Embed Size (px)
Citation preview
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
Islet autoimmunitysingle multiple
Genetic susceptibility
Clinical diabetes
Markers of ‘pre-diabetes’ in the blood
Target autoantigens of autoantibodies in T1DM
Insulin
Glutamic Acid Decarboxylase (GAD)
IA-2/IA-2
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
Follow-up visits (blood samples and questionnaires)
Birth9 mo
2 yr 5 yr 8 yr 11 yr
1610 offspring were eligible and entered in the study
14 yr
Supported by Juvenile Diabetes Research Foundation JDRF
Age2 years
Insulin autoantibodies
Multiple autoantibodies
Clinicaldiabetes
Disease is ‘generally’ progressive
Time from first Ab (years)
Dia
bete
s (%
)
86420
100
80
60
40
20
086420
100
80
60
40
20
0
multiple antibodies
Single IAA
Hummel et al., Ann Intern Med, June 2004
Progression to multiple Abs is necessary for disease
0 2 4 6 8 100
2
4
6
8
10
Islet autoantibodies in BABYDIAB offspring – multiple AAbs are early
Age (years)
Islet Abs (7.8%)
Multiple islet Abs (3.7%)
Single islet Abs
Hummel et al., Ann Intern Med, June 2004
First antibody is insulin/proinsulin
1086420
8
6
4
2
0
IAA
IA2A
GADA
1086420
8
6
4
2
0
Age (years)
Cu
mu
lativ
e fr
equ
ency
(%
)
Not all IAA positive children develop multiple antibodies
Who does is defined very early
by maturity of antibody response
(affinity)
104
105
106
107
108
1010
1011
IAA
Aff
init
y (L
/mo
l)
109
1012
multipleAbs
IAAonly
IAA affinity is high in children who developmultiple islet Abs
P<0.0001
Achenbach, J Clin Invest, 2004
0 10 20 30 40 50 600
20
40
60
80
100
ins1-, ins2-, Tg+ (n=25, P<0.01)
ins1+, ins2-, Tg+ (n=25)
Weeks of age
% D
iab
ete
s F
ree
Lack of progression to diabetes of NOD mice lacking both insulin native genes.
Ins1-, ins2-: n=Ins1+, ins2-: n=
2525
1014
2123
11
24
Life table update 5/19/05
Nakayama et al, Nature, 2005
What influences the development of islet autoimmunity?
Genetics
Environment
0 2 4 6 8
0
5
10
15
20
25
30
Mu
ltip
le a
uto
antib
od
ies
(%) both parents or
parent + sibling
mother only
father only
Age (years)
P = 0.05
Development of islet autoantibodies - Proband relationship affects risk
P < 0.0001
0 2 4 6 8Age (years)
0
5
10
15
20
Mul
tiple
Ab
freq
uenc
y (%
)
DR3/4-DQ8
DR4/4-DQ8
Moderate DR4-DQ8
Moderate DR3Protective
Neutral
Development of islet autoantibodies- HLA DR-DQ affects risk
Walter et al, Diabetologia 2003 (updated 2004)
HLA and family history are independent- risk of 50% achieved with combination
Age (years)
Cu
mu
lativ
e M
ulti
ple
Ab
fre
que
ncy
(%)
86420
40353025201510
50
Child of T1DM parent
DR3/4, 4/4 child of T1DM parent
DR3/4, 4/4 child of T1DM parentAnd multiple family history50
45
Environment is likely to be major reason for rising incidence
0
10
20
30
40
50
60
70
80
1950 1975 2000 2025 2050
YRS
INC
IDE
NC
E (
per
100
,000
/yr)
OBSERVED
PREDICTED
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
10
8
6
4
2
0108642
% w
ith m
ultip
le A
bs
Age (years)
POS GADA or IA2A at birthn = 476
NEG GADA and IA2A at birthn = 244
P = 0.007
Koczwara et al, Diabetes 2004
Father T1D
Breast feeding onlyBreast feeding only 55 %55 %
Milk based food supplementsMilk based food supplements 40 %40 %
Non-gluten solid foodsNon-gluten solid foods 3.5 % !3.5 % !
Gluten foodsGluten foods 1.5 % !1.5 % !
Ziegler et al, JAMA 2003
Food supplementation before 3 months of age in 1610 BABYDIAB offspring
Age (years)
Gluten-containing food
Non gluten solid food
Milk based supplements only:
Breast feeding only
8642 0
Isle
t au
toa
ntib
od
y fr
equ
enc
y (%
) 25
20
15
10
5
p < 0.005
Food supplementation before age 3 months and islet Abs risk in BABYDIAB offspring
Ziegler et al, JAMA 2003Norris et al, JAMA, 2003
Limitations of BABYDIAB and national studies
The Environmental Determinants of Diabetes in the Young
Novel international study to identify environmental triggers in
type 1 diabetessupported by NIH, NIDDK, JDRF
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
Islet autoimmunity
Genetic susceptibility
Clinical diabetes
Diabetic complications
INSULIN NEEDS FOLLOWING CD3 ANTIBODY
THERAPY IN NEW-ONSET TYPE 1 DIABETES
New England Journal of Medicine 2005
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
Anti-CD3 Europa
Inclusion criteria:Newly diagnosed diabetesAge 12-39 yearsIslet antibody positiveC-Peptid basal > 0.2 pmol/l Insulin therapy < 4 weeks
Treatment6 days of infusion with 8 mg ChAgly CD3 each dayfollow-up 48 months
Phase II Trialmulticentric, placebo controlled (80 patients were randomized)
0.10
0.20
0.30
0.40
0.50
0.60
0.70
Baseline 6m 12m 18m
ChAglyCD3
Placebo
IU/kg/day
P=0.015 P=0.006 P=0.03
Anti-CD3 new onset trialInsulin needs
Keymuellen et al, NEJM 2005
0 0.2 0.4 0.6 0.8 1.0 1.2 1.4
ChAglyCD3
Placebo
IU/kg/day
Insulin needs at 18 months: >P50 patients
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
6m 12m 18mT0
> P50
nM/min
Evolution of C-peptide release after glucose stimulation : effect of initial secretory response
Therapy with oral insulinin patients
with islet autoantibodies
Projected risk of30- 50% in 5 years
DPT-1 Oral Study - Time to Diabetes - By Treatment
Subset: IAA Confirmed > 80 nU/ml1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0.0
Sur
viva
l Dis
trib
utio
n F
unct
ion
0 1 2 3 4 5 6 7
Years Followed
130133
122121
10496
8669
6646
4032
2312
Number at Risk
P- Value= 0.015(Log Rank Test)
Oral InsulinOral Placebo
STRATA: Oral Insulin Oral Placebo
ControlControl
TreatedTreated
Diabetes Care 2005; 28:1068-76
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
