TYPE 1 DIABETES MELLITUS

1. DR. PRIYANKA BHARDWAJ
PATHOLOGY DEPARTMENT

2.  A group of metabolic disorders sharing the
common underlying feature of hyperglycemia.
 Hyperglycemia in diabetes results from defects in
insulin secretion, insulin action, or, most
commonly, both.

3.  The total number of people with diabetes
worldwide was estimated to be between 151
million and 171 million at the turn of the century,
and is expected to rise to 366 million by 2030.
 The prevalence of diabetes in the developing
world are due to sedentary life styles, with India
and China being the largest contributors to the
world's diabetic load.

4.  The chronic hyperglycemia and metabolic
dysregulation may be associated with secondary
damage in multiple organ systems, especially the
kidneys, eyes, nerves, and blood vessels.
 Diabetes is the leading cause of end-stage renal
disease, adult-onset blindness, and non traumatic
lower extremity amputations.
DIAGNOSIS
 Blood glucose values are normally maintained in a
very narrow range, usually 70 to 120 mg/dl.

5.  The diagnosis of diabetes is established by
elevation of blood glucose by any one of three
criteria:
1. A random glucose concentration greater than
200 mg/dl, with classical signs and symptoms
2. A fasting glucose concentration greater than
126 mg/dl on more than one occasion.
3. An abnormal oral glucose tolerance test
(OGTT), in which the glucose concentration is
greater than 200 mg/dl 2 hours after a standard
carbohydrate load.

6.  Individuals with fasting glucose concentrations
less than 100 mg/dl, or less than 140 mg/dl
following an OGTT, are considered to be
euglycemic.
 Fasting glucose concentrations greater than 100
mg/dl but less than 126 mg/dl, or OGTT values
greater than 140 mg/dl but less than 200 mg/dl,
are considered to have impaired glucose tolerance,
also known as “pre-diabetes.”
 It is defined as elevated blood sugar that does not
reach the criterion accepted for an outright
diagnosis of diabetes.


7.  Individuals with pre-diabetes have an elevated
risk for developing frank diabetes.
 Pre-diabetic individuals have a significant risk of
progressing to overt diabetes.
 Pre-diabetics are at risk for cardiovascular
disease, as a result of the abnormal carbohydrate
metabolism as well as the coexistence of other risk
factors such as low levels of high-density
lipoprotein, hypertriglyceridemia, and increased
plasminogen activator inhibitor-1 (PAI-1).

8. I) Type 1 DM ( IDDM )
a) Autoimmune (Type I A)
b) Non autoimmune/ idiopathic (Type 1 B)
II) Type 2 DM (NIDDM)
III) Type 3 DM (Other specific types of DM)
A) Specific defined gene mutation
a . Maturity onset diabetes of youth (MODY)
i) MODY- I : Hepatic nuclear factor 4α (FINF4A) gene
mutation

9. ii) MODY-2: Glucokinase gene mutation
iii) MODY-3: Hepatic nuclear factor 1 α gene mutation
iv) MODY-4: Insulin promotor factor I (IPF 1) gene
mutation
v) MODY-5: Hepatic nuclear factor 1 13 HINF 1 B)
gene mutation
vi)MODY-6: Neurogenic Differentiation 1 (NEURODI)
gene mutation
Vii) MODY-X: Unidentified gene mutation
b) Insulin gene mutation
c) Insulin receptor gene mutation
d) Exocrine pancreatic defect

10. E) Diabetes associated with genetic syndromes
Prader willi syndrome
F) Diabetes associated with Drug therapy
IV) Type 4 DM Gestational diabetes mellitus (GDM)

11. Introduction
Type1 diabetes
 Insulin Dependent diabetes mellitus, or Juvenile
onset DM.
 Average onset is in childhood or early adulthood
(usually before 30 years of age)
 Due to pancreatic islet destruction predominantly
by an autoimmune process.
 Cell mediated response:
- Type 1 diabetes is caused by a T cell mediated
autoimmune destruction of the pancreatic beta
cells.

12.  Immune mediated in over 90% of cases and
idiopathic in less than 10% .

15.  Pathogenesis of Type 1A DM is explained on the
basis of 3 mutually-interlinked mechanisms:
a)Genetic susceptibility.
b) Autoimmune factors.
c) Certain environmental factors.
 Pathogenesis of Type 1B DM remains idiopathic.

16. Genetic susceptibility
 Higher concordance rates are seen in
monozygotic vs dizygotic twins.
 Over a dozen susceptibility loci for type 1 diabetes
are now known.
 Most important is the HLA locus on
chromosome 6p21; the HLA locus contributes as
much as 50% of the genetic susceptibility to type 1
diabetes.
 The polymorphisms in the HLA molecules are
located in or adjacent to the peptide-binding -

17.  - pockets consistent with the notion that disease-
associated alleles code for molecules that have
particular features of antigen display.
 This disease have either a HLA-DR3 OR HLA-DR4
haplotype.
 40% to 50% of type 1 diabetics are combined
DR3/DR4 heterozygotes.
 Individuals who have either DR3 or DR4
concurrently with a DQ8 haplotype (which
corresponds to DQA1*0301-DQB1*0302 alleles)
demonstrate one of the highest inherited risks for
type 1 diabetes in siblings.

18.  HLA-disease association reflect the ability of
specific HLA molecules to present self antigens or
T-cell selection and tolerance.
 HLA-mediated susceptibility represents ∼50% of
the genetic susceptibility to T1D.
 HLA class haplotypes have been ranked in a risk
hierarchy.
 Those in the general population with the highest
risk genotype DRB1*03-DQA1*0501-
DQB1*0201/DRB1*0401-DQA1*0301-DQB1*0302
have a 5% absolute risk of getting diabetes by the
age of 15 years.

19.  IA2-A are associated with specific DR alleles,
 GADA are associated with DR3 and
 IAA are associated with DR4,
 The recently discovered ZnT8 antibodies are
associated with a single base pair change in the
SLC30A8 gene.
 ZnT8 causes changes in the secretory pathway,
which leads to apoptosis and thus directly
reduction of β cell mass or activation of
underlying autoimmunity.

20.  The HLA contains lots of genes close together that
are transferred from the parent to the child in
adjacent ‘DNA chunks’ or haplotypes that are said
to be in ‘linkage disequilibrium’.
 The principal susceptibility markers for T1D are
HLA class II DQB1*0302 on the DR4 haplotype
and DQB1*0201 on the DR3 haplotype .

21.  Several NON-HLA genes also confer susceptibility
to type 1 diabetes.
 The first disease-associated NON-MHC gene to be
identified was insulin, with variable number of
tandem repeats(VNTR’S) in the promoter region
being associated with disease susceptibility.
 The mechanism underlying this association is
unknown.
 These polymorphisms influence the level of
expression of insulin in the thymus, thus altering
the negative selection of insulin-reactive T cells.

22. A second locus linked with susceptibility to T1D: a
variable number tandem repeat region(VNTR’S) in
the promoter of the INS gene, which is important
for regulation of INS production.
 Alleles in this region are divided into three classes
distinguished by the number of DNA base pair
repeats.
 Class I alleles have a mean of 570 base pairs,
class II alleles 1200 base pairs and
class III alleles have 2200 base pairs.

23.  Class I alleles are associated with higher INS
expression in the pancreas when compared with
class III alleles, but the opposite is true in the
thymus where class I alleles are expressed at 2–3-
fold lower levels.
 Protection from T1D is associated with the class
III allele.
 This is likely to alter the selection of T cells in the
thymus and may therefore influence tolerance to
INS.

24.  CTLA-4 is a surface molecule found on activated T
cells that produces a negative signal for T cell
activation.
 The cytotoxic T-lymphocyte antigen (CTLA-4)
gene encoded on chromosome 2q33 gene for T1D
susceptibility.
 CTLA-4 gene expression can increase T cell self-
reactivity and therefore play an important role in
autoimmune diseases such as T1D.

25.  PTPN22, a gene found on chromosome 1p13 that
encodes lymphoid protein tyrosine phosphatase,
to be associated with susceptibility to T1D .
 An SNP contributes to susceptibility to T1D
because of increased negative regulation of T cell
activation.
 Polymorphisms in CTLA4 and PTPN22 and
autoimmune thyroiditis; linked with susceptibility
to type 1 diabetes.
 Both CTLA-4 and PTPN-22 inhibit T-cell
responses, so polymorphisms is responsible for
excessive T-cell activation.

26.  The interleukin 2 receptor alpha (IL2RA) region
on chromosome 10p15 associated with T1D.
 IL2RA encodes the α-chain of the IL-2 receptor
complex, which is responsible for binding IL-2, a
key player in the proliferation of regulatory T cells.
 The polymorphism reduces the activity of this
receptor, which is critical for the maintenance of
functional regulatory t cells.

27.  The association of IL2RA with T1D and identified
two SNPs associated with the increased risk of
T1D.
 SNP SS52580101 to be the most closely associated
with T1D.
 T1D-susceptible alleles are associated with
decreased concentrations of IL2RA.

28.  IFIH1 (interferon induced with helicase C domain
1) On chromosome 2q24.3 as the sixth gene to be
strongly associated with T1D. The strongest
association was found with RS1990760.
 IFIH1 contributes to innate immune responses by
releasing the cytokine interferon-gamma and
inducing apoptosis of virally infected cells.
 This molecule provide molecular insights that
viruses and enteroviruses, in particular, contribute
to the initiation of T1D,
 CoxsackieB4 infection recently demonstrated in
the pancreas of individuals with T1D.

29.  Vitamin D has important immunomodulatory
properties, and the active form vitamin D3 (1,25
dihydroxyvitamin D3) shown to inhibit T cell
proliferation.
 The protective effect to T1D in infancy conferred
by vitamin D supplementation.
 Genetic studies of vitamin D-associated genes and
T1D have been complicated.

30.  The association of polymorphisms in the
CYP27B1 and CYP24A1 genes involved in the
activation and inactivation, respectively, of the
vitamin D precursor enzyme 1α-hydroxylase in
T1D.
 No association identified for the CYP24A1 gene;
 An association with T1D identified for the
CYP27B1 gene on 12Q13.1–Q13.3, in which the C
allele of RS10877012 was significantly associated
with increased risk of T1D.
 A potential genetic explanation for the observed
effects of vitamin D in T1D has been identified,
and further studies of vitamin D in T1D are
ongoing.

31.  KIAA0350, also known as CLEC 16A, is a gene of
unknown function on chromosome 16p13.2.
 Its structure, it has a C-type lectin-binding
domain, which indicates for cell surface receptor.
 It is expressed in immune cells, particularly B
lymphocytes, dendritic cells and NK T cells.

33. Environmental Factors
 Environmental factors, especially viral infections,
involved in triggering islet cell destruction type 1
diabetes.
 Type 1 diabetes and infection with mumps,
rubella, coxsackie B, or cytomegalovirus, among
others.
 At least three different mechanisms have been
proposed to explain the role of viruses in the
induction of autoimmunity.
 The first is “bystander” damage, wherein viral
infections induce islet injury and inflammation,
leading to the release of sequestered β-cell
antigens and the activation of autoreactive T cells.

34.  The second possibility is that the viruses produce
proteins that mimic β-cell antigens, and the
immune response to the viral protein cross-reacts
with the self-tissue (“molecular mimicry”).
 The third hypothesis suggests that “predisposing
virus” might persist in the tissue of interest, and
subsequent re-infection with a related virus
 “Precipitating virus” that shares antigenic
epitopes leads to an immune response against the
infected islet cells.

35.  These mechanisms contribute to β-cell damage,
and no causative viral infection is established.
 Infections may be protective; the underlying
mechanisms of such a protective effect are
unknown.
 No causal association between childhood
vaccinations and the risk of developing type 1
diabetes.
 Most autoimmune diseases, the pathogenesis of
type 1 diabetes represents interplay of genetic
susceptibility and environmental factors.

36. Mechanisms of β-cell destruction
 Clinical onset of type 1 diabetes is often abrupt,
the autoimmune process usually starts many years
before the disease becomes evident, with
progressive loss of insulin reserves over time.
 The classic manifestations of the disease
(hyperglycemia and ketosis) occur late in its
course, after more than 90% of the β cells have
been destroyed.
 In type 1 diabetes pathogenesis have emerged
from studies of the non obese diabetic mouse
model, which shares features of autoimmune islet
destruction observed in the human disease.

37.  The fundamental immune abnormality in type 1
diabetes is a failure of self-tolerance in T-cells.
 This failure of tolerance may be result of some
combination of defective clonal deletion of self-
reactive T-cells in the thymus, as well as defects in
the functions of regulatory T cells or resistance of
effector T- cells to suppression by regulatory cells.
 Autoreactive T-cells not only survive but are
poised to respond to self-antigens.
 The initial activation of these cells is thought to
occur in the peri pancreatic lymph nodes, perhaps
in response to antigens that are released from
damaged islets.

38.  The activated T cells then traffic to the pancreas,
where they cause β cell injury.
 Multiple T-cell populations have been implicated
in this damage, including TH1 cells (which may
injure β cells by secreted cytokines, including
IFN-γ and TNF), and CD8+ CTLs (which directly
kill β cells).
 The islet auto-antigens that are the targets of
immune attack may include insulin itself, as well
as the β-cell enzyme glutamic acid decarboxylase
(GAD), and islet cell autoantigen 512 (ICA512).

39.  A role for antibodies in type 1 diabetes is
suspected that autoantibodies against islet
antigens are found with type 1 diabetes,
 Asymptomatic family members at risk for
progression to overt disease; the presence of islet
cell antibodies is used as a predictive marker for
the disease.
 Autoantibodies are involved in causing injury or
are produced as a consequence of islet injury.
Auto immune antibodies

40.  Islet autoimmunity can be detected multiple islet
autoantibodies and their characteristics.
 Combinations of antibodies to insulin
(IAA), glutamic acid decarboxylase (GADA) and
the tyrosine phosphatase IA-2, Insulin
autoantibodies (IAAs), Islet cell autoantibodies
(ICAs) are found in individuals at risk or who have
recently developed T1D.
 The presence of antibodies in the zinc transporter
(ZNT8).
 Islet autoantibodies are indicative of ongoing
autoimmune β-cell destruction.
 Autoimmunity would therefore require
identification of infants at genetic risk of T1D.

41.  Autoimmunity would therefore require
identification of infants at genetic risk of T1D.
 The autoimmune process begins early in life: islet
autoantibodies are detected at the age of 5 years in
T1D cases;
 By the age of 2 years, antibodies to INS (generally
the first to appear) have been detected as early as 6–
12 months.
 Most autoimmune diseases, the pathogenesis of type
1 diabetes represents interplay of genetic
susceptibility and environmental factors.

43. Thank you