How does diabetes destroy or damage nerves?

How Diabetes Damages Nerves

Chronic hyperglycemia in diabetes causes nerve damage through multiple interconnected mechanisms, primarily involving oxidative stress, inflammation, and microvascular dysfunction that lead to progressive degeneration of nerve fibers, particularly affecting small unmyelinated C and Aδ fibers first before progressing to larger myelinated fibers. 1, 2

Primary Pathogenic Mechanisms

Metabolic Injury from Hyperglycemia

• Chronic hyperglycemia is the fundamental driver that triggers a cascade of damaging biochemical pathways in nerve tissue 1, 3
• Elevated blood glucose creates oxidative stress in diabetic neurons, generating reactive oxygen species that directly damage cellular components 3, 2
• Hyperglycemia activates multiple harmful biochemical pathways simultaneously, including the polyol pathway, advanced glycation end-product formation, and protein kinase C activation 3
• These metabolic imbalances affect glucose and lipid metabolism, creating a toxic cellular environment for nerve cells 2

Microvascular Compromise

• Dysfunction of the microvasculature (vasa nervorum) that supplies blood to nerves reduces oxygen delivery, further exacerbating neural damage 4, 5
• Impaired blood flow creates an ischemic environment that compounds the metabolic injury from hyperglycemia 5
• The combination of direct hyperglycemic toxicity and indirect vascular insufficiency creates a "double hit" to nerve tissue 4

Inflammatory Damage

• Hyperglycemia induces inflammatory stress in sensory neurons, Schwann cells (which support nerve fibers), and the microvascular endothelium 2
• This inflammatory cascade contributes to progressive nerve fiber degeneration 2, 5
• The inflammatory damage is both a consequence of metabolic dysfunction and an independent contributor to ongoing nerve injury 5

Pattern of Nerve Fiber Damage

Small Fiber Involvement First

• Small nerve fibers (unmyelinated C fibers and thinly myelinated Aδ fibers) are damaged earliest, often before large fiber involvement is detectable 1, 6
• Small fibers constitute 70-90% of peripheral nerve fibers and regulate temperature perception, pain sensation, and autonomic functions like sweating and blood flow 1
• This early small fiber damage explains why patients often develop painful neuropathy symptoms (burning, stabbing pain) and autonomic dysfunction before conventional nerve conduction studies show abnormalities 1

Progressive Large Fiber Damage

• As the disease progresses, larger myelinated Aα and Aβ fibers become affected, leading to loss of vibration sense, proprioception, and motor function 7, 6
• The longest axons are typically damaged first, which is why diabetic neuropathy characteristically begins in the feet and progresses proximally in a "stocking-glove" distribution 4

Structural Consequences

Nerve Fiber Degeneration

• Epidermal nerve fiber density (ENFD) progressively diminishes as axons of afferent neurons degenerate 4
• The remaining nerve fibers undergo physical and chemical changes that render them hypersensitive to painful stimuli while simultaneously becoming hyposensitive to normal stimuli 4
• This paradoxical combination explains both the painful symptoms and the loss of protective sensation that increases ulceration risk 1

Impaired Regeneration

• Nerve regenerative capacity is decreased in diabetes, contributing to progressive dysfunction 8
• This impaired regeneration results from decreased levels of neurotrophic factors, reduced expression of their receptors, altered cellular signaling pathways, and abnormal expression of cell adhesion molecules 8
• The inability to adequately repair ongoing damage accelerates the progression of neuropathy 8

Clinical Implications

Why Glycemic Control Matters

• Improved glycemic control can slow progression but does not reverse established neuronal loss 1
• Good glycemic control decreases the incidence of diabetic neuropathy, though more than half of diabetic patients still develop this complication despite optimal glucose management 2
• This underscores that while hyperglycemia is the primary driver, once nerve damage occurs, it is largely irreversible 1

Timing of Damage

• In type 2 diabetes, neuropathy may already be present at diagnosis due to prolonged unrecognized hyperglycemia 1, 5
• In type 1 diabetes, neuropathy typically appears approximately 10 years after disease onset 5
• Up to 50% of diabetic peripheral neuropathy may be asymptomatic, placing patients at risk for insensate foot injury 1

Key Clinical Pitfall

The most important caveat is that conventional nerve conduction studies only assess large myelinated fiber function and will be normal in early diabetic neuropathy when only small fibers are damaged 1. This can lead to missed diagnoses if clinicians rely solely on electrophysiology. Small fiber assessment requires specialized testing such as quantitative sensory testing, skin biopsy for intraepidermal nerve fiber density, or corneal confocal microscopy 1.