Chronic Inflammatory Diseases in Diabetes (14)

Question 1

What is acute inflammation?

Answer 1

Short-term response to an injury
It can resolve or lead to chronic inflammation

Question 2

What is chronic inflammation?

Answer 2

Long-term inflammation
Can be caused by persistent infections, prolonged exposure to toxic agents or auto-immunity

Question 3

Why is there an observed increase in granulocytes during inflammation?

Answer 3

Neutrophils, Eosinophils, Basophils
contain intracellular granules

• Released in response to external stimuli (degranulation)
• Indiscriminately kill invading organisms
• Apoptosis is inhibited
• Damage host cells and themselves

Question 4

Why is there an observed increase in macrophages during inflammation?

Answer 4

Phagocytes

• Become highly phagocytic
• Release pro-inflammatory cytokines

Question 5

Why is there an observed increase in lymphocytes during inflammation?

Answer 5

T cells, B cells, NK cells

• Differentiate into adaptive immunity cells
• Release pro-inflammatory cytokines

Question 6

What disorders can chronic inflammation lead to?

Answer 6

Alzheimer’s
Arthritis
Cancer
Cardiovascular Disease
Neurological Diseases
Pulmonary Diseases
Type 2 Diabetes

Question 7

How does tumour necrosis factor-α (TNF-⍺) relate to type 2 diabetes?

Answer 7

Pro-inflammatory cytokine

Inhibition of TNF⍺ may prevent insulin resistance

TNF⍺ knock-out mice are resistant to developing insulin resistance

Question 8

How do JNK1 and JNK2 relate to type 2 diabetes?

Answer 8

Block Insulin Receptor Substrate (IRS) signalling downstream of insulin receptor

JNK knock-out mice are resistant to insulin resistance

Question 9

How does interleukin-10 (IL-10) relate to type 2 diabetes?

Answer 9

Anti-inflammatory cytokine

Treatment with recombinant IL-10 may block insulin resistance

Question 10

How does chronic inflammation in obesity/diabetes affect the liver?

Answer 10

Increased lipid content/fat build-up
Increased cytokine production
ER stress

Eventually leading to insulin resistance systemically / inflammation

Question 11

How does chronic inflammation in obesity/diabetes affect adipose tissue?

Answer 11

Adipocyte hypertrophy
Increased lipolysis
Macrophage recruitment and polarity switch - (anti-inflamm M2 -> pro-inflamm M1)
Increased cytokine production
ER stress

Eventually leading to insulin resistance systemically / inflammation

Question 12

How does chronic inflammation in obesity/diabetes affect the skeletal muscle?

Answer 12

Increased FFA uptake
Macrophage recruitment/activation
ER stress

Eventually leading to insulin resistance systemically / inflammation

Question 13

What cellular changes lead to and occur after adipocyte death.

Answer 13

Obesity can lead to adipocyte death following inflammation, macrophage switch etc.

Dying adipocytes stimulate M1 macrophages to release pro-inflammatory TNF⍺ and IL-6 systemically

Question 14

How does TLR4 signalling affect inflammation?

Answer 14

Activated by non-esterified fatty acids (NEFA) to dimerise

Downstream signalling causes the transcription of pro-inflammatory cytokines- causes the inflammatory response to be out of control

Continuous positive feedback loop to recruit more macrophages

Question 15

How do pro-inflammatory cytokines TNFα and IL-6 contribute to insulin resistance?

Answer 15

Their downstream signalling effectors inhibit insulin receptor signalling.

Examples- JNK inhibits IRS1 and SOCS3 inhibits JAK and IRS1

Question 16

What are some cellular changes in obesity that lead to chronic inflammation?

Answer 16

Pro-inflammatory cytokines/factors are upregulated
TNFα, IL-6

Other immune components or regulatory factors are dysregulated
Leptin, adiponectin, IL-10

Question 17

How do pharmacologic interventions affect inflammation and diabetes/obesity?

Answer 17

Diabetes causes chronic activation of the inflammatory system

Some evidence that drugs that lower glucose also block inflammation
Anti-inflammatory drugs may have metabolic effects