Diabetes Mellitus

PATHOPHYSIOLOGY

Divinagrace E. Elen 12.06.17

 Quote of the Day
When strong winds blow you off course, always
remember you are the man of your ship. Nothing
can control your journey and where it goes but
you - and you alone.
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Type 1 DM
Destruction of B cells |
Insulin deficiency 3
“ Type 1 diabetes is an
autoimmune disease in which
islet destruction is caused
primarily by immune effector
cells reacting against
endogenous B-cell antigens.

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“ Type 1 diabetes is an
autoimmune disease in which
islet destruction is caused
primarily by immune effector
cells reacting against
endogenous B-cell antigens.

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 Ketoacidosis
Type 1 DM – The Autoimmune Disease and coma

Or else

• Most commonly develops in

childhood (but may also do so in
REQUIRES INSULIN
any age)
• Manifests at puberty FOR SURVIVAL!
• Progresses with age

Genetic susceptibility
• A disease of genetic and environmental risks
• HLA-DR3 or -DR4 with DQ8 (High risk)
• Erroneous T-cell selection
• Molecular mimicry
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 Age
B cell mass

Features of DM –
Not evident until 70-
80% of the B-cells
are destroyed

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Honeymoon phase
• 1-2 years after
initial onset of ssx

• Glycemic control
achieved

• Modest or no
insulin at all is
needed

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 Type 1 DM – The Autoimmune Disease

Fundamental Immune Abnormality:

FAILURE OF SELF- MECHANISMS OF B
TOLERANCE IN T CELLS CELL DESTRUCTION
SPECIFIC FOR ISLET Ags

• Initial activation: Peripancreatic lymph nodes (Ags Suspected

from damaged islets) role of
• T cells traffic to pancreas causing B-cell injury (Th1, ANTIBODIES
IFN-y, TNF, CD8+ CTLs)
• Islet autoantigens: Insulin, B-cell enzyme glutamic
acid decarboxylase, and ICA512 12
Spared Spared

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• Pancreatic islets: Insulitis, modest
infiltration of lymphocytes -> atrophy
• Destruction more by T lymphocytes
• Triggers: Coxsackie, rubella, enteroviruses
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2
Type 2 DM
Non-autoimmune | Resistance

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“ Type 2 diabetes is a complex
disease that involves an
interplay of genetic and
environmental factors and a pro-
inflammatory state. No evidence
of autoimmune basis.

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“ Type 2 diabetes is a complex
disease that involves an
interplay of genetic and
environmental factors and a pro-
inflammatory state. No evidence
of autoimmune basis.

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Type 2 DM - The Diabetes of Obesity

Environmental
Genetic Factors
Factors
Highly heritable
Obesity (> 80%,
– 1st degree
central or visceral,
relatives have 5-
most important)
10-fold risk
Sedentary lifestyle
(Lack of exercise)

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 Type 2 DM – The Cardinal Metabolic Defects

1.
Decreased response of
peripheral tissues,
especially skeletal muscle,
adipose tissue, and liver,
to insulin
2.
Inadequate insulin
secretion in the face of
insulin resistance and
hyperglycemia (B-cell
dysfunction)

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 Type 2 DM – The Cardinal Metabolic Defects

Insulin resistance 2.
-> Hyperglycemia Inadequate insulin
-> B-cell secretion in the face of
hyperfunction and insulin resistance and
hyperinsulinemia hyperglycemia (B-cell
dysfunction)
(early stages)

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 INSULIN RESISTANCE

▰ Failure of target tissues to respond normally

to insulin

▰ Major tissues involved: Liver, skeletal

muscle and adipose tissue

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Insulin Resistance: Failure -

To inhibit
Of glucose
lipoprotein
uptake and
To inhibit lipase in
glycogen
endogenous adipose tissue
synthesis to
glucose -> excess
occur in skeletal
production in circulating free
muscle following
the liver -> high fatty acids
a meal -> high
fasting blood (FFAs) ->
post-prandial
glucose levels amplify the state
blood glucose
of insulin
level
resistance
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How can exercise improve
insulin sensitivity?

Increased
TRANSLOCATION
of GLUT-4 to the
surface of skeletal
muscle cells

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 SO WHAT IS REALLY THE RELATIONSHIP
BETWEEN OBESITY AND INSULIN RESISTANCE?

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 ▰ Central adipose: More lipolytic
▰ Excess FFAs -> DAG ->
Free Fatty Acids Attenuate signalling through
insulin receptor pathway ->
Increased gluconeogenesis

▰ Reduced in obesity -> Insulin

Adipokines resistance
▰ Leptin and adiponectin

▰ In response to excess nutrients

Inflammation such as FFAs and glucose ->
inflammasome-> IL-1B -> Pro-
inflammatory cytokines ->
Peripheral tissues 26
B-Cell Dysfunction

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B-Cell Dysfunction

- Requirement for the development of

overt diabetes

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Promoting B-cell dysfunction

Impact of
genetics Abnormal “incretin
effect”: Reduced
Amyloid GIP and GLP-1
deposition which promote insulin
within islets relsease
(long-standing)
Chronic
Excess FFAs hyperglycemia
(Lipotoxicity) (Glucotoxicity) 29
 Monogenic Forms of Diabetes

Maturity-onset diabetes of the

young (MODY) – Glucokinase
Result from either a mutation (loss of function)
primary defect in B-
cell function or a Insulin receptor mutations –
defect in insulin (1) Synthesis, (2) Binding,
receptor signaling (3) TK activity

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Thank you!

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