THIRD STAGE: Endocrine unit 10 (WK

4)

Genetics and Immuno-

pathogenetics of Diabetes Mellitus
Dr. Sawsan Mohammed Jabbar AL-Hasnawi
University of Kerbala / College of Medicine / Department of Medical
Microbiology
By the end of this lecture, you
should be able to:
 1. identify the immuno-pathogenesis
of DM.***
 2. summarize the immuno-genetics of
DM.***
 3. differentiate between immune and
nonimmune genetics of diabetes.***
Immunopathogenesis of DM

 Type 1 diabetes is an autoimmune

disorder in which the body attacks its
pancreatic beta cells.
 The onset of type 1 diabetes is
attributed to both an inherited risk
and external triggers, such as diet or
an infection.
 Type 1 diabetes appears to develop as the
consequence of an imbalance between
pathogenic and regulatory T lymphocytes.
 CD4+ T cells and CD8+ T cells appear to
mediate beta cell destruction. CD8+ T
lymphocytes are capable of destroying beta
cells by the release of granules containing
granzyme or perforin or via Fas-ligand
interactions.
 Circulating T lymphocytes directed against
a wide range of islet antigens have been
identified, these are called islet
autoantibodies.
 Markers of the immune destruction of
the β-cell include islet cell
autoantibodies(ICA), autoantibodies to
insulin(IAA) , autoantibodies to
glutamic acid decarboxylase (GAD65),
autoantibodies to the tyrosine
phosphatases IA-2A and IA-2β and
Zinc transporter 8 antibodies (ZnT8).
 One and usually more of these
autoantibodies are present in 85–90%
of individuals when fasting
hyperglycemia is initially detected.
Type 1 Diabetes (T1D) Genetics
Genetics of IDDM

 About 18 regions of the genome have

been linked with influencing type 1
diabetes risk.
 These regions, each of which may
contain several genes, have been
labeled IDDM1 to IDDM18.
Genome Screens for T1D
IDDM1 6p21 IDDM13 2q34-q35
IDDM2 11p15 IDDM14 Not yet proved

IDDM3 15q26 IDDM15 6q21

IDDM4 11q13 IDDM16 Not yet proved

IDDM5 6q25-q27 IDDM17 10q25

IDDM6 18q21 IDDM18 5q31-q33
IDDM7 2q31
IDDM8 6q27-qter
IDDM9 3q21-q25
IDDM10 10p11-q11
IDDM11 14q24-q31
IDDM12 2q33
 The most well studied is IDDM1,
which contains the HLA genes that
encode immune response proteins.
 There are two other non-HLA genes
which have been identified thus far.
One of these non-HLA genes, IDDM2,
is the insulin gene, and the other non-
HLA gene maps close to IDDM12
(CTLA4), which has a regulatory role
in the immune response.
IDDM1 Contains the HLA
Genes
 The HLA region is a cluster of genes on
chromosome 6. The genes encode
glycoproteins that are found on the
surfaces of most cells and help the immune
system to distinguish between self (its own
cells, e.g., beta cells of the pancreas) and
non-self (e.g., bacteria, viruses).
 HLA alleles may increase the risk of
diabetes, have no effect, or even be
protective.
 The HLA genes encode proteins called major
histocompatibility complex (MHC), and there
are two main classes of MHC proteins, Class
I MHC and MHC class II. If T cells bind to
the chain of amino acids that presented on
an MHC, the T cell immediately orchestrates
powerful attacks by the body's other
immune cells.
 Ideally, the body only contains T cells that
bind to chains from infectious organisms
(viruses, bacteria, etc.) and tumor cells.
 The alternative is found in autoimmune
diseases such as diabetes: T cells bind to
chains from the body's healthy cells.
 There are many different alleles of the
HLA genes, leading to many different
variants of MHC proteins and allowing a
variety of chains to be presented to cells.
 The inheritance of particular HLA alleles
can account for over half of the genetic
risk of developing type 1 diabetes.
 The genes encoding class II MHC proteins
are most strongly linked with diabetes, and
these genes are called HLA-DP, HLA-DQ,
and HLA-DR.
 In the general population, only half of the
people inherit a copy (allele) of DR gene
called DR3 and DR4, and less than 3% of
the people have two alleles.
 However, in type 1 diabetes at least one
allele of DR3 or DR4 is found in 95% of
Caucasians, and individuals with both DR3
and DR4 are particularly susceptible to
type 1 diabetes.
 Conversely, the DR2 allele is protective
 Similar to the DR gene, certain alleles
of the DQ gene are risk factors for
developing the disease, whereas other
alleles of DQ are protective.
 There is also a tendency for people
who inherit DR3 or DR4 to inherit
DQ, which adds to their genetic risk
of developing diabetes.
 Conversely, the protective alleles of
DR and DQ tend to be inherited
together.
 The IDDM1 locus contains many
diabetes susceptibility genes, the
two alleles DQB1 and DRB1 are
the most important.
 One of the protective HLA
haplotypes is DQA1*0102,
DQB1*0602.
MHC Region – Chromosome 6p21
IDDM2
 Insulin(INS) gene
 Chromosome 11p15.
 Several single nucleotide
polymorphisms (SNPs) have been
found within the INS gene, of
which cause non-synonymous
amino acid changes in the mature
protein .
IDDM12
 Cytotoxic T Lymphocyte
Associated-4 (CTLA-4)
 Chromosome 2q33.
 Encodes a T cell receptor that plays
role in T cell apoptosis
 Dysfunction of CTLA-4 is
consistent with development of T1D
IDDM12
 When the T cell is presented with a chain
of amino acids, its T-cell receptor binds to
the HLA molecules that are presenting the
chains.
 For the T cell to become fully activated,
there is additional signaling between co-
stimulatory receptors and corresponding
ligands on the antigen-presenting cell.
These co-stimulatory receptors are
encoded by the candidate genes for type 1
diabetes susceptibility CTLA4.
Other Type 1 Diabetes Susceptibility Loci:
IDDM3–IDDM18
Type 2 Diabetes (T2D) Genetics
Type 2 Diabetes
 Is group of genetically heterogeneous
metabolic disorders that cause glucose
intolerance
– Involves impaired insulin secretion
and/or insulin action

 ~90% of individuals with diabetes have

T2D

 Polygenic and multifactorial

– Caused by multiple genes that may
interact
– Caused by genetic and environmental risk
factors
Genetics and T2D
 Individuals with a positive family history are about
2-6 times more likely to develop T2D than those
with a negative family history
– Risk ~40% if T2D parent; ~80% if 2 T2D
parents

 Higher concordance for MZ versus DZ twins

 Has been difficult to find genes for T2D

– Late age at onset
– Polygenic inheritance
– Multifactorial inheritance
 in type 2 diabetes, many genes are
thought to be involved. "Diabetes
genes" may show only a subtle
variation in the gene sequence, and
these variations may be extremely
common.
 The difficulty lies in linking such
common gene variations, known as
single nucleotide polymorphisms
(SNPs), with an increased risk of
developing diabetes.
1.The Sulfonylurea Receptor
(ABCC8)
 Sulfonylureas are a class of drugs used
to lower blood glucose in the treatment
of type 2 diabetes. These drugs interact
with the sulfonylurea receptor of
pancreatic beta cells and stimulate
insulin release.
 The sulfonylurea receptor is encoded by
the ABCC8 gene, and genetic variation of
ABCC8 may impair the release of insulin.
2.The Insulin Hormone
(INS)
 The INS gene encodes the precursor
to the hormone insulin. Genetic
variations of the insulin gene (variable
number tandem repeats and SNPs)
may play a role in susceptibility to
type 1 and type 2 diabetes.
3.The Calpain 10 Enzyme
(CAPN10)
 Calpain 10 is a calcium-activated
enzyme that breaks down proteins.
 A genetic variant of CAPN10 may
alter insulin secretion, insulin action,
and the production of glucose by the
liver.
4.The Glucagon Receptor
(GCGR)
 Glucagon is a key hormone in the
regulation of glucose levels.
 As such, the GCGR gene which
encodes its receptor is a candidate
diabetes susceptibility gene. A
mutant glucagon receptor has been
associated with diabetes.
 5.The Enzyme Glucokinase (GCK)
 6.The Glucose Transporter GLUT2
 7.The Transcription Factor HNF4A
 8.The Insulin Receptor (INSR)
 9.The Potassium Channel KCNJ11
 10.The Enzyme Lipoprotein Lipase
(LPL)
 11.The Transcription Factor PPARG
 12.The Regulatory Subunit of a
Phosphorylating Enzyme (PIK3R1)
Maturity Onset Diabetes of
the Young (MODY) Genetics
MODY
 Account for ~ 5% of type 2 diabetes

 Single gene defects

– Autosomal dominant inheritance
– Multiple generations affected

 Early age at onset (< age 25 years)

 Characterized by the absence of obesity, no

ketosis and no evidence of beta cell
autoimmunity
MODY Genes
No. %
Type Gene Locus Protein Mutations MODY
MODY1 HNF4A 20q12-q13.1 Hepatocyte nuclear 12 ~5%
factor 4-alpha

MODY2 GCK 7p15-p13 Glucokinase ~200 ~15%

MODY3 HNF1A 12q24.2 Hepatocyte nuclear >100 ~65%

factor 1-alpha

MODY4 IPF1 13q12.1 Insulin promotor Few

factor-1

MODY5 HNF1B 17cen-q21.3 Hepatocyte nuclear Few <3%

factor 1-beta

MODY6 NEUROD1 2q32 Neurogenic Few

differentiation factor
1
references

 The Genetic landscape of diabetes.

Laura Dean, MD and Jo McEntyre,
PhD.