceptibility Islet autoimmunity single multiple Clinical diabetes

  3. Markers of ‘pre-diabetes’ in the blood

  4. Target autoantigens of autoantibodies in T1DM Insulin Glutamic Acid Decarboxylase (GAD) IA-2/IA-2b

  5. Prospective birth studies in type 1 diabetes • BABYDIAB, Munich Germany • DAISY Diabetes Autoimmunity Study, Denver, Colorado • Australian BABYDIAB study • DIPP Diabetes Prediction and Prevention Study, Finland

  6. Genetic heirarchy of T1DM prevalence Family history of T1DMRisk None 0.3% First degree relative 3-5% Identical twin 50%

  7. BABYDIAB since 1989: Prospective study from birth in offspring of mothers and/or fathers with T1DM 1610 offspring were eligible and entered in the study Follow-up visits (blood samples and questionnaires) Birth 2 yr 5 yr 8 yr 11 yr 14 yr 9 mo Supported by Juvenile Diabetes Research Foundation JDRF

  8. Disease is ‘generally’ progressive Clinical diabetes Multiple autoantibodies Insulin autoantibodies 2 years Age

  9. Progression to multiple Abs is necessary for disease 100 100 80 80 multiple antibodies 60 60 Diabetes (%) 40 40 20 20 Single IAA 0 0 0 0 2 2 4 4 6 6 8 8 Time from first Ab (years) Hummel et al., Ann Intern Med, June 2004

  10. Multiple islet Abs (3.7%) Single islet Abs Islet autoantibodies in BABYDIAB offspring – multiple AAbs are early 10 Islet Abs (7.8%) 8 6 4 2 0 0 2 4 6 8 10 Age (years) Hummel et al., Ann Intern Med, June 2004

  11. GADA IA2A First antibody is insulin/proinsulin 8 8 6 6 IAA Cumulative frequency (%) 4 4 2 2 0 0 2 2 4 4 6 6 8 8 10 10 0 0 Age (years)

  12. Not all IAA positive children develop multiple antibodies Who does is defined very early by maturity of antibody response (affinity)

  13. IAA affinity is high in children who develop multiple islet Abs P<0.0001 1012 1011 1010 109 IAA Affinity (L/mol) 108 107 106 105 104 multiple Abs IAA only Achenbach, J Clin Invest, 2004

  14. Lack of progression to diabetes of NOD mice lacking both insulin native genes. Life table update 5/19/05 25 25 21 23 10 14 2 4 1 1 Ins1-, ins2-: n= Ins1+, ins2-: n= Nakayama et al, Nature, 2005

  15. What influences the development of islet autoimmunity? Genetics Environment

  16. Development of islet autoantibodies - Proband relationship affects risk both parents or parent + sibling 30 25 20 P < 0.0001 15 Multiple autoantibodies (%) 10 father only 5 P = 0.05 mother only 0 0 2 4 6 8 Age (years)

  17. Development of islet autoantibodies - HLA DR-DQ affects risk DR3/4-DQ8 20 DR4/4-DQ8 15 10 Multiple Ab frequency (%) Moderate DR4-DQ8 5 Neutral Moderate DR3 Protective 0 0 2 4 6 8 Age (years) Walter et al, Diabetologia 2003 (updated 2004)

  18. DR3/4, 4/4 child of T1DM parent And multiple family history DR3/4, 4/4 child of T1DM parent HLA and family history are independent- risk of 50% achieved with combination 50 45 40 35 30 25 Cumulative Multiple Ab frequency (%) 20 15 10 5 Child of T1DM parent 0 0 2 4 6 8 Age (years)

  19. Environment is likely to be major reason for rising incidence 80 70 60 INCIDENCE (per 100,000/yr) PREDICTED 50 40 30 20 OBSERVED 10 0 1950 1975 2000 2025 2050 YRS

  20. Environmental factors that may affect the development of islet autoantibodies Neonatal and maternal: - Maternal autoimmunity - Diet - Vaccinations - Infections

  21. Risk for developing islet Abs in relation to birth autoantibody status in offspring of T1D mothers 10 P = 0.007 8 NEG GADA and IA2A at birth n = 244 6 % with multiple Abs Father T1D 4 POS GADA or IA2A at birth n = 476 2 0 2 4 6 8 10 Age (years) Koczwara et al, Diabetes 2004

  22. Food supplementation before 3 months of age in 1610 BABYDIAB offspring Ziegler et al, JAMA 2003

  23. Food supplementation before age 3 months and islet Abs risk in BABYDIAB offspring 25 Gluten-containing food p < 0.005 20 15 Islet autoantibody frequency (%) 10 Breast feeding only 5 Milk based supplements only: Non gluten solid food 0 2 4 6 8 Ziegler et al, JAMA 2003 Norris et al, JAMA, 2003 Age (years)

  24. Limitations of BABYDIAB and national studies

  25. Novel international study to identify environmental triggers in type 1 diabetessupported by NIH, NIDDK, JDRF

  26. TEDDY centers • Colorado (Denver) • Georgia/Florida • Washington • Germany (Munich) • Finland (Tampa, Oulu, Turku) • Sweden (Malmö) Data Coordinating Center (Tampa, Florida)

  27. TEDDY • Genetic screening: 220,800 babies worldwide to identify children at increased genetic risk for T1DM • To include > 7000 babies into intense follow-up programme • duration: • 4 years recruitment • 15 years individual follow-up

  28. Purpose of natural history studies Predict and prevent disease

  29. Natural history of type 1 diabetes Genetic susceptibility Islet autoimmunity Clinical diabetes Diabetic complications

  30. INSULIN NEEDS FOLLOWING CD3 ANTIBODY THERAPY IN NEW-ONSET TYPE 1 DIABETES Bart Keymeulen1, Evy Vandemeulebroucke1, Anette G. Ziegler2, Chantal Mathieu3, Leonard Kaufman4, Geoff Hale5, Frans Gorus1, Michel Goldman6, Markus Walter2, Sophie Candon7, Liliane Schandene6, Laurent Crenier6, Christophe De Block8, Jean-Marie Seigneurin9, Pieter De Pauw1, Denis Pierard1, Ilse Weets1, Peppy Rebello5, Pru Bird5, Eleanor Berrie5, Mark Frewin5, Herman Waldmann5, Jean-François Bach7, Daniel Pipeleers1, Lucienne Chatenoud7 New England Journal of Medicine 2005

  31. Anti-CD3 Europa Phase II Trialmulticentric, placebo controlled (80 patients were randomized) Inclusion criteria: Newly diagnosed diabetes Age 12-39 years Islet antibody positive C-Peptid basal > 0.2 pmol/l Insulin therapy < 4 weeks Treatment 6 days of infusion with 8 mg ChAgly CD3 each day follow-up 48 months

  32. ChAglyCD3 Placebo Anti-CD3 new onset trialInsulin needs IU/kg/day 0.70 P=0.015 P=0.006 P=0.03 0.60 0.50 0.40 0.30 0.20 0.10 Baseline 6m 12m 18m Keymuellen et al, NEJM 2005

  33. ChAglyCD3 Placebo 0 0.2 0.4 0.6 0.8 1.0 1.2 1.4 IU/kg/day Insulin needs at 18 months: >P50 patients

  34. Evolution of C-peptide release after glucose stimulation : effect of initial secretory response nM/min 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1 T0 6m 12m 18m > P50

  35. Therapy with oral insulin in patients with islet autoantibodies Projected risk of 30- 50% in 5 years

  36. DPT-1 Oral Study - Time to Diabetes - By Treatment Subset: IAA Confirmed > 80 nU/ml 1.0 0.9 0.8 Treated 0.7 0.6 0.5 Survival Distribution Function Control 0.4 P- Value= 0.015 (Log Rank Test) 0.3 Number at Risk 0.2 130 133 122 121 104 96 86 69 66 46 40 32 23 12 Oral Insulin Oral Placebo 0.1 0.0 0 1 2 3 4 5 6 7 Years Followed Oral Placebo Oral Insulin STRATA: Diabetes Care 2005; 28:1068-76

  37. prevent.diabetes@lrz.uni-muenchen.de Thank you Markus Walter, Michael Hummel, Sandra Hummel, Kerstin Koczwara, Peter Achenbach, Thomas Kaupper, Martin Füchtenbusch, Ezio Bonifacio, Annette Knopff, Ulrike Mollenhauer, Andrea Baumgarten, Angelica Locher, Steffi König, Sabine Marienfeld, Christiane Winkler, Diana Zimmermann, Daniela Hanak, Doris Huber

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