W6 28 pathology of diabetes mellitus

Question 1

Classify type I and II diabetes

Answer 1

Type I - absolute insulin deficiency accounting for 10% of cases
Type II - relative insulin deficiency accounting for 80-90% cases

Question 2

What are the normal functions of insulin?

Answer 2

Acts on adipose tissue, striated muscle and liver cells
It causes glucose uptake, fat generation (lipogenesis) and suppresses gluconeogenesis, increased glycogen synthesis

Question 3

What type of a reaction is type I diabetes?

Answer 3

T-cell mediates (type IV) hypersensitivity reaction

Question 4

What is the pathogenesis of type I diabetes? (pg313)

Answer 4

Results in a destruction of beta-cells in the islets of Langerhans
Due to a combination of cytokines mediated and cytotoxic effect:
- CD4+ T cells release cytokines that mediate inflammation and damage to the beta cells
- CD8+ cytotoxic T cells which cause direct cell death

Question 5

What are the genetic and environmental aetiological causes of type I diabetes?

Answer 5

Genetic - HLA locus is the most important, non-HLA genes also implicated
Environmental - viral (mumps, rubella etc)

Thought to be a precipitating event which triggers the immune system to recognise beta cells as needing destruction. As the process starts and beta cell mass decreases, it takes a while for symptoms of diabetes to arise.

Question 6

What is the pathogenesis of type II diabetes?

Answer 6

Insulin resistance
Beta-cell dysfunction - failure of beta-cell hyperplasia to compensate for insulin resistance, has a genetic component
(genetic and environmental)

Question 7

What is insulin resistance characterised by?

Answer 7

(predominantly caused by obesity)
Characterised by:
- decreased uptake of glucose in muscle
- reduced glycolysis and fatty acid oxidation in the liver
- inability to suppress hepatic gluconeogenesis

Question 8

How does obesity cause insulin resistance?

Answer 8

Obesity results in less sensitive intracellular insulin signalling via multiple pathways
(don’t need pathways - pg314 to read)

Question 9

How does beta cell dysfunction occur?

Answer 9

Normal response in a healthy pancreas is for beta cells to become hyperplastic, so make more insulin to compensate for the inefficiency of the signalling pathway. If that is successful, that ensures normoglycaemia.
If there is failure of the beta cell to show hyperplastic compensation, then eventually diabetes will ensue.

Question 10

What are the implications of diabetes?

Answer 10

Complications of hyperglycaemia:
Atherosclerosis, deposition of extracellular matrix material, inflammation, cell injury/death

Question 11

What 3 mechanisms cause the complications of diabetes?

Answer 11

Advanced glycation end productions (AGEs)
Activation of protein kinase C (PKC)
Increased susceptibility to oxidative stress

Question 12

What are advanced glycation end-products (AGEs)?

Answer 12

AGEs are sugars attached onto proteins or lipids within the cells
They form via the non-enzymatic attachment of a sugar to a protein or lipid

Question 13

What are the effects of AGEs?

Answer 13

Activation of specific receptor (RAGE)
Derive cross-linking of extracellular matrix proteins

Question 14

What does activation of RAGE do?

Answer 14

Causes:
Pro-inflammatory activity from intimal macrophages
Production of ROS in endothelium
Pro-coagulant activity in endothelial cells and macrophages
Proliferation of vascular smooth muscle
(Inflammatory and coagulation processed would promote progression to atherosclerosis)

Question 15

What does direct cross-linking of extracellular matrix proteins do?

Answer 15

Causes:
Reduced elasticity in larger vessels
Thickened endothelial basement membrane
Entrapment of proteins and LDL

Question 16

What are the effects or activating protein kinase C?

Answer 16

Increases secretion of growth factor VEGF leading to neovascularisation
Increases endothelin 1 and decreases NO production leading to vasoconstriction
Increases TGF-b inducing deposition of ECM material
Increases NFkB, inducing inflammation

Question 17

What does increased susceptibility to oxidative stress do?

Answer 17

Excess intracellular glucose (eg in nerves) is metabolised by aldose reductase, using NADPH as a co-factor
NADPH is also required for regeneration of the antioxidant glutathione reductase
Excess glucose therefore reduces glutathione, predisposing cells to oxidative stress, leading to nerve damage

Question 18

What are some diabetic complications?

Answer 18

Accelerated atherosclerosis causing ischaemic heart disease, cerebrovascular disease, renal vascular disease, peripheral vascular disease
Diabetic retinopathy
Diabetic neuropathy (affecting sensory, motor, autonomic systems)
Diabetic nephropathy

Question 19

How is diabetic nephropathy caused?

Answer 19

Partly caused by deposition of ECM a material within the glomerulus, partly caused by ischaemic damage
(Nephropathy = proteinuria and declining renal function)