Hermin Aminah

Genetic Of Diabetes
Mellitus

Robin And Cotrans, Pathologic Basic of disease)

Classification

1 2 3
Type 1 DM Type 2 DM Monogenic
form of
Diabetes
Histology of Pancreas
Insulin synthesis and secretion
Insulin action
 1 Type 1 Diabetes
Mellitus

Pathogenesis
 an autoimmune disease: pancreatic
islet destruction caused by T
lymphocytes reacting against poorly
defined B-cell antigens

Pathogenesis:
Genetic susceptibility cell
destruction
Environmental Factor ( > 90%
manifest)
Mechanisms of cell destruction

T lymphocytes react against cell

antigens and cause cell damage
CD4+ T cells macrophages
CD8+ Cytotoxic T lymphocytes direct
kill cell
Locally produced cytokines:
IFN-, TNF & IL-1 (produced by
macrophage)
Autoantibodies: Rx with cell
antigens
Genetic susceptibility

The MHC locus

Class II molecules of the MHC on Chr
6p21 (HLA-D):
DQB1*0302 alele primary determinant of
susceptibilityfor the HLA-DR4 haplotype
DQB1*0602 alele protective against
diabetes
Non-MHC genes:
Polymorphism insulin genes
Environmental Factor

Viruses e.g Coxackieviruses group B,

mumps, measles, CMV, rubella,
Inf.mononucleosis

1. Infections induce tissue damage &

inflammation
2. Viruses produce protein-antigens

cell destruction
3. Predisposing and precipitating virus
 2 Type 2 Diabetes
Mellitus

Pathogenesis
Type 2 Diabetes Mellitus

DM because :
Not enough insulin is being made
The body tissue are not responding
proprly to insulin
Pathogenesis:
ability of peripheral tissue to insulin
(insulin resistance)
cell dysfunction (inadequate insulin
secretion)
Insulin resistance

To the effect of insulin on glucose uptake

metabolism or storage
abnormalities of the insulin signaling pathway
Down regulation insulin receptor
activity of insulin receptor phosphorylation &
tyrosinkinase
level active intermediate in insulin signaling
pathway
Impairment of translocation, docking and
fusion of GLUT-a-containing vesicles with the
plasma membrane
3 Monogenic Form of
Diabetes Mellitus
Genetic Defects in -Cell Function

primary defect in -cell function that occurs

without -cell loss, affecting either -cell
mass and/or insulin production.
(1) autosomal-dominant inheritance, with
high penetrance;
(2) early onset, usually before age 25 and
even in the neonatal period, as opposed to
after age 40 for most patients with type 2
diabetes;
(3) absence of obesity; and
(4) absence of -cell autoantibodies.
 maturity-onset diabetes of the young
(MODY)
Mutations of the glucokinase (GCK) gene
increase the glucose threshold that triggers
insulin release, causing mild increases in
fasting blood glucose (familial mild fasting
hyperglycemia).
The other five genes mutated in MODY
encode transcription factors that control
insulin expression in cells and -cell mass;
one such factor, IPF1 (also known as PDX1),
plays a central role in the development of the
pancreas
Mutations of KCNJ11 and ABCC8 genes
Genetic Defects in Insulin Action

Lipoatrophic diabetes This rare group of

genetic disorders has in common insulin
resistance, diabetes, hypertriglyceridemia,
acanthosis nigricans, and abnormal fat
deposition in the liver (hepatic steatosis)
Dominant-negative mutations in the DNA-
binding domain of PPARG interfere with
the function of wild-type PPAR (Peroxisome
proliferator-activated receptor gamma) in the
nucleus, leading to severe insulin resistance
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