77 - Pathology of Diabetes Flashcards
Macrovascular effects of DM
Diabetic patients develop atheroma in the usual areas (coronaries, carotids, aorta and iliacs etc.) and suffer the sequelae)
Diabetes associated with diabetic ketoscidosis
Type 1
Diabetes associated with hyperosmolar coma
Type 2
Effect of type 1 DM on cardiovascular disease
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)
Organ that major pathological changes in DM affect
Blood vessels Macrovascular circulation (larger muscular and elastic arteries) Microvascular circulation (capillaries and arterioles)
What leads to DM atheroma?
1-4
- 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
Major clinical problems associated with DM microvascular injury
1-4
- Kidney “Diabetic nephropathy”
- Retina “Diabetic retinopathy”
- Delayed wound healing
- Foot ulcers
Cause of DM microvascular complications
1
2 a, b
• 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)
Can arterioles get atheromas?
No
Irreversible glycosylation of proteins in DM
Advanced glycation end products (will persist after blood glucose has returned to normal)
Common first presentation of DM
Proteinuria (from diabetic nephropathy)
How can DM affect the kidneys? 1 2 3 4
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)
Gross appearance of kidneys with late-stage diabetic nephropathy
Shrunken, pitted surface
Appearance of a diabetic glomerulus (microscopic)
1
2
Spherical balls of collagen (Kimmelstiel-Wilson nodules, probably not functionally important, just good for ID of DM).
Hyaline arteriolosclerosis
Most common reason for dialysis now in Australia
Diabetic nephropathy
Proportion of people with DM who suffer diabetic retinopathy
80% over 20 years
Cause of diabetic retinopathy
Primary process is ischaemia due to microvascular injury and reduced perfusion.
Vascular proliferation in retinopathy is a response to the ischaemia.
Cause of impaired would healing in DM
Related to impaired perfusion in the setting of microvascular injury
Contribution by macrovascular disease, increased susceptibility to infection, ± neuropathy
Problem with foot ulcers in DM
1
2 a, b, c
• 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
Three metabolic pathways that might explain why chronic hyperglycaemia is damaging to tissues
- Advanced Glycation End products (AGEs)
- Activation of Protein Kinase C
- Intracellular hyperglycaemia and abnormal Polyol pathways
Advanced glycation end products in DM
1
2
3
- 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
Effect of advanced glycation end products in DM
1-4
- 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
Effect of protein kinase C activation
1-4
- 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
Intracellular hyperglycaemia and abnormal polyol pathways
1
2
3
- 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
Hepatic conditions associated with DM
Non-alcoholic steatohepatitis or non-alcoholic fatty liver disease
