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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 l.jpg

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

Anette-G. Ziegler

Institut für Diabetesforschung and Krankenhaus München-Schwabing


Slide2 l.jpg

Natural history of type 1 diabetes Approaches to future therapy

Genetic susceptibility

Islet autoimmunity

single multiple

Clinical diabetes


Markers of pre diabetes in the blood l.jpg
Markers of ‘pre-diabetes’ in the blood Approaches to future therapy


Target autoantigens of autoantibodies in t1dm l.jpg
Target autoantigens of autoantibodies in T1DM Approaches to future therapy

Insulin

Glutamic Acid Decarboxylase (GAD)

IA-2/IA-2b


Prospective birth studies in type 1 diabetes l.jpg
Prospective birth studies in type 1 diabetes Approaches to future therapy

  • BABYDIAB, Munich Germany

  • DAISY Diabetes Autoimmunity Study, Denver, Colorado

  • Australian BABYDIAB study

  • DIPP Diabetes Prediction and Prevention Study, Finland


Genetic heirarchy of t1dm prevalence l.jpg
Genetic heirarchy of T1DM prevalence Approaches to future therapy

Family history of T1DMRisk

None 0.3%

First degree relative 3-5%

Identical twin 50%


Slide7 l.jpg

BABYDIAB since 1989: Approaches to future therapy

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


Slide8 l.jpg

Disease is ‘generally’ progressive Approaches to future therapy

Clinical

diabetes

Multiple

autoantibodies

Insulin autoantibodies

2 years

Age


Slide9 l.jpg

Progression to multiple Abs is necessary for disease Approaches to future therapy

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


Slide10 l.jpg

Multiple islet Abs (3.7%) Approaches to future therapy

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


First antibody is insulin proinsulin l.jpg

GADA Approaches to future therapy

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)


Slide12 l.jpg

Not all IAA positive children develop multiple antibodies Approaches to future therapy

Who does is defined very early

by maturity of antibody response (affinity)


Slide13 l.jpg

IAA affinity is high in children who develop Approaches to future therapy

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


Slide14 l.jpg

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


What influences the development of islet autoimmunity l.jpg
What influences the development of islet autoimmunity? insulin native genes.

Genetics

Environment


Slide16 l.jpg

Development of islet autoantibodies insulin native genes.

- 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)


Slide17 l.jpg

Development of islet autoantibodies insulin native genes.

- 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)


Hla and family history are independent risk of 50 achieved with combination l.jpg

DR3/4, 4/4 child of T1DM parent insulin native genes.

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)


Environment is likely to be major reason for rising incidence l.jpg
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


Environmental factors that may affect the development of islet autoantibodies l.jpg
Environmental factors that may affect the development of islet autoantibodies

Neonatal and maternal:

- Maternal autoimmunity

- Diet

- Vaccinations

- Infections


Slide21 l.jpg

Risk for developing islet Abs in relation to islet autoantibodies

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



Slide23 l.jpg

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)



Slide25 l.jpg

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


Teddy centers l.jpg
TEDDY centers in type 1 diabetes

  • Colorado (Denver)

  • Georgia/Florida

  • Washington

  • Germany (Munich)

  • Finland (Tampa, Oulu, Turku)

  • Sweden (Malmö)

    Data Coordinating Center (Tampa, Florida)


Teddy l.jpg
TEDDY in type 1 diabetes

  • 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 l.jpg
Purpose of natural history studies in type 1 diabetes

Predict and prevent disease


Slide29 l.jpg

Natural history of type 1 diabetes in type 1 diabetes

Genetic susceptibility

Islet autoimmunity

Clinical diabetes

Diabetic complications


Insulin needs following cd3 antibody therapy in new onset type 1 diabetes l.jpg
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 l.jpg
Anti-CD3 Europa TYPE 1 DIABETES

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


Slide32 l.jpg

ChAglyCD3 TYPE 1 DIABETES

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


Slide33 l.jpg

ChAglyCD3 TYPE 1 DIABETES

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


Slide34 l.jpg

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


Slide35 l.jpg

Therapy with oral insulin effect of initial secretory response

in patients

with islet autoantibodies

Projected risk of

30- 50% in 5 years


Slide36 l.jpg

DPT-1 Oral Study - Time to Diabetes - By Treatment effect of initial secretory response

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


Slide37 l.jpg

[email protected] effect of initial secretory response

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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