Metabolic Disease - Week 4 Flashcards
From which process does the majority of retinal ATP production come from?
Oxidative metabolism
What systems have ATP usage the highest?
Any system for:
- dark current
- neurotransmission
- ionic transport
- cGMP, GTP production
remember by *dinc
What happens when blood glucose homeostasis is impaired?
Biochemical abnormalities in cells and tissues
Also diabetes
How does having diabetes affect risk of blindness?
25 times increased risk of blindness
What are three types of diabetes and their usual time of onset?
Type 1: little or no insulin. Less than 18 years old (unless you are Sean)
Type 2: resistance to insulin. Over 40 years old.
Gestational DM: during pregnancy
List ophthalmic complications of diabetic retinopathy [5]
- corneal abnormalities
- glaucoma
- iris neovascularisation
- cataracts
- neuropathies
Which disease is the leading cause of new blindness?
Diabetic retinopathy
DR, because you’ll need a doctor to fix your blind eyes … I dunno
Prevalence of diabetic retinopathy?
28.5% among those with diabetes aged 40 years and older
Biochemical effect of hyperglycaemia?
Stimulates insulin secretion, promoting uptake of glucose by muscle and adipose tissue
Biochem effect of hypoglycaemia?
Elicits secretion of glucagon, epinephrine, cortisol, growth hormone, and counter-regulatory hormones that antagonise insulin action
Which mechanisms in the body are more efficient: glucose clearance or accumulation?
Clearance
How high is the glycemic index for foods that raise glucose levels gradually?
Low
Which glycaemic index level is associated with increased risk certain diseases? And what are they?
High
Diabetes, CVD, and AMD
In type 1 diabetes, what does intensive blood glucose control reduce the risk of and by how much?
Eye disease - by 76%
Kidney disease - by 50%
Nerve disease - by 60%
CVD - by 42%
Non-fatal heart disease, stroke or death from cardiovascular causes - by 57%
Ekncn - ekans n
What does DME stand for? And what does it mean?
Diabetic Macular Edema
- leakage into the retina. causes swelling of the retina and vision loss
What happens to the retina in proliferative Diabetic Retinopathy?
The retina is pulled away from its source of nutrition due to the growth of new blood vessels
- retina will die
What is the likelihood of the development of new blood vessels in severe non-proliferative Diabetic Retinopathy? What does this lead to?
Very high. Results in Proliferative diabetic retinopathy
What is the biochemical effect of hyperglycemia?
hyperglycemia stimulates insulin secretion, promoting uptake of glucose by muscle and adipose tisue
What is the biochemical effect of hypoglycemia? What is secreted?
Hypoglycemia causes secretion of:
- glucagon
- epinephrine
- cortisol
- growth hormone
- counter-regulatory hormones
All these will antagonize insulin action
*GG C? EC! (it’s like you win a game and say gg, and you’re like ‘see?’ it’s ‘easy’)
When testing for hyperglycemia (and diabetes) What percentage of glycosylated haemoglobin do you want to see for a patient to NOT have hyperglycemia?
A low percentage of glycosylated haemoglobin
How does the percentage of glycosylated haemoglobin (i.e. HbA1c) affect the probability of Diabetic Retinopathy?
As percentage of HbA1c increases, so too does the probability of DR
What are the aims in Type 2 Diabetic therapy?
- HbA1c less than 7%
- Blood pressure of 144/82 mmHg
- also need to keep their lipids down
How does reducing the percentage amount of HbA1c influence the risk of complications in type 2 diabetes?
For every 1% decrease in HbA1c: you get a 35% reduction in the risk of complications
How does hyperglycemia and diabetic retinopathy affect the capillary basement membranes?
They get THICCer
Consequences of a thick capillary basement membrane?
- higher pressure in vessel
- less elasticity/flexibility
- smaller lumen (less blood volume)
- more difficult perfusion/diffusion/active transport (it’s harder for oxygen to get through)
Can diabetic retinopathy cause vessel and capillary death?
Yes
Define pericytes
contractile cells that wrap around endothelial cells that line the capillaries and venules throughout the body
Pathological effects of Diabetic Retinopathy?
- pericyte loss
- retinal capillary cell death
- increased vascular permeability
- progressive vascular occlusion
How is glucose normally metabolised?
Through:
- Glycolysis
- TCA cycle
- Electron Transport Chain (ETC)
What pathways does Hyperglycemia influence that increase oxidative stress?
- polyol pathway
- hexosamine pathway
How does hyperglycemia affect the production of advanced glycation end products?
Increases it
How does hyperglycemia affect protein kinase C activation?
activates it
What are the pathway steps influenced by Hperglycemia? (pathways relating to glucose?)
- Increased glucose flux through polyol pathway
- Advanced glycation end-product formation
- Activation of PKC
- Increased activity through hexosamine pathway
How does treatment with an aldose reductase inhibitor affect sorbitol levels (from the polyol pathway)?
Reduces sorbitol levels
How does treatment with an aldose reductase inhibitor affect nerve fibre density?
Increases it
Effect of increased sorbitol?
- glycates nitrogen on proteins
- contributes to increased advanced glycation end products
Ho do AGE precursors damage cells?
Several ways:
- modification of intracellular proteins
- diffuse out of cell and modify ECM molecules
- diffuse out of cell and modify circulating proteins (such as albumin)
How can you reduce accumulation of AGE in hyperglycemia?
Treatment with Aminoguanidine
How did Aminoguanidine effect the histopathology seen in hyperglycemia?
reduced:
- abnormal endothelial cells
- pericyte dropout
- acellular capillaries
Explain the effect of PKC activation
PKC activation modifies gene expression, resulting in:
- increased vascular permeability
- fibrosis and increased risk of vascular occlusion
- blood flow abnormalities
- increased pro-inflammatory genes
How does hyperglycemia lead to PKC activation?
Hyperglycemia increases the synthesis of DAG (Diacylglycerol), which then activates PKC beta, omega, and alpha
Hyperglycemia – DAG – PKC
What does Streptozotocin do?
Kills insulin producing pancreatic beta-cells i.e. causing diabetes
How was the action of PKC in diabetes examined in rats?
Mice made diabetic with streptozoticin and fluoroscein staining revealed blood vessel leakage.
PKC was then silenced with an interfering RNA, which stopped the leakage.
What type of pathway is the Hexosamine pathway?
It is a glucose metabolic pathway
Explain the hexosamine biosynthesis pathway
- F-6-P is converted to GA-6-P with GFAT
- The G.A-6-P is N-acetylated to form GluNac-6-phosphate
- This is dephosphorylated and linked to UDP to create UDP-GluNAc
- UDP-GluNAc is then used for protein glycosylation
*F6P = Fructose-6-phosphate, GA6P = glucosamine-6-phosphate, GluNAc = N-acetylgucosoamine
What is GFAT (or GFA)?
Glutamine fructose-6-phosphate-aminotransferase. Is the rate limiting enzyme in the hexosamine pathway
Define glycosylation
the controlled enzymatic modification of a molecule, especially a protein, by adding a sugar molecule
