Transcript Gestational Diabetes and long

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
Markers of ‘pre-diabetes’ in the blood
Target autoantigens of autoantibodies
in T1DM
Insulin
Glutamic Acid Decarboxylase (GAD)
IA-2/IA-2b
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
Genetic heirarchy of T1DM prevalence
Family history of T1DM
Risk
None
0.3%
First degree relative
3-5%
Identical twin
50%
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
9 mo
5 yr
8 yr
11 yr
14 yr
Supported by Juvenile Diabetes Research Foundation JDRF
Disease is ‘generally’ progressive
Clinical
diabetes
Multiple
autoantibodies
Insulin autoantibodies
2 years
Age
Progression to multiple Abs is necessary
for disease
100
Diabetes (%)
80
multiple antibodies
60
40
20
Single IAA
0
0
2
4
6
8
Time from first Ab (years)
Hummel et al., Ann Intern Med, June 2004
Islet autoantibodies in BABYDIAB offspring
– multiple AAbs are early
10
Islet Abs (7.8%)
8
6
Multiple islet Abs (3.7%)
4
Single islet Abs
2
0
0
2
4
6
Age (years)
8
10
Hummel et al., Ann Intern Med, June 2004
Cumulative frequency (%)
First antibody is insulin/proinsulin
8
6
IAA
4
GADA
2
IA2A
0
0
2
4
6
Age (years)
8
10
Not all IAA positive children develop
multiple antibodies
Who does is defined very early
by maturity of antibody response
(affinity)
IAA affinity is high in children who develop
multiple islet Abs
1012
P<0.0001
IAA Affinity (L/mol)
1011
1010
109
108
107
106
105
104
multiple
Abs
IAA
only
Achenbach, J Clin Invest, 2004
Lack of progression to diabetes of NOD mice
lacking both insulin native genes.
% Diabetes Free
100
ins1-, ins2-, Tg+ (n=25, P<0.01)
80
ins1+, ins2-, Tg+ (n=25)
Life table update 5/19/05
60
40
20
0
0
10
20
30
40
50
60
Weeks of age
Ins1-, ins2-: n= 25
Ins1+, ins2-: n= 25
21
23
10
14
2
4
1
1
Nakayama et al, Nature, 2005
What influences the development
of islet autoimmunity?
Genetics
Environment
Development of islet autoantibodies
Multiple autoantibodies (%)
- Proband relationship affects risk
both parents or
parent + sibling
30
25
20
P < 0.0001
15
10
father only
5
P = 0.05
mother only
0
0
2
4
Age (years)
6
8
Development of islet autoantibodies
- HLA DR-DQ affects risk
DR3/4-DQ8
Multiple Ab frequency (%)
20
DR4/4-DQ8
15
10
Moderate
DR4-DQ8
Neutral
Moderate DR3
Protective
5
0
0
2
4
6
8
Age (years)
Walter et al, Diabetologia 2003 (updated 2004)
Cumulative Multiple Ab frequency (%)
HLA and family history are independent
- risk of 50% achieved with combination
DR3/4, 4/4 child of T1DM parent
And multiple family history
50
45
40
35
30
25
20
15
10
5
0
DR3/4, 4/4 child of T1DM parent
Child of T1DM parent
0
2
4
6
Age (years)
8
INCIDENCE (per 100,000/yr)
Environment is likely to be major
reason for rising incidence
80
70
60
50
40
30
20
10
0
PREDICTED
OBSERVED
1950
1975
2000
YRS
2025
2050
Environmental factors that may affect
the development of islet autoantibodies
Neonatal and maternal:
- Maternal autoimmunity
- Diet
- Vaccinations
- Infections
Risk for developing islet Abs in relation to
birth autoantibody status in offspring of T1D mothers
% with multiple Abs
10
P = 0.007
8
NEG GADA and IA2A at birth
n = 244
6
Father T1D
4
POS GADA or IA2A at birth
n = 476
2
0
2
4
6
Age (years)
8
10
Koczwara et al, Diabetes 2004
Food supplementation before 3 months of
age in 1610 BABYDIAB offspring
Breast feeding only
55 %
Milk based food supplements
40 %
Non-gluten solid foods
3.5 % !
Gluten foods
1.5 % !
Ziegler et al, JAMA 2003
Islet autoantibody frequency (%)
Food supplementation before age 3 months
and islet Abs risk in BABYDIAB offspring
25
p < 0.005
Gluten-containing food
20
15
10
Breast feeding only
5
Milk based supplements only:
Non gluten solid food
0
2
4
6
Age (years)
8
Ziegler et al, JAMA 2003
Norris et al, JAMA, 2003
Limitations of BABYDIAB and national
studies
Novel international study to
identify environmental triggers in
type 1 diabetes
supported by NIH, NIDDK, JDRF
The Environmental Determinants of Diabetes in the Young
TEDDY centers
•
•
•
•
•
•
Colorado (Denver)
Georgia/Florida
Washington
Germany (Munich)
Finland (Tampa, Oulu, Turku)
Sweden (Malmö)
Data Coordinating Center
(Tampa, Florida)
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
Purpose of natural history studies
Predict and prevent disease
Natural history of type 1 diabetes
Genetic susceptibility
Islet autoimmunity
Clinical diabetes
Diabetic complications
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
Anti-CD3 Europa
Phase II Trial
multicentric, 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
Anti-CD3 new onset trial
Insulin needs
IU/kg/day
0.70
P=0.015
P=0.006
P=0.03
0.60
ChAglyCD3
Placebo
0.50
0.40
0.30
0.20
0.10
Baseline
6m
12m
18m
Keymuellen et al, NEJM 2005
Insulin needs at 18 months: >P50
patients
ChAglyCD3
Placebo
0
0.2
0.4
0.6
0.8
IU/kg/day
1.0
1.2
1.4
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
> P50
18m
Therapy with oral insulin
in patients
with islet autoantibodies
Projected risk of
30- 50% in 5 years
DPT-1 Oral Study - Time to Diabetes By Treatment
Subset: IAA Confirmed > 80 nU/ml
1.0
Survival Distribution Function
0.9
0.8
Treated
0.7
0.6
0.5
Control
0.4
P- Value= 0.015
(Log Rank Test)
0.3
0.2
Number at Risk
0.1
130
133
122
121
104
96
86
69
66
46
40
32
23
12
1
2
3
4
5
6
Oral Insulin
Oral Placebo
0.0
0
Years Followed
STRATA:
Diabetes Care 2005; 28:1068-76
Oral Insulin
Oral Placebo
7
[email protected]
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