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

prevent.diabetes@lrz.uni-muenchen.deThank 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