T2 Diabetes and Neurological Complications

Sensory neurons are affected, specifically nociceptors.
Glove and stocking pattern of nerve damage:
- Damage to peripheral nerves is slow and progressive.
- Distal portions of nerves are affected first due to the length of the axon, disregarding the nerve root.
Perception of sensory nerve damage varies:
- Some experience tingling followed by pain.
- Others feel numbness.
- Changes are subtle and occur over years, leading to signs being ignored or attributed to aging.
Causes:
- Pain receptors firing spontaneously without a known trigger.
- Difficulties with signal processing in the spinal cord, leading to allodynia (pain from non-painful stimuli).

High blood sugar in diabetes leads to damage in blood vessels and nerves when not managed.

Caused by:
- Defective insulin secretion by pancreatic β-cells.
- Inability of insulin-sensitive tissues to respond to insulin.
Insulin release and activity are crucial for glucose homeostasis; therefore, mechanisms involved in synthesis, release, and detection of insulin are tightly regulated.
Defects in these mechanisms can cause metabolic imbalance and disease development.

Metformin:
- First-line medication.
- Lowers glucose production in the liver (gluconeogenesis).
- Improves body's sensitivity to insulin.
Sulfonylureas and Glinides (Gliclazide):
- Help the body secrete more insulin and maximize its effectiveness.
Thiazolidinediones:
- Increase the sensitivity of body tissues to insulin.
Insulin:
- High doses are used to ensure absorption in functioning cells.

Statins:
- Lower bad cholesterol.
- Commonly prescribed to manage diabetes due to increased risk of heart diseases, such as heart attack and stroke.
SGLT2 inhibitors:
- Reduce sugar absorption in the kidneys, passing it out in urine and reducing blood sugar levels.
Aspirin:
- Low-dose aspirin inhibits COX-1.
- Reduced COX-1 activity lowers prostaglandin levels, which normally increase platelet aggregation and blood clotting.
Amitriptyline:
- Acts on painkilling pathways in the brain.
- Treats pain and low mood.
Gabapentin:
- Blocks pain by affecting pain messages traveling through the brain and spine.
- Typically used to treat epilepsy.

Diabetic nephropathy:
- Caused by hyperglycemia and hypertension, leading to glomerular damage.
- Pathological changes include thickening of basement membrane, atrophy, and arteriosclerosis.
- Initially results in glomerular hyperfiltration and high blood pressure, followed by progressive loss of renal function.
- Occurs in 30–40% of patients within 25 years.

Diabetic peripheral neuropathy:
- Damage to nerves outside the brain and spinal cord.
- Affects nerves in feet and hands (motor, sensory, or both).
- Annual foot checks are recommended.
- Causes pins and needles sensation.
Diabetic sensory neuropathy:
- Damage to nerves that transmit touch, temperature, pain, and other sensations.
- Affects nerves in feet and legs, but can also affect arms and hands.
Blood sugar spikes:
- High sugar levels alter blood circulation consistency, leading to an increase in body temperature that spreads within the body.
- Blood vessels regulate body temperature and glucose levels.

Definition:
- Sensory receptors activated by noxious stimuli that damage or threaten the body's integrity.
- Nociceptors and temperature nerves are in the spinothalamic tract.
Physiology:
- Two types of nerve fibers for pain: A-delta fibers and C-fibers (normally inactive).
- Transduction: Activation of A-delta and C-fibers by inflammatory mediators (e.g., platelets, mast cells, prostaglandins) due to tissue injury.
- Transmission: Fibers transmit impulses to the spinal cord.
- Modulation: Impulses are sent to the brain.
- Perception: Brain releases a response to the pain stimuli.
How drugs inhibit nocireception:
- Aspirin:
  - Reduces production of prostaglandins (sites of pain) by inhibiting the COX enzyme, thus reducing transduction.
  - $Aspirin \rightarrow \downarrow Prostoglandins$
  - $COX \text{ enzyme inhibition} \rightarrow \downarrow Prostoglandins$
- Opioids:
  - Reduce the transmission and modulation of impulses of A-delta and C fibers.

Definition:
- Pain caused by a disease of the somatosensory system.
- The somatosensory system allows for perception of touch, pressure, and temperature.
- Somatosensory nerves arise in the skin, muscles, nociceptors, chemoreceptors, and thermoreceptors.
Physiology:
- Sensory processes involve a thalamic nucleus receiving a sensory signal directed to the cerebral cortex.
- Diseases of the somatosensory nervous system (e.g., diabetes and HIV) can lead to altered transmission of sensory signals into the spinal cord and altered modulation into the brain.
Treatment and pain management:
- Amitriptyline:
  - Acts on painkilling pathways in the brain; treats pain and low mood.
- Gabapentin:
  - Blocks nerve pain by affecting pain messages traveling through the brain and down the spine; typically used to treat epilepsy.

To treat unwanted sensations (e.g., phantom limb syndrome).
- Involves placing a needle in the designated space and injecting medication (e.g., epidural anesthesia).
- Involves implanting an electrode.

Increased risk of macro-vascular thromboembolic events.
- Glucose levels can be affected by bacterial infections or other factors triggered by the acute illness.
- Hyperglycemia: occurs if not enough insulin is given (low blood sugars).
- Hypoglycemia: occurs if too much insulin is given (high blood sugar).