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

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DAISY Diabetes Autoimmunity Study, Denver, Colorado. Australian BABYDIAB study ... Crenier6, Christophe De Block8, Jean-Marie Seigneurin9, Pieter De Pauw1, Denis ... – PowerPoint PPT presentation

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


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 T1DM Risk
  • 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
8
6
4
2
0
8
6
4
2
0
Time from first Ab (years)
Hummel et al., Ann Intern Med, June 2004
10
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
First antibody is insulin/proinsulin
8
8
6
6
IAA
Cumulative frequency ()
4
4
2
2
0
0
10
8
6
4
2
10
8
6
4
2
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
Plt0.0001
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
10 14
21 23
1 1
2 4
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 lt 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
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
8
6
4
2
0
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
10
8
6
4
2
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 lt 0.005
20
15
Islet autoantibody frequency ()
10
Breast feeding only
5
Milk based supplements only
Non gluten solid food
0
8
6
4
2
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 gt 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 gt 0.2 pmol/l
  • Insulin therapy lt 4 weeks
  • Treatment
  • 6 days of infusion with 8 mg ChAgly CD3 each day
  • follow-up 48 months

32
Anti-CD3 new onset trialInsulin needs
IU/kg/day
0.70
P0.015
P0.006
P0.03
0.60
0.50
0.40
0.30
0.20
0.10
Baseline
6m
12m
18m
Keymuellen et al, NEJM 2005
33
Insulin needs at 18 months gtP50 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
6m
12m
18m
T0
gt 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 gt 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
STRATA
Oral Insulin
Diabetes Care 2005 281068-76
37
prevent.diabetes_at_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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