From the Guidelines
Diabetic neuropathy develops through multiple interconnected physiological mechanisms primarily driven by chronic hyperglycemia, leading to increased oxidative stress, activation of the polyol pathway, formation of advanced glycation end products, microvascular damage, neuroinflammation, mitochondrial dysfunction, and impaired neurotrophic factors, ultimately resulting in axonal degeneration, demyelination, and progressive sensory, motor, and autonomic dysfunction 1.
Key Mechanisms
- Elevated blood glucose leads to increased oxidative stress, with excessive production of reactive oxygen species that damage nerve cells and blood vessels supplying them
- Hyperglycemia activates the polyol pathway, converting excess glucose to sorbitol and fructose, which accumulate in nerves and cause osmotic stress and depletion of critical antioxidants like glutathione
- Advanced glycation end products (AGEs) form when glucose binds to proteins, altering their structure and function, particularly affecting myelin sheaths and axonal transport
- Microvascular damage occurs as hyperglycemia impairs blood flow to nerves, creating ischemic conditions that further damage nerve fibers
- Neuroinflammation plays a significant role, with increased pro-inflammatory cytokines contributing to nerve damage
- Mitochondrial dysfunction develops as hyperglycemia disrupts energy production in nerve cells, while impaired neurotrophic factors reduce nerve maintenance and repair capabilities
Clinical Implications
- Symptoms of diabetic neuropathy typically begin distally and advance proximally as the condition progresses
- Early symptoms may include pain, dysesthesia, numbness, and loss of proprioception
- Cardiac autonomic neuropathy (CAN) is associated with mortality independently of other cardiovascular risk factors and may be asymptomatic in its early stages 1
- Optimal glucose control is crucial to prevent or delay the development of neuropathy in patients with type 1 diabetes and to slow the progression of neuropathy in patients with type 2 diabetes 1
From the Research
Physiological Mechanism of Diabetic Neuropathy
The physiological mechanism of diabetic neuropathy is complex and involves multiple factors, including:
- Glucose and lipid imbalances 2
- Insulin resistance 2
- Oxidative stress 2
- Inflammation 2
- Altered gene expression 2
- Changes in the blood vessels that supply the peripheral nerves 3
- Metabolic disorders, such as the enhanced activation of the polyol pathway 3
- Myo-inositol depletion 3
- Increased non-enzymatic glycation 3
Key Mechanisms
Key mechanisms that contribute to neurovascular dysfunctions in diabetic neuropathy include:
- Interactions between the nervous system and the immune system 3
- Glial cell activation 3
- Changes in the interactions between the nervous system and the immune system that occur in parallel with glial cell activation 3
Treatment Strategies
Treatment strategies for diabetic neuropathy focus on preventative care and pain management, including:
- Intensive glycemic control with insulin in patients with type 1 diabetes 4
- First-line pharmacologic therapy, such as gabapentinoids (pregabalin and gabapentin) and duloxetine 4, 5, 6
- Additional pharmacologic modalities, such as tapentadol and 8% capsaicin patch 4, 6
- Nonpharmacological treatments, such as spinal cord stimulation (SCS) and transcutaneous electrical nerve stimulation (TENS) 4, 5, 6