Keystone
Diabetes in Youth
Snowmass: Jan 23, 2008
Clinical diabetes and Endocrinology
Book on Immunology Diabetes
www.barbaradaviscenter.org_
With teaching slides
“Monogenic” Type 1
Diabetes
• IPEX (Immune Dysfunction/
Polyendocrinopathy/ Enteropathy/ X-Linked)
• APS-1
• Insulin Folding Mutations
Awaiting Bone Marrow Transplant for child with IPEX syndrome
9 Months
IPEX: Immune Dysfunction,
Polyendocrinopathy, Enteropathy, X-linked
• Scurfin gene (Foxp3/JM2)
- Controls Regulatory T Cells!
• Approximately 80% of children with
syndrome develop diabetes!
• Bone marrow transplant can reverse
BDC
Comparison APS-I and APS-II
APS-I
APS-II
• Onset Infancy
• Siblings
AIRE gene mutated
• Not HLA Associated
• Immunodeficiency
Asplenism
Mucocutaneous Candidiasis
• 18% Type 1 DM
• 100% anti-interferon Abs
•
•
•
•
Older Onset
Multiple Generations
DR3/4 Associated
No Defined
Immunodeficiency
• 20% Type 1 DM
APS-I Loss
Thymic Tolerance to
“Peripheral” Antigens
• Knockout of the AIRE gene abrogates
expression of many “peripheral antigens”
within the thymus such as insulin
• IDDM2 locus is insulin gene and Pugliese
(Miami) and Polychronakos (Montreal)
have shown, protective allele associated
with greater thymic insulin messenger
RNA.
MODEL AIRE Role in Preventing
Autoimmunity
Autoreactive
thymocyte
Tolerization of
autoreactive thymocyte
TCR
MHC + Peptide
Thymic Medullary
Epithelial Cells
AIRE
Self-peptides from
"peripheral" antigens
Mathis/Benoist
Europium-ELISA completely differentiated APS1
patients from non-APS1 patients, AD and T1D patients.
1.50
1.25
Index of hIFNa Ab
1.00
0.75
0.50
0.25
0.00
-0.25
APS1
non-APS1
Normal Ctrl
AD
T1D
Check List APS-I Visit
New Symptoms History
New Signs Physical
Oral Candidiasis
New Antibodies (21-OH, GAD, IA-2)
Ca, Pi, Mg
Na, K
ALT
ACTH, TSH, (LH, FSH)
HbA1c
Blood Smear (Howell-Jolly)
Platelet Count
Other
Eisenbarth GS, Gottlieb PA. New Engl J Med 2004;350:2068-79
Eisenbarth GS, Gottlieb PA. New Engl J Med 2004;350:2068-79
Development of 21-hydroxylase Autoantibodies in Patients
with Type 1A Diabetes
1.4
21-ydroxylase AutoAb
1.2
1
0.8
0.6
0.4
0.2
0
-0.2
0
5
10
15
20
25
AGE
30
35
40
45
Proportion AD free by MICA (21OH+ follow-up group)
Fraction survival
1.00
5.1/5.1
not
0.75
0.50
p=0.001
0.25
0.00
0.0
2.5
5.0
7.5
Follow-up time
10.0
12.5
Premature Mortality in Patients with Addison’s
Disease: A Population-Based Study
J clin endocrinol Metab 91:4859, 2006
Percent Dying 6.7 yr follow-up; mean start age 52.8
30
25
20
15
10
5
0
Addison's
N=507 deaths of 1675 patients
Expected
N=199 deaths
Peak Cortisol
(ug/dl)
21-Hydroxylase Autoantibody Positive
Patients
50
40
30
20
10
0
1
10
100
1000
ACTH (pg/ml
10000
PALM
ELBOW
Transglutam
inase
Deamidation
of Gliadin
Peptides
increases
affinity for
DQ2!
Figure 1. MZT Twins: Survival analysis of progression to diabetes
by age in probands and non-probands
100
90
Percent Not Diabetic
80
70
60
50
P<0.0001
40
Non-proband
30
20
Proband
10
0
0
10
20
30
40
50
60
70
9
3
1
Age
Probands
n= 83
Non-probands n= 83
51
73
16
45
8
28
1
19
80
Figure 4. Survival analysis of progression to Ab+ or diabetes
by age in MZ twin mates
100
90
Percent neither Ab+ nor diabetic
80
70
60
50
40
30
20
10
0
0
10
20
83
70
38
30
40
50
60
Age first positive Ab+ and/or diabetes
Non-proband
n=
26
15
5
2
70
80
Figure 2. Correlation between the age of onset of diabetes
in MZT proband and his/her twin mate
(for those twin mates who developed diabetes)
Age of Onset in Initially Discordant Twin
60
50
40
30
Li
ne
of
Id
e
i
nt
ty
p< 0.0001
r2= 0.7083
20
10
0
0
10
20
30
40
Age of Onset in Proband Twin
50
60
J. Noble
TERMINOLOGY
Allele:
Haplotype:
Genotype
DRB1*0401
DRB1*0401
DQB1*0302
DRB1*0401
DQB1*0302
DRB1*0301
DRB1*02
DQB1*02
DQB1*0402
 -chain
Leu56
-chain
Asp57
BDC
BDC
DAISY Study Population
General population cohort
Sibling/offspring cohort
screened = 31,881
offspring
Enrolled
387
456
384
1,227
high risk
moderate risk
average-low risk
All
siblings
51 (7.6%)
111 (17%)
509
53 (14%)
65 (17%)
254
671
372
HLA-defined IDDM risk groups
Denver population, n=9,338
IDDM risk by age 20
HLA-DR
DQB1
High 1:15
3/4
0201/0302
2.4
Moderate
1:60-1:200
4/x
4/4
3/3
0302/
0302/
0201/0201
12.7
3.0
1.4
Average 1:300
3/x
3/4
0201/
0201/not 0302
12.5
1.0
Lower than 1:300
4/x, 4/4
others
/not 0302
6.6
60.4
DAISY 7/96
Frequency %
Autoantibody positive
(% )
% Autoantibody Positive
100
90
80
70
60
50
40
30
20
10
0
High risk sibling
High risk offspring
Mod risk sibling
Mod risk offspring
Low risk sibling
Low risk offspring
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Age (y)
High risk sib: 49
Mod risk sib:
62
Low risk sib: 221
High risk offsp: 51
Mod risk offsp: 110
Low risk offsp: 506
43
60
216
49
106
477
40 33 26 22 20 14 11 10 8 7
50 45 39 34 30 28 23 19 16 10
198 181 160 139 109 88 66 55 44 34
44 40 33 28 21 19 15 10 8 6
92 83 69 58 49 41 33 27 20 14
430 378 324 271 228 191 153 128 109 89
6
8
27
3
12
72
4
3
24
1
12
52
2
2
19
0
8
38
0
0
0
0
0
0
(% )
A u to a n tib o d y p o s it
% A u t o a n t ib o d y P o s it iv e
100
90
80
70
60
50
40
30
20
10
0
H ig h r is k
M o d r is k
L o w r is k
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15
Ag e (y)
High risk:
Mod risk:
Low risk:
380 345 295 236 192 169 138 103 75 35 17
441 388 267 186 137 115 100 92 76 59 26
383 326 272 237 211 185 171 154 128 88 55
MHC Haplotype Sharing Increases DR3/4 Sibling Risk
Haplotype Determination:
Siblings Share
Both Haplotypes
Siblings Share
One Haplotype
Siblings Share
No Haplotype
Family B
Family C
Family A
Haplotypes
A
B
C
D
A
B
C
D
A
B
C
D
HLA-A
1
2
29
2
2
68
1
30
2
1
3
31
HLA-DRB1
3
4
4
6
4
8
3
3
3
3
4
4
Diabetic
Proband
DAISY
Sibling
Diabetic
Proband
DAISY
Sibling
Diabetic
Proband
DAISY
Sibling
HLA-A
1
29
1
29
2
30
2
1
1
31
2
3
HLA-DRB1
3
4
3
4
4
3
4
3
3
4
3
4
A
C
A
C
A
D
A
C
B
D
A
C
% Autoantibody Positive
100
Share 2
90
Share 0 or 1
% Diabetic
100
90
80
80
70
70
60
60
50
50
40
40
30
30
20
20
10
10
0
0
0.0 2.5 5.0 7.5 10.0 12.5 15.0 0.0
Age (y)
Share 2
Share 0 or 1
2.5
5.0
7.5 10.0 12.5 15.
Age (y)
ODDS RATIO
7
6
5
4
3
2
IN
PT S
PN
22
C
D
25
12
q2
ER 4
B
B
3e
PT
PN
K
2
IA
A
03
50
C
TL
A
4
C
D
25
H
LA
cl
as
s
II
1
Modified from Todd et al. Robust Associations of four new chromosome regions
from genome-wide anlayses of type 1 diabetes Nature Genetics June 6 2007