77 - Pathology of Diabetes

Question 1

Macrovascular effects of DM

Answer 1

Diabetic patients develop atheroma in the usual areas (coronaries, carotids, aorta and iliacs etc.) and suffer the sequelae)

Question 2

Diabetes associated with diabetic ketoscidosis

Answer 2

Type 1

Question 3

Diabetes associated with hyperosmolar coma

Answer 3

Type 2

Question 4

Effect of type 1 DM on cardiovascular disease

Answer 4

Individuals with type 1 diabetes have a ten-times higher risk for cardiovascular events (eg, myocardial infarction, stroke, angina, and the need for coronary artery revascularisation)

Question 5

Organ that major pathological changes in DM affect

Answer 5

Blood vessels 
Macrovascular circulation (larger muscular and elastic arteries)
Microvascular circulation (capillaries and arterioles)

Question 6

What leads to DM atheroma?

1-4

Answer 6

• Increased hepatic production of atherogenic lipoproteins
• Suppression of lipid uptake in peripheral tissues
• Abnormal endothelial function with pro-coagulant results
• Associated abnormalities frequently seen in DM including hyperlipidaemia and hypertension

Question 7

Major clinical problems associated with DM microvascular injury
1-4

Answer 7

• Kidney “Diabetic nephropathy”
• Retina “Diabetic retinopathy”
• Delayed wound healing
• Foot ulcers

Question 8

Cause of DM microvascular complications
1
2 a, b

Answer 8

• Relate to the long term effects of hyperglycaemia on cells and extracellular matrix
• Particularly glycosylation of proteins
- Initially labile (Schiff bases)
- Later stable (Advanced glycation end products)

Question 9

Can arterioles get atheromas?

Answer 9

No

Question 10

Irreversible glycosylation of proteins in DM

Answer 10

Advanced glycation end products (will persist after blood glucose has returned to normal)

Question 11

Common first presentation of DM

Answer 11

Proteinuria (from diabetic nephropathy)

Question 12

How can DM affect the kidneys?
1
2
3
4

Answer 12

1) Chronic hyperglycaemia makes wall of glomeruli thick and leaky (diabetic glomerulosclerosis).
2) Impairment of arteriolar and capillary function decreases effectiveness of immune system.
3) Capillary necrosis (deep medullary capillaries of kidney die)
4) Renal arteries become atheromatous (leading to benign nephrosclerosis, infarcts)

Question 13

Gross appearance of kidneys with late-stage diabetic nephropathy

Answer 13

Shrunken, pitted surface

Question 14

Appearance of a diabetic glomerulus (microscopic)
1
2

Answer 14

Spherical balls of collagen (Kimmelstiel-Wilson nodules, probably not functionally important, just good for ID of DM).
Hyaline arteriolosclerosis

Question 15

Most common reason for dialysis now in Australia

Answer 15

Diabetic nephropathy

Question 16

Proportion of people with DM who suffer diabetic retinopathy

Answer 16

80% over 20 years

Question 17

Cause of diabetic retinopathy

Answer 17

Primary process is ischaemia due to microvascular injury and reduced perfusion.
Vascular proliferation in retinopathy is a response to the ischaemia.

Question 18

Cause of impaired would healing in DM

Answer 18

Related to impaired perfusion in the setting of microvascular injury

Contribution by macrovascular disease, increased susceptibility to infection, ± neuropathy

Question 19

Problem with foot ulcers in DM
1
2 a, b, c

Answer 19

• Chronic: May render someone bed bound for weeks or months
• Very difficult to treat:
- Poor wound healing
- Difficulty eradicating infection
- Neuropathy leading to repeated minor trauma
–> Sometimes amputation is the only option if the person is to return to a mobile, active life

Question 20

Three metabolic pathways that might explain why chronic hyperglycaemia is damaging to tissues

Answer 20

• Advanced Glycation End products (AGEs)
• Activation of Protein Kinase C
• Intracellular hyperglycaemia and abnormal Polyol pathways

Question 21

Advanced glycation end products in DM
1
2
3

Answer 21

• Result of reactions between molecules derived from glucose and the amino groups of various proteins inside and outside cells
• These form normally, but the rate of formation shoots up in hyperglycaemia
• The AGEs bind to a specific receptor (RAGE) on inflammatory cells including macrophages and T cells, endothelial cells, and vascular smooth muscle

Question 22

Effect of advanced glycation end products in DM

1-4

Answer 22

• Release of pro-inflammatory cytokines and growth factors from macrophages
• Generation of reactive oxygen species in endothelial cells
• Increased pro-coagulant activity in endothelial cells
• Proliferation and matrix production by vascular smooth muscle cells

Question 23

Effect of protein kinase C activation

1-4

Answer 23

• Pro-angiogenic growth factors like VEGF
• Elevated Endothelin-1 and reduced NO, both leading to a tendency to small vessel constriction
• Pro-fibrogenic growth factors like TGF-β, increasing production of basement membrane and matrix
• Pro-inflammatory cytokines from endothelium

End result is increased vessel thickness, stickiness, leakiness

Question 24

Intracellular hyperglycaemia and abnormal polyol pathways
1
2
3

Answer 24

• Persisting hyperglycaemia leads to increased intracellular glucose concentration (even in tissue without insulin receptors)
• This excess is metabolized through intermediates called Polyols to fructose
• This pathway depletes glutathione

Question 25

Hepatic conditions associated with DM

Answer 25

Non-alcoholic steatohepatitis or non-alcoholic fatty liver disease