1. ETIOPATHOGENESIS
OF
TYPE 1 DIABETES
DR. SYED MOHD RAZI

2. TYPE 1 DIABETES
Juvenile onset diabetes.
Insulin dependent diabetes mellitus (IDDM).
“ Results from β cell destruction, ususally leading to
absolute insulin deficiency.”
Diabetes Care, volume 36, supplement 1, January 2013

3. ETIOLOGY OF T1DM
Multifactorial Etiologies :-
1. Genetics
2. Autoimmunity, autoantibodies & cellular immunity.
3. Environment.
Cold Spring Harb Perspect Med 2012;2:a007641)

4. TYPE 1 DIABETES MELLITUS
MONOGENIC : Single gene defect.
APS-I: AIRE autosomal recessive
XPID: Scurfy Gene X-linked

5. APS-SYNDROMES
APS-I:>=2 of Candidiasis, Hypopara,Addison’s
APS-II:Addison’s + Autoimmune Thyroid and/or Type 1 Diabetes.
APS-III: Thyroid Autoimmune + other autoimmune [not above].
APS-IV: Two or more organ-specific autoimmune, not I,II, or III.
Betterle et al. Endocrine Reviews 23:327-364
Neufeld and Blizzard: 1980, Pinchera, in Symposium Autoimmune Endocrine Aspects of Endocrine
Disorders

6. XPID: X-linked polyendocrinopathy,
immune dysfunction and diarrhea
Other Names
IPEX: Immunodysregulation, Polyendocrinopathy, Enteropathy, X-linked
XLAAD: X-Linked Autoimmunity Allergic Dysregulation
Foxp3 Gene Mutation
Loss of Regulatory T Lymphocytes
Bone Marrow Transplant with Chimera “Cures” Scurfy Mouse and Man
Greenspans b & c endocrinology 9th edition

7. POLYGENIC
Summation of small effects of
multiple genes creating diabetes
susceptibility (e.g. NOD mouse)

8. ANIMAL MODELS OF T1DM
Polygenic Spontaneous Animal Models : Nonobese
Diabetic Mouse
Most intensively studied.
Mutations causing absence of I-E ( similar to DR) &
unsually I-A ( similar to DQ).
Inheritance polygenic & more Diabetic females .
T cell mediated destruction.
Diabetes prevented by introduction of I-E or I-A .
William’s Textbook of Endocrinology, 12thEdition

9. OLIGOGENIC
MHC+few major genes
Genetic heterogeneity with
different major non-MHC genes
for different families (e.g. BB rat)

10. ANIMAL MODELS OF T1DM
Oligogenic Animal Models : Biobreeding Rat
1st intensively studied rat model.
Diabetes prone rat -> AR mutation & severe T cell
lymphopenia.
Disease depends -> specific class II allele mutations .
Anti-inflammatory drugs prevent diabetes.
Long-Evans Tokushima Lean Rat
Cbl-b mutation altering T cell functioning.
William’s Textbook of Endocrinology, 12thEdition

11. GENETICS OF T1DM
T1DM--- Multifactorial disease. (Noble & Erlich 2012)
Risk of T1DM in general U.S. population- 1 in 300.
Risk in 1degree relatives of T1DM pt. -- 1 in 20.
Concordance rate in---- Monozygotic twins -30-50%.
Dizygotic twins - 6-10%.
Cold Spring Harb Perspect Med 2012;2:a007641)

12. GENETICS OF T1DM Cont…
85% of cases occur -> pt. with no family H/O.
(Hämälainen & Knip 2002).
Risk in children of T1DM: mother – 2% & with T1DM
father- 7% ( Redondo et al. 2001).
> 50 loci identified. ( Cooper et al.2008)
No single locus : Necessary or sufficient.
Cold Spring Harb Perspect Med 2012;2:a007641)

13. J. Noble
HLA
Human Leukocyte Antigen
human MHC
cell-surface proteins
important in self vs. nonself
distinction
present peptide antigens to T cells
CLASS I: A,B,C CLASS II: DR,DQ,DP

14. HUMAN LEUKOCYTE ANTIGEN(HLA)
HLA (Chr6p21)  Greatest contribution (60%)
Strongest association HLA II genes (Redondo et al.2001)
MHC variability -> differences in β cell antigen
presentation.
Cold Spring Harb Perspect Med 2012;2:a007641)

15. HUMAN LEUKOCYTE ANTIGEN(HLA)
HLA is named as– Gene locus name-> Asterisk-> serologic
specificity -> specific allele-> silent nucleotide
polymorphism.
Highest risk genotype ---
DRB1*0301,DQA1*0501,DQB1*0201,DRB1*0302,
DQA1*0301,DQB1*0302.
Protective genotypes ----DQA1*0102,DQB1*0602.
William’s Textbook of Endocrinology, 12thEdition

16. STRUCTURE OF HLA GENE
The Major Histocompatibility Complex
Class II Class III Class I
Human
Chromosome 6
DP DQ DR B C A
Antigen Processing Complement Cytokines Class I-like genes
Genes Proteins and pseduogenes
Class III Class I
Class I Class II
Mouse
Chromosome 17
K I-A I-E D L

17. HLA SUSCEPTIBILITY
HBDI Families: Odds Ratio
5
* *
4
*p< 0.05 vs. control
Odds ratio
3 haplotype
2
1
* * * * * *
0
HBDI Families: Transmission from Heterozygous Parents
* *
461 389 40 51 182 82 99 20 121 55 124 27 135 34
Transmission frequency (%)
80
60 High risk
Moderate risk
40
Protective
20
0
02 1
02 1
02 2
03 1
03 4
01 3
05 02
3
01 2
01 1
02 02
01 503
01 2
02 3
03 2
01 50
01 40
30
60
05 60
30
01 50
01 30
04 /0
30
01 /0
3
6
/0
/0
/0
/0
/0
/0
/0
01
01
/0
/0
/0
/0
/0
03
01

18. OTHER LOCI
IDDM2 : II nd highest impact on disease development.
(OR 1.5)
locus located : VNTR region upstream insulin.
Shorter repeats confer higher risk & vice versa.
( Pugliese et al. 1997).
Other loci are – CTLA4 , PTPN22, CD25( Concannon et al.2008)
Cold Spring Harb Perspect Med 2012;2:a007641)

19. NON HLA LOCI IN T1DM
Cold Spring Harb Perspect Med 2012;2:a007641)

20. The IDDM2 Locus
IDDM2 Insulin Gene (INS)
Predisposing
Class I VNTR
26-63 repeats
21 alleles
IDDM2 Insulin Gene (INS)
Protective
Class III VNTR
140-200 repeats
15 alleles
VNTR = Variable Number of Tandem Repeats

21. AUTOIMMUNITY , AUTOANTIBODIES
& CELLULAR IMMUNITY
Autoimmunity specific to β cells.( atkison et al.)
Specific mechanisms responsible  Yet to be
elucidated . ( La Torre 2010)
Cellular immune response Remains controversial.
( Roep 2003)
Cold Spring Harb Perspect Med 2012;2:a007641)

22. INDUCTION OF Βcell
AUTOIMMUNITY
1. Molecular mimicry.
2. Alteration of self antigens.
3.Defective MHC expression.
4. Breakdown of central tolerance.
5.Defective dendritic cell trafficking.
6.Sensitivity to free radicals & cytokines.
7.Ever elusive local viral infection.
8.Defects in peripheral tolerance.
Cold Spring Harb Perspect Med 2012;2:a007641)

23. AUTOANTIBODIES
Considered as surrogate marker of autoimmunity.
Present long before clinically evident disease.
(Ziegler 2010)
Autoantibodies  “ smoke of fire” old view.
Crucial role of B cells & antibodies in pathogenesis.
( Marino et al. 2011)

24. AUTOANTIBODIES
Autoantibodies  0.5% general population .
 3-4% relatives of T1DM pt.
 70-80% of newly diagnosed pt.
Autoantibodies titer & number independent
predictors.
High titers, younger age, high risk HLA  More
accurate prediction.
Cold Spring Harb Perspect Med 2012;2:a007641)

25. 10000
Anti-insulin autoantibodies (nU/ml)
1000
100
10
1
5 10 15 20 25 30 35
Age (years)
Insulin Autoantibodies Versus Age of
Diabetes Onset
Diabetes Care 11:736-739, 1988

26. AUTOANTIBODIES
Combination of antibodies  Increased risk.
5 yr risk with  1 antibody 20-25%
 2 antibodies 50-60%.
3 antibodies 70%.
4 antibodies 80%. (winter 2011 ,DPT 1)
Cold Spring Harb Perspect Med 2012;2:a007641)

27. 100 Progression to Diabetes
vs Number of
80
Autoantibodies
60 3 Abs (GAD, ICA512, Insulin)
2 Abs 3 Ab n = 41 1 8 1
40 1 Ab
2 Abs n = 44 27 15
20 4 2 1
0 1 Abs n = 93 23 14
10 6 4
0 2.5 5 7.5 10 12.5 15

28. AUTOANTIBODIES
IAA Antibodies  measured within a week of
exogenous insulin. ( winter 2011).
IAA assays  cumbersome. (Bonifacio 2010)
GAD antibodies  Most predominant in LADA.
(Leslie et al. 2008)
( Cold Spring Harb Perspect Med 2012;2:a007641)

29. AUOTANTIBODIES
Markers of the immune destruction of the β -cell include
Ab Sensitivity Specficity
GAD 65 70-90 % 99 %
IAA 40-70 % 99 %
Tyrosine phosphatase 50-70 % 99 %
ZnT8 more auto Ab50-70 present in 85–90% of individuals
1 or are % 99 %
the time of diagnosis
Greenspan’s b&c endorinology 9th ed

30. T1DM RISK STRATIFICATION
Cold Spring Harb Perspect Med 2012;2:a007641)

31. ENVIRONMENT
Discordance in monozygotic twins.
Rise in global incidence.
Variance in geographical prevalence.
Assimilation of local incidence rate in migrants.
(Atkinson 2001)
Cold Spring Harb Perspect Med 2012;2:a007641)

32. ACCELERATOR & OVERLOAD
THEORY
Environmental stress
Increase insulin demand
β cell overloading
Accelerating β cell damage (Fourlanos et al.2008)
Cold Spring Harb Perspect Med 2012;2:a007641)

33. HYGIENE HYPOTHSIS
“ Rising incidence of autoimmune diseases in general
due to reduced or altered stimulation by
environmental factor”.
(Cook 2009 )
Cold Spring Harb Perspect Med 2012;2:a007641)

34. FERTILE FIELD HYPOTHESIS
Microbial infection
Other antigens react easily.
Auto- reactive T cells.
(Von Herrath et al. 2003)
Cold Spring Harb Perspect Med 2012;2:a007641)

35. OLD FRIENDS HYPOTHESIS
“Normal GIT commensals implicate dietary exposure
as regulator of the immune system & self tolerance.”
(Vaarala et al. 2008)
Cold Spring Harb Perspect Med 2012;2:a007641)

36. THRESHOLD HYPOTHESIS
Mathematical model calculating risk of T1DM.
Contribution of genetics & environment as function of
invariables subject to calculation.
( Wasserfall et al. 2011)
Cold Spring Harb Perspect Med 2012;2:a007641)

37. ENVIRONMENTAL FACTORS
Infectious agents
No direct evidence.
Rubella incorrectly cited evidence for this activity.
(Gale 2008)
Enteroviral association with the disease. ( Jaiden et al.2010)

38. ENVIRONMENTAL FACTORS
Increased risk in early weaning & exposure to cow’s
milk . ( TRIGR Study Group et al. )
Increased susceptibility associated with the timing of
exposure to cereal & gluten. ( DIASY, BABY- DIAB)
Low Vit. D  not only association but a cause of
T1DM. ( North – South Gradient Hypothesis , Karvonen 2000)

39. Ziegler, JAMA 2003: 290:721
BabyDiab and DAISY
30
Islet autoimmunity, %
25
Age introduction
20 <=3 mo.
15 >6 mo.
10 >3 to6 mo. gluten (Ziegler) or
5 cereal (Norris) greatly
0
0 2 4 6 8
increases
Age (years) development of anti-
islet autoantibodies in
DR3/4 DQ8: Norris JAMA 290:1713 infants followed from
birth.
25
Islet Autoimmunity, %
20
15 <=3 mo.
4 o 6 mo.
10 >=7 mo.
5
0
0 2 4 6 8
Age (years)

40. ENVIRONMENTAL FACTORS
Nitrosamine compounds  T1DM ( Kostraba et al. 1992)
Maternal child blood group incompatibility.
Other obstretic factors pre-ecclampsia.
 Neonatal respiratory distress.
 Low birth weight.
 Caesarean section.
 Maternal age.
 Birth order.
 Gestational age. (Mc Kinney et al. 1997)
Cold Spring Harb Perspect Med 2012;2:a007641)

41. Stages:Type IA Diabetes
I Genetic Susceptibility
II Triggering
III Active Autoimmunity
IV Progressive Metabolic Abnormalities
V Overt Diabetes
VI Insulin Dependence

42. 1986 NEJM “Stages” in Development of T1Diabetes
(?Precipitating Event)
Genetic Overt
Predisposition immunologic
abnormalities Progressive
loss insulin
Beta cell mass
release
Normal insulin
release Overt
Glucose diabetes
normal
C-peptide
present
No
C-peptide
Age (years)

43. PATHOGENESIS & NATURAL
HISTORY OF T1DM
Cold Spring Harb Perspect Med 2012;2:a007641)

44. RELAPSING & REMITTING MODEL OF
T1DM

45. THANKS