Late Stage Pathophysiology Flashcards
Which vessels do macrovascular complications of diabetes involve? Where abouts?
. Disease of large/medium blood vessels
. Cerebrovascular, coronary artery, and peripheral vascular disease (brain, heart, peripheries)
What are microvascular complications of diabetes a result of? Which areas are most affected?
. Thickening of capillary and arteriole walls from chronic hyperglycaemia
. Eyes and kidneys most affected (retinopathy and nephropathy)
Which individuals are most at risk from diabetic ketoacidosis (DKA)?
Type I diabetics, as these individuals are insulin-dependent (B-cells don’t produce enough insulin)
Which type of diabetes is insulin-dependent? Which type is insulin-independent?
Type I diabetes is insulin-dependent because there’s autoimmune attack on the B-cells so that they can’t produce insulin
Type II is insulin-independent because their B-cells can produce insulin, it’s just that their cells no longer respond to the insulin
What is DKA caused by?
. Lack of insulin
. Body starts metabolising fatty acids, producing acidic ketone bodies
What does DKA stand for?
Diabetic Ketoacidosis
What does HHS stand for?
Hyperosmolar Hyperglycaemic State
Which individuals are most at risk from HHS?
Type II diabetics
What is HHS?
When there’s very high blood sugar (greater than 30mmol/L, which causes changed osmotic gradients (lower water potential in blood due to lots of glucose)
Which tissue type is most notably damaged from chronic hyperglycaemia?
Endothelium
How can diabetes lead to diabetic retinopathy?
. Chronically high blood sugar damages small blood vessels in retina
. Vessels leak fluid or haemorrhage, distorting vision
. Advanced stage: new abnormal blood vessels proliferate on the surface of the retina, which can lead to scarring and cell death in retina
How can a urine test indicate diabetic nephropathy?
Small quantities of albumin in urine
How can diabetes lead to diabetic nephropathy?
. Damage to glomeruli (capillary network)
. High blood sugar causes high blood pressure due to osmotic effects
. Kidney can be perforated due to high pressure, so kidneys lose ability to filter blood effectively –> microalbuminuria
Which specific cell types does hyperglycaemia damage? Why are these cells affected?
. Capillary endothelial cells in retina
. Mesangial cells in renal glomerulus
. Neurones and Schwann cells in peripheral nerve
. These cells can’t control their internal glucose concentration, unlike other cells
Describe the polyol pathway and its effects.
. Aldose reductase usually converts toxic aldehydes to inactive alcohols
. When glucose too high, aldose reductase also reduces glucose to sorbitol, which is then oxidised to fructose
. Aldose reductase uses NADPH to do this
. NADPH also used to regenerate reduced glutathione (antioxidant), so using NADPH for conversion of glucose to sorbitol decreases the amount of reduced glutathione produced
. Polyol pathway increases risk of oxidative stress by decreasing amount of reduced gluthathione
Describe how PKC (protein kinase C) is activated by hyperglycaemia and its effects.
. Hyperglycaemia increases synthesis of diacylglyerol
. Diacylglycerol activates protein kinase C
. PKC has variety of effects on gene expression
Describe the hexosamine pathway.
. F6P converted to glucosamine-6-phosphate by GFAT enzyme
. Glucosamine-6-phosphate converted to UDP and N-acetyl glucosamine
. N-acetyl glucosamine transferred to transcription factors, causing changes in gene expression
. Transcription factors Sp1, growth factor-B1, and plasminogen activator/inhibitor-1
. Leads to vascular damage
What is the effect of the hexosamine pathway?
Vascular damage
What is the effect of the polyol pathway?
Increased risk of oxidative stress (due to decreased amounts of reduced gluthathione)
How does hyperglycaemia affect free radical production?
Hyperglycaemia increases free radical production via mitochondrial pathways
How can insulin resistance lead to macrovascular complications
. Insulin resistance leads to influx of FFAs to intra-arterial cells
. Mitochondria oxidise FFAs
. Overproduction of ROS
What is ROS?
Reactive Oxygen Species
Which part of the eye is highly susceptible to diabetic neuropathic damage? Why is this?
Cornea because it is the most densely innervated tissue in the body
Why are cataracts more common in diabetics?
. Excess glucose converted to sorbitol by aldose reductase
. Sorbitol accumulates in lens, where it induces apoptosis in the lens epithelial cells
. Leads to development of cataracts
What is vitreous humour?
The jelly-like fluid of the eyeball behind the lens
How can diabetes affect the vitreous humour?
Glucose-mediated collagen cross-linking disrupted so cross-links break and gel becomes liquid
Describe the AGE (advanced glycation end products) pathway
. AGE precursors diffuse out of cell and modify molecules in the extracellular matrix
. Changes signalling between matrix and cell, causing cellular dysfunction
. AGE precursors modify circulating proteins (e.g. albumin)
. Modified proteins bind to AGE receptors, causing production of inflammatory cytokines and growth factors
. These cause vascular pathology
What do AGEs do?
. Accumulation of AGEs causes capillary basement membranes to thicken, increases collagen cross-linking, and reduces basement membrane degradation
. Endothelial cell dysfunction causes increased intracapillary pressure and loss of pericytes (cells surrounding endothelium), which increases vascular permeability
What is proliferative retinopathy?
. Retinal ischaemia stimulates production of angiogenic growth factors, including VEGF (vascular endothelial growth factors)
. Formation and proliferation of new vessels
What does non-proliferative retinopathy involve?
Micro-aneurysms
What does proliferative retinopathy involve?
Neovascularisation and vitreous haemorrhage
Can early intervention help diabetic retinopathy?
Yes, diagnosing at the mildly non-proliferative grade is much better than at the proliferative grade
What is the macula?
The fovea of the retina where there’s the highest concentration of cone cells, responsible for clear vision
What is maculopathy? Give a consequence of this.
. Blood retinal barrier breaks down
. Vascular leakage at macula leads to macula oedema
. Common cause of blindness in patients with diabetic arteries
Name some ways in which diabetic retinopathy can be prevented or delayed.
. Good control of blood glucose, BP, lipids
Glycaemic control, BP, lipids
How can established retinopathy be treated?
Laser photocoagulation
How can proliferative retinopathy be treated?
. VEGF inhibitors
. Retinal ischaemia stimulates production of angiogenic growth factors, like VEGF
. Inhibiting VEGF inhibits angiogenesis (formation and proliferation of new vessels)
What do intravitreal steroid injections do?
Prevents breakage of collagen cross-links in vitreous humour to maintain its jelly-form instead of degrading to liquid
What is ESRD?
End Stage Renal Disease
What are podocytes?
Cells that surround the capillaries in the Bowman’s capsule
How
Annual screening for microalbuminuria
Lifetime risk 50% (1/3 remain, 1/3 normal, 1/3 proteinuria)
Glucose, lipids, BP
cardiovascular risk is increased 2-4 fold in microalbuminuria, ~9 fold in proteinuria and ~20-fold once serum creatinine is >180 μmol/l
What is microalbuminuria? Why does it happen? What is it a sign of?
. Moderate increase in level of albumin in urine
. Occurs when there’s increased permeability for albumin in the glomerulus (in diabetics due to glucose changing osmotic gradients and intracapillary pressure to glomerulus more permeable)
. Sign of renal disease
