Microvascular complications of diabetes mellitus

Question 1

What does poor diabetes control increase the risk of?

Answer 1

Microvascular AND macrovascular complications

Question 2

What are some sites of microvascular complications? What do they cause

Answer 2

• Retinal arteries → retinopathy
• Glomerular arterioles → nephropathy
• Vasa nervorum → neuropathy
  
  • Vasa vasorum = small blood vessels which supply the nerves

NOTE: -pathy = damage

Question 3

What are the risk factors for microvascular complications?

Answer 3

• Severity of hyperglycaemia
• Hypertension
  
  • The higher the SBP, the higher the risk of microvascular complications
  • NOTE: There is a link between hypertension and diabetes - they often co-exist
• Genetic predisposition
• Hyperglycaemic memory
  
  • This refers to the phenomenon where prolonged exposure to hyperglycemia can epigenetically modify gene expression
  • This effect is sustained even after hyperglycemic control is therapeutically achieved
  • Therefore, patients who had poorly controlled diabetes at some point, even if their blood sugar levels are controlled now, are at an increased risk of microvascular complications

Question 4

Describe the mechanism of how hyperglycaemia can lead to microvascular complications.

Answer 4

• Hyperglycaemia and hyperlipidaemia leads to hypoxia and oxidative stress
• This activate inflammatory signalling cascades, leading to local activation of pro-inflammatory cytokines and hence inflammation
• Inflammation causes damage to organs

Important pathways to remember

Question 5

What are some important things to remember about diabetic retinopathy?

Answer 5

• Main cause of visual loss in people with diabetes
• Main cause of blindness in people of working age

Question 6

What would a normal retina look like when looking through a fundoscope?

Answer 6

• Optic disc - more medial (nasal)
• Macula - more lateral (temporal)
  
  • ​Macula involved in visual acuity (central vision) and colour vision
• Lots of blood vessels

Question 7

What are the 4 types of retinopathy?

Answer 7

• Background diabetic retinopathy
• Pre-proliferative diabetic retinopathy
• Proliferative retinopathy
• Maculopathy

Question 8

What would background diabetic retinopathy look like when looking through a fundoscope?

Answer 8

• Hard exudates
  
  • Yellow flecks - cheese colour
  • This is due to leakage of lipid contents from the retinal blood vessels
• Microaneurysms
  
  • Red dots
  • This is due to localised dilation (bulging) of the micovessel vessel walls
• Blot haemorrhages
  
  • The microaneurysms can rupture and leak blood

If untreated, this leads to pre-proliferative diabetic retinopathy

Question 9

How is background diabetic retinopathy managed?

Answer 9

• Improve control of blood glucose
• Warn patient that warning signs are present

Question 10

What would pre-proliferative diabetic retinopathy look like when looking through a fundoscope?

Answer 10

• Cotton wool spots (also called soft exudates)
  
  • ​These represent retinal ischaemia
  • EXTRA:
    
    • Ischaemia → hypoxia → blockage of axoplasmic flow (as this requires energy) → deposition of intra-axonal organelles (these are the cotton wool spots that we see)

If untreated, new vessels will grow → proliferative retinopathy

NOTE: Axonal transport = a cellular process responsible for movement of substances (e.g. organelles) to and from the cell body, through the cytoplasm of its axon (i.e. axoplasm)

Question 11

What would proliferative retinopathy look like when looking through a fundoscope?

Answer 11

There are visible new vessels on the optic disc or elsewhere in the retina

• NOTE: Mechanism
  
  • Significant amount of retinal BVs already damaged (due to microaneurysms → haemorrhages etc.)
  • This leads to the body releasing a growth hormone which stimulates the formation of new blood vessels to try and restore blood supply to the retina
  • However these blood vessels are weaker, which can cause problems

Question 12

How is pre-proliferative and proliferative diabetic retinopathy managed?

Answer 12

Panretinal photocoagulation

• Laser therapy
• Laser beams fired into retina to destroy the ischaemic tissue
• Reduced area of ischemic tissue reduces the stimulus for new blood vessel formation (neovasacularisation)
• The point of this is not to improve vision as vision will already be poor due to the ischaemia
• But you want to prevent the condition from getting even worse
  
  • ​You want to prevent the formation of new blood vessels as this is what causes problems

Question 13

What would maculopathy look like when looking through a fundoscope?

Answer 13

• Same disease as background diabetic retinopathy
  
  • BUT this time near the MACULA
• ​Hard exudates near macula
• Because the problem is near the macula, it’s more likely to cause damage to the macula than a problem elsewhere in the retina
  
  • This can threaten direct vision

Question 14

How is maculopathy managed?

Answer 14

Only needs a GRID of photocoagulation

• NOT panretinal photocoagulation
• There is only a problem around the macula
• So you only need treatment (photocoagulation) there - not the whole retina

Question 15

What are the features of diabetic nephropathy?

Answer 15

Presents with:

• Hypertension
• Progressively increasing proteinuria
• Progressively deteriorating kidney function
• Classic histological features

Question 16

What is a dangerous consequence of diabetic nephropathy?

Answer 16

Presence of diabetes and CKD increases the risk for cardiovascular events

Question 17

What are the 3 types of histological features to look at in diabetic nephropathy?

Answer 17

• Glomerular
• Vascular
• Tubulointerstitial

Question 18

What histological glomerular changes will be seen in diabetic nephropathy?

Answer 18

• Mesangial expansion
• Basement membrane thickening
• Glomerulosclerosis
  
  • Scarring of the glomerular capillaries (meaning loss of functional filtration tissue)

Mesangium:

• Essentially a supporting framework which forms between the glomerular capillaries
• Made up of:
  
  • Mesangial cells
  • Extracellular matrix

Question 19

COME BACK Describe the pathophysiology of diabetic nephropathy (online and Laz)

Question 20

Describe the epidemiology of diabetic nephropathy in diabetes.

Answer 20

Type 1

• 20-40% after 30-40 years

Type 2

• Probably equivalent to T1DM but epidemiology affected by certain factors
  
  • Age at development of disease (i.e. of T2DM)
  • Racial Factors
  • Age at presentation of T2DM
• Loss (i.e. most deaths) due to cardiovascular morbidity??

Question 21

What are the ranges of proteinuria?

Answer 21

• Normal Range: <30mg/24hrs
• Microalbuminuric Range: 30 - 300mg/24hrs
• Assymptomatic Range: 300 - 3000mg/24hrs
• Nephrotic Range: >3000mg/24hr

These ranges represent the amount of urine found in the urine

Question 22

COME BACK What are the strategies for intervention or management of diabetic nephropathy?

Answer 22

• Diabetes control
• Blood pressure control
• Inhibition of the activity of RAS system
  
  • EXPLAIN THIS
• Stopping smoking
  
  • Smoking stimulates oxidative stress because of increased formation of reactive oxidative species

Question 23

What is the most common cause of neuropathy?

Answer 23

Diabetes

• Therefore diabetes is the most common cause of lower limb amputation

Question 24

What does neuropathy result from?

Answer 24

Neuropathy results when the vasa nervorum get blocked

• Vasa nervorum = small blood vessels which supply the nerves

Question 25

What are the different types of diabetic neuropathy?

Answer 25

* Peripheral polyneuropathy * Mononeuropathy * Mononeuritis multiplex * Radiculopathy * Autonomic neuropathy * Diabetic amyotrophy * *Also known as proximal diabetic neuropathy* * *Caused by damage to the nerves of the lumbosacral plexus* * *​Affects thighs, hips, buttocks* * *Motor and sensory symptoms*

Question 26

COME BACK Describe the initiation and progression of neuropathy.

Question 27

What is peripheral neuropathy?

Answer 27

Peripheral neuropathy is damage to the **peripheral nerves** * Longer nerves more likely to be affected * Therefore it is more common in tall people * Longest nerves supply feet * So generally the feet are affected first * You present with loss of sensation * So the danger is that patients will not sense an injury to the foot * *e.g. Stepping on a nail**​* * You also get loss of motor function NOTE: Peripheral neuropathy is most common type of neuropathy in diabetes patients

Question 28

In which patients is peripheral neuropathy more likely to occur?

Answer 28

* Tall patients * Patients with poor glucose control

Question 29

How do you test for peripheral neuropathy?

Answer 29

* Loss of sensation - **monofilament examination** * *This is when you touch the patient with a single filament to see if they can feel it* * *​You apply a bit of pressure - not light touch* * *Touch them at various points on their foot (mostly sole)* * Loss of vibration sense - use a tuning fork * Loss of ankle jerk * *This is the reflex you get when you hit the Achilles tendon* * Multiple fractures on foot - detect using x-ray * This is part of Charcot's joint * *Charcot's joint = progressive degeneration of a weight bearing joint* * *This is due to the fact that you have a loss of sensation, so you can't detect any trauma* * *Therefore you get repetitive microtraumas* * *This triggers the inflammatory response as a repair process but this ends up making the bones weaker and susceptible to further trauma → vicious cycle* * *Problems with motor control can also generate unnatural pressure on certain joints, leading to additional microtrauma.*

Question 30

What is mononeuropathy?

Answer 30

Mononeuropathy is damage to a **single nerve** * Usually sudden motor loss * You can get a wrist drop or a foot drop * Cranial nerve palsy *(i.e. nerve damage)* * Double vision due to 3rd nerve palsy * *CN 3 = oculomotor nerve* * *Responsible for eye movement* * *Double vision becuase you get damage to one nerve (i.e. on one side) so both your eyes are not properly aligned so cannot both focus on one image*

Question 31

What are the two types of 3rd nerve palsies? Which one do you get in diabetes?

Answer 31

* **Pupil sparing** * You get this one in diabetes * Aneurysm causing Explanation: * Essentially the parasympathetic fibres which control pupil constriction run on the outside of the nerve * And the somatic motor fibres which supply the extrinsic eye muscles run on the inside * So if you have nerve compression, then the parasympathetic fibres on the outside will be affected * **Compression by intracranial aneurysm** * *Aneurysm = weakening in a blood vessel wall, leading to outward bulging (usually arterial)* * *​*So you get a _fixed dilated pupil_ * However, if you have ischaemia, it means you have reduced blood supply to the nerves * **This is what happens in diabetes due to blockage of the vasa nervorum** * Therefore, you get enough blood flow to the periphery so the parasympathetic nerve fibres are fine * BUT there is not enough blood supply to the somatic motor fibres on the inside so they get damaged

Question 32

How does pupil sparing 3rd nerve palsy present?

Answer 32

Eye is usually 'down and out' * 4th nerve pulls eye down *(trochlear)* * 6th nerve pulls eye out *(abducens)* Pupil DOES respond to light

Question 33

What is mononeuritis multipex?

Answer 33

Mononeuritis multiplex is a random combination of peripheral nerve lesions * *Isolated damage to at least two separate nerves* * *Can affect both sensory and motor function, depending on the nerves affected*

Question 34

What is radiculopathy?

Answer 34

Radiculopathy is compression *(pinching)* of a spinal nerve root * So essentially you get pain in the dermatome of the pinched spinal nerve * Usually affects a dermatome on the abdomen or chest wall

Question 35

What is autonomic neuropathy?

Answer 35

Autonomic neuropathy is damage to the sympathetic and parasympathetic nerves * *i.e. Form of polyneuropathy which affects the autonomic nervous system* So you get loss of sympathetic and parasympathetic nerve function to GI tract, bladder, cardiovascular system

Question 36

What are the features of autonomic neuropathy?

Answer 36

**GI tract problems** * Difficulty swallowing * Delayed gastric emptying * Constipation OR nocturnal diarrhoea * *Depending on which branch of the ANS is damaged* * *​PNS - increased gut motility* *→ constipation if damaged* * *​SNS - decreased gut motility → diarrhoea if damaged* **Bladder dysfunction** **Cardiovascular problems** * Postural hypotension * Collapsing on standing → can be disabling * Cardiac autonomic supply affected * *Can have lots of different clinical manifestations* * *​e.g. resting tachycardia, exercise intolerance* * Case reports of sudden cardiac death * *ANS dysregulation → arrythmias → cardiac arrest → sudden cardiac death* NOTES - definitions: * Exercise intolerance * Response to the challenges of exercise fail to achieve levels considered normal for the individual's age and gender * Arrythmia * Abnormal heart rhythm due to abnormal electrical activity in the heart * Cardiac arrest * Sudden loss of blood flow due to the heart failing to pump blood around the body * This is the result of an _electrical_ problem