Late Stage Pathophysiology

Question 1

Which vessels do macrovascular complications of diabetes involve? Where abouts?

Answer 1

. Disease of large/medium blood vessels

. Cerebrovascular, coronary artery, and peripheral vascular disease (brain, heart, peripheries)

Question 2

What are microvascular complications of diabetes a result of? Which areas are most affected?

Answer 2

. Thickening of capillary and arteriole walls from chronic hyperglycaemia
. Eyes and kidneys most affected (retinopathy and nephropathy)

Question 3

Which individuals are most at risk from diabetic ketoacidosis (DKA)?

Answer 3

Type I diabetics, as these individuals are insulin-dependent (B-cells don’t produce enough insulin)

Question 4

Which type of diabetes is insulin-dependent? Which type is insulin-independent?

Answer 4

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

Question 5

What is DKA caused by?

Answer 5

. Lack of insulin

. Body starts metabolising fatty acids, producing acidic ketone bodies

Question 6

What does DKA stand for?

Answer 6

Diabetic Ketoacidosis

Question 7

What does HHS stand for?

Answer 7

Hyperosmolar Hyperglycaemic State

Question 8

Which individuals are most at risk from HHS?

Answer 8

Type II diabetics

Question 9

What is HHS?

Answer 9

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)

Question 10

Which tissue type is most notably damaged from chronic hyperglycaemia?

Answer 10

Endothelium

Question 11

How can diabetes lead to diabetic retinopathy?

Answer 11

. 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

Question 12

How can a urine test indicate diabetic nephropathy?

Answer 12

Small quantities of albumin in urine

Question 13

How can diabetes lead to diabetic nephropathy?

Answer 13

. 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

Question 14

Which specific cell types does hyperglycaemia damage? Why are these cells affected?

Answer 14

. 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

Question 15

Describe the polyol pathway and its effects.

Answer 15

. 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

Question 16

Describe how PKC (protein kinase C) is activated by hyperglycaemia and its effects.

Answer 16

. Hyperglycaemia increases synthesis of diacylglyerol
. Diacylglycerol activates protein kinase C
. PKC has variety of effects on gene expression

Question 17

Describe the hexosamine pathway.

Answer 17

. 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

Question 18

What is the effect of the hexosamine pathway?

Answer 18

Vascular damage

Question 19

What is the effect of the polyol pathway?

Answer 19

Increased risk of oxidative stress (due to decreased amounts of reduced gluthathione)

Question 20

How does hyperglycaemia affect free radical production?

Answer 20

Hyperglycaemia increases free radical production via mitochondrial pathways

Question 21

How can insulin resistance lead to macrovascular complications

Answer 21

. Insulin resistance leads to influx of FFAs to intra-arterial cells
. Mitochondria oxidise FFAs
. Overproduction of ROS

Question 22

What is ROS?

Answer 22

Reactive Oxygen Species

Question 23

Which part of the eye is highly susceptible to diabetic neuropathic damage? Why is this?

Answer 23

Cornea because it is the most densely innervated tissue in the body

Question 24

Why are cataracts more common in diabetics?

Answer 24

. 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

Question 25

What is vitreous humour?

Answer 25

The jelly-like fluid of the eyeball behind the lens

Question 26

How can diabetes affect the vitreous humour?

Answer 26

Glucose-mediated collagen cross-linking disrupted so cross-links break and gel becomes liquid

Question 27

Describe the AGE (advanced glycation end products) pathway

Answer 27

. 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

Question 28

What do AGEs do?

Answer 28

. 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

Question 29

What is proliferative retinopathy?

Answer 29

. Retinal ischaemia stimulates production of angiogenic growth factors, including VEGF (vascular endothelial growth factors)
. Formation and proliferation of new vessels

Question 30

What does non-proliferative retinopathy involve?

Answer 30

Micro-aneurysms

Question 31

What does proliferative retinopathy involve?

Answer 31

Neovascularisation and vitreous haemorrhage

Question 32

Can early intervention help diabetic retinopathy?

Answer 32

Yes, diagnosing at the mildly non-proliferative grade is much better than at the proliferative grade

Question 33

What is the macula?

Answer 33

The fovea of the retina where there’s the highest concentration of cone cells, responsible for clear vision

Question 34

What is maculopathy? Give a consequence of this.

Answer 34

. Blood retinal barrier breaks down
. Vascular leakage at macula leads to macula oedema
. Common cause of blindness in patients with diabetic arteries

Question 35

Name some ways in which diabetic retinopathy can be prevented or delayed.

Answer 35

. Good control of blood glucose, BP, lipids

Glycaemic control, BP, lipids

Question 36

How can established retinopathy be treated?

Answer 36

Laser photocoagulation

Question 37

How can proliferative retinopathy be treated?

Answer 37

. VEGF inhibitors
. Retinal ischaemia stimulates production of angiogenic growth factors, like VEGF
. Inhibiting VEGF inhibits angiogenesis (formation and proliferation of new vessels)

Question 38

What do intravitreal steroid injections do?

Answer 38

Prevents breakage of collagen cross-links in vitreous humour to maintain its jelly-form instead of degrading to liquid

Question 39

What is ESRD?

Answer 39

End Stage Renal Disease

Question 40

What are podocytes?

Answer 40

Cells that surround the capillaries in the Bowman’s capsule

Question 41

How

Answer 41

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

Question 42

What is microalbuminuria? Why does it happen? What is it a sign of?

Answer 42

. 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