Diabetic Neuropathy: Definition and Pathophysiology
Definition
Diabetic neuropathy is nerve damage affecting the peripheral nervous system (most commonly) or central nervous system as a chronic complication of diabetes mellitus. 1
The condition encompasses:
Diabetic peripheral neuropathy (DPN): Damage to peripheral nerves, presenting most commonly as distal symmetric polyneuropathy (DSPN)—a length-dependent, symmetrical injury starting in the feet and progressing proximally 1, 2
Diabetic central neuropathy: Less common damage to the brain, cerebellum, brainstem, spinal cord motor neurons, and spinal sensory nerve fibers 1
Diabetic autonomic neuropathy: Involvement of autonomic nerves affecting cardiovascular, gastrointestinal, genitourinary, and sudomotor systems 1, 3
Up to 50% of diabetic peripheral neuropathy cases are asymptomatic, yet these patients remain at high risk for foot ulceration and amputation due to loss of protective sensation. 2, 3
Pathophysiology
The pathophysiology of diabetic neuropathy is multifactorial, with hyperglycemia serving as the primary initiating factor that triggers multiple interconnected pathogenic mechanisms 4, 5:
Primary Metabolic Pathways
Hyperglycemia-induced metabolic disruptions in peripheral nerves represent the fundamental pathogenic mechanism, activating several damaging biochemical pathways: 4
Polyol pathway activation: Excess glucose is converted to sorbitol by aldose reductase in neurons and Schwann cells, leading to intracellular accumulation of sorbitol and fructose, causing osmotic stress and depletion of myoinositol 4, 6
Protein kinase C (PKC) activation: Hyperglycemia increases diacylglycerol synthesis, which activates PKC isoforms, leading to altered gene expression, vascular dysfunction, and impaired nerve blood flow 4, 6
Advanced glycation end products (AGEs): Non-enzymatic glycation of proteins produces AGEs that bind to receptors (RAGE), triggering inflammatory cascades and oxidative stress 5, 6
Hexosamine pathway flux: Increased glucose metabolism through this pathway leads to abnormal protein glycosylation and altered gene transcription 6
Oxidative Stress as the Unifying Mechanism
Oxidative stress serves as the central mediator linking all hyperglycemia-induced pathways to nerve damage. 4, 6
All activated metabolic pathways converge to generate reactive oxygen species (ROS) that overwhelm cellular antioxidant defenses 4
Oxidative stress directly damages neuronal mitochondria, lipids, proteins, and DNA, leading to neuronal dysfunction and death 5, 6
This represents a unifying theme for all mechanisms of diabetic neuropathy pathogenesis 4
Vascular and Inflammatory Components
Microvascular dysfunction and inflammation contribute significantly to nerve damage: 7, 5
Reduced oxygen delivery through the vasa nervorum (blood vessels supplying nerves) causes nerve ischemia 8
Inflammatory processes mediated by cytokines, chemokines, and immune cells directly damage nerve tissue 5, 8
Endothelial dysfunction in nerve microvasculature impairs nerve perfusion and nutrient delivery 7, 6
Nerve Fiber Involvement
The pathophysiology affects different nerve fiber types with varying clinical manifestations 1, 2:
Small fiber dysfunction: Affects unmyelinated C-fibers and thinly myelinated Aδ-fibers responsible for pain and temperature sensation, causing burning pain, dysesthesia, and loss of thermal perception 1, 5
Large fiber dysfunction: Affects heavily myelinated Aα- and Aβ-fibers responsible for vibration, proprioception, and motor function, causing numbness, loss of balance, and muscle weakness 1, 2
Length-Dependent Pattern
Diabetic sensorimotor polyneuropathy represents a diffuse, symmetrical, length-dependent injury, making it the prototypical example of this pattern. 2
The longest nerves are affected first (feet and lower legs), with symptoms progressing proximally in a "stocking-glove" distribution as the disease advances 2, 8
This pattern reflects the vulnerability of longer axons to metabolic stress and impaired axonal transport 8
Temporal Progression
The pathophysiological changes evolve over time with prolonged hyperglycemic exposure: 5, 8
Early stages involve reversible metabolic and functional changes in nerve conduction 7
Progressive stages show structural damage including axonal degeneration, demyelination, and loss of nerve fibers 8
Advanced stages demonstrate irreversible nerve fiber loss and secondary complications including foot ulceration and Charcot neuroarthropathy 2, 3