Biochemoistry of Diabetic Complications Flashcards
Why don’t we get excessive ketosis in T2DM?
Low levels of circulating insulin inhibit HSL, inhibiting lipolysis so there are less FFA left to make ketones
What are the small vessel complications of diabetes?
Retinopathy
Peripheral neuropathy
Nephropathy
What are the large vessel complications of diabetes?
Peripheral vascular disease (Atherosclerosis)
Ischaemic heart disease
Stroke
How does glucolipotoxicity lead to the development of micro/macrovascular complications?
Mitochondrial dysfunction
Oxidative stress
Inflammation
Leads to deregulation of cellular pathways
- Altered gene expression can promote thrombogenesis
- blood flow abnormalities can increase vasoconstriction
- increased vascular permeability
What induces mitochondrial superoxide overproduction?
Excess glucose and FFA increase oxidative phosphorylation in mitochondria, which produces more ROS which exceed the body’s antioxidant capacity
What are the effects of increased ROS?
- Oxidative stress = direct damage
- Activation of pro-inflammatory signalling pathways
- Activation of signalling pathways that impair insulin signalling in target tissues
These all cause mitochondrial damage and impaired nutrient metabolism - Beta-oxidation of FFA reduced and metabolites are diverted to other pathways, increasing ROS formation
Quick review of how hyperglycaemia promotes ROS overproduction
Excess glucose causes more substrates that overload the mitochondria, making ROS -> upstream metabolites are diverted from glycolysis and go to overflow pathways (to be discussed)
What are the 4 main overflow pathways for hyperglycaemia?
- Polyol
- Hexosamine
- Protein kinase C
- AGE
How does the polyol pathway work?
Aldose reductase has a small affinity or glucose only and usually doesn’t convert much to sorbitol. With hyperglycaemia, increased sorbitol is made (polyol) which leads to oxidative stress (aldose reductase activity uses up antioxidants) and osmotic imbalance.
How is AGE produced in hyperglycaemia?
Non-enzymatic glycation as a spontaneous process to form a Schiff base
This can be rearranged to an Amadori produce which is a ketoamine. (this is what happens in HbA1C!)
However with hyperglycaemia an IRREVERSIBLE formation of advanced-glycation end products (AGE)occurs over days.
What is the effect of AGE?
- Structural and functional abnormalities in proteins
- Generate ROS
- Can generate an immune response
- Decrease renal clearance of excess AGE
What proteins are modified by AGE?
- Intracellular proteins in cells that are insulin-independent
- Cell surface proteins
- Circulating proteins (albumin, apolipoproteins): circulating proteins that have been modified can activate AGE receptors on Macrophages, endothelial cells and vascular SM and activate signalling cascades
What is the effect of this modification?
Increased stiffness of vessel walls
Atherosclerosis due to endothelial cell dysfunction
How does the protein kinase C pathway work?
Hyperglycaemia increases PKC production, causing an increase in VEGF and TGF-beta and a decrease in eNOS (causes tissue iscaemia and endothelial injury)
How does the hexosamine path work?
N-acetyl glucosamine is added to serine and threonine residues and causes pathologic changes in gene expression
Has also been linked to development of insulin resistance
How does hyperglycaemia cause diabetic retinopathy?
Polyol pathway, PKC pathway and oxidative stress.
- Vascular damage due to increased permeability and microaneurysm
- Angiogenesis in response to VEGF etc. and macular oedema
How does hyperglycaemia cause diabetic neuropathy?
Multifocal axon degeneration in peripheral nerves = sensory loss.
- Systemic oxidative stress
- AGE myelin accumulation causes demyelination and Schwann cell death
How does hyperglycaemia cause diabetic nephropathy?
Thickening of basement membrane by AGE
Glomerular hypertrophy and damage later causes leakage to urine (ROS also contribute)
Why does diabetes increase CVD risk?
- Metabolic abnormalities (dyslipidaemia, chronic low-grade inflammation and hypertension)
- Lipoprotein remodelling (dyslipidaemic triad)
- Inflammatory processes (vessel wall inflammation causes endothelial dysfunction)
What are the characteristics of endothelial cell dysfunction in diabetes?
Impaired relaxaion
Pro-thrombosis
Pro-inflammation
Insulin resistance
How does endothelial cell dysfunction cause macrovascular complications?
Decreased vasodilation and insulin resistance causes dysfunction.
This simultaneously contributes to CHD/atherosclerosis and diabetes/dyslipidaemia
What is the dyslipidaemic triad?
- High TG levels (overproduction of VLDL)
- Increased LDL (esp. small and dense)
- Low levels of HDL cholesterol
How does CETP contribute to cholesterol homeostasis?
Facilitates bi-directional cholesterol and TG transfer between lipoproteins
- Between ApoA1-containind HDL and Apo-B containing particles
How do adiposity and insulin resistance cause dyslipidaemia?
- Increased TG: FFA released by adipose tissue
- VLDL increased production by liver
- Decreased endothelial LPL = decreased TG clearance
How does the production of specifically small and dense lipoproteins affect complications?
Small, dense LDL can cross the artery wall and is more susceptible to glycation, causing increased atherosclerosis
Small, dense HDL has reduced efficacy of reverse cholesterol transport and because the ApoA1 is unstable is renally cleared, reducing HDL-C
