BS - Metabolic Eye Diseases - Week 4 Flashcards
True or false
The eye is not the most metabolically active of all tissue.
False, it is the most metabolically active
Describe the three types of diabetes, and their onset.
Type 1 - little or no insulin produced, <18 years of age onset
Type 2 - resistance to insulin, >40 years of age onset
Gestational diabetes mellitus - during pregnancy
What is the risk of blindness in those with diabetes?
25x
Name 5 ophthalmic complications of diabetic retinopathy.
Corneal abnormalities Glaucoma Iris neovascularisation Cataracts Neuropathies
What is the prevalence of diabetic retinopathy?
28.5% among those with diabetes >40.
What percentage of blindness does diabetic retinopathy account for?
10%
What is the main problem behind diabetic retinopathy?
Hyperglycaemia
What does hyperglycaemia promote?
Insulin secretion, promoting glucose uptake by muscle and adipose
What happens to the capillaries in diabetic retinopathy (3)?
Pericyte loss
Increased vascular permeability
Progressive vascular occlusion
What happens to the capillary basement membrane in diabetic retinopathy?
Becomes thicker
What are 5 metabolic consequences of hyperglycaemia?
Increased production of advanced glycation end products
Increased flux through the polyol pathway
Protein kinase C activation
Increased hexosamine pathway
These collectively increase oxidative stress
What is a consequence of increased polyol pathway activity in hyperglycaemia?
NADPH is oxidised to NADP+, needed for glutathione, and also increases sorbitol
What is a consequence of increased sorbitol?
Glycates nitrogen on proteins
Can sorbitol cross cell membranes, and what is a consequence of this?
Cannot, and therefore accumulates. It produces oxidative stress on cells by drawing water into the insulin-independent tissue.
What effect does aldose reductase inhibitor have (4)?
Protects against neuropathy, and can be used to treat hyperglycaemia.
Reduces sorbitol levels, and increases nerve fibre density.
How do glycation end-products damage cells (3)?
Modification of intracellular proteins
Diffuse out of cells and modify ECM molecules
Diffuse out of cells and modify circulating proteins in blood such as albumin
What can be used to prevent accumulation of glycation end-products?
Aminoguanidines
PKC activation results in what four consequences?
Increased vascular permeability
Fibrosis (increased risk of vascular occlusion)
Bloodflow/autoregulation abnormalities
Increased pro-inflammatory factors
What effect does hyperglycaemia have on PKC and how?
It increases the synthesis of diacylglycerol, activating protein kinase C
Describe an experimental setup to confirm PKC association with hyperglycaemia (4).
Mice made diabetic using streptozotocin.
Fluorescein angiography not confined to blood vessels indicating leakage.
Small interfering RNA used to silence PKC.
Fluorescein leakage stopped.
What is produced by the hexosamine pathway?
Amino acid precursors for proteoglycans, glycolipids, and glycoproteins.
Does hyperglycaemia increase or decrease hexosamine pathway activity, and what does this result in?
Increases activity, resulting in too many N-acetylglucosaminne donated, leading to altered genes and proteins.
What effect does hyperglycaemia have on GAPDH? What is it like in the retina?
Decreases activity
Activity in the retina is decreased only of glycaemic control is poor, otherwise normal.
What is the common link between all four pathways and hyperglycaemia?
Increased oxidative stress inhibits glycolysis and pushes substrates upstream into alternate pathways.
