Diabetic peripheral neuropathy (DPN)

Learn more about diabetic peripheral neuropathy including pathophysiology, symptom presentation, diagnostic challenges and recommendations, and management approaches.

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Introduction to diabetic peripheral neuropathy

Defining diabetic peripheral neuropathy

Diabetic peripheral neuropathy is a common neuropathic complication associated with diabetes.1,2 It is commonly defined by the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after exclusion of other causes.1,3,4

Alternative terms used in literature to describe this condition include “diabetic distal symmetric polyneuropathy” and “diabetic polyneuropathy”.1,4

Many people with diabetes display signs of neuropathy but report no symptoms.3,5,6 Alternatively, some patients will experience symptoms such as pain.3,5,6 Neuropathic pain related to diabetic peripheral neuropathy, known as painful diabetic peripheral neuropathy, can have a considerable impact on a patient’s quality of life.5,6

Neuropathic pain associated with painful diabetic peripheral neuropathy is commonly reported in patients’ feet and typically follows a distal-to-proximal progression, often starting in the toes and gradually moving upwards.1,5,7,8

Epidemiology of diabetic peripheral neuropathy

The incidence of diabetes and its complications, one of which being diabetic peripheral neuropathy, is increasing annually, driven by poor dietary habits and unhealthy lifestyles worldwide.1,9,10

 

Reported prevalences of diabetic peripheral neuropathy vary widely1,2,7,10

The discrepancy in reported prevalences is due to multiple factors such as differing definitions of diabetic peripheral neuropathy, diagnostic methods, study quality and design, patient characteristics, and ethnic differences1,2,7,9

According to a pooled prevalence based on a worldwide meta-analysis of 29 studies (N=50,112 participants with type 1 diabetes, type 2 diabetes, or mixed type)9:

The same meta analysis found that the pooled prevalence of diabetic peripheral neuropathy was higher among patients with type 2 than those with type 1 diabetes9:

Type 1: 17.5% (95% [CI] 4.8–30.2%)

Study limitations of this meta-analysis included9:

Type 2: 31.5% (95% [CI] 24.4–38.6%)

Every year 1.2 million Americans are diagnosed with diabetes, and as of 2021, about 38.4 million Americans are living with the condition.11 Assuming a prevalence of 30% for diabetic peripheral neuropathy,9 we can estimate that ~11.5 million Americans are currently affected by this condition.

Exploring the pathophysiology of diabetic peripheral neuropathy

Multiple factors contribute to the pathogenesis of diabetic peripheral neuropathy, including:

Learn more about how the mechanisms of nerve damage due to diabetes manifest as symptoms in diabetic peripheral neuropathy.

Excess glucose and lipids due to diabetes and metabolic syndrome components

Excess glucose and lipids in the diabetic environment disrupt the normal pathways used for their own breakdown and produce excess electron donors, which cannot be processed by the mitochondria.5 This causes a chain of injurious events leading to mitochondrial dysfunction in sensory fibers.5

With fewer functional mitochondria in the cell body and along the axons (bioenergetic failure), energy-starved sensory fibers lose their ability to function and undergo degeneration.5

The axons farthest from the cell body, such as in the feet, are the most vulnerable because fewer functional mitochondria successfully travel from the cell body (located in the dorsal root ganglion) along the entire length of the axons to their most distal terminals (impaired mitochondrial trafficking).5 This may explain the distal-to-proximal disease progression seen in diabetic peripheral neuropathy.5

Poor microcirculation and neurovascular deficits in diabetic peripheral neuropathy

Vascular and neural diseases are closely related, because blood vessels depend on normal nerve function and nerves depend on adequate blood flow.13 

Hyperglycemia and its downstream effects damage the microvasculature,14,17 and diabetes can lead to reduced concentration of blood vessel formation mediators such as vascular endothelial growth factor.14

Upon progression of diabetic peripheral neuropathy, vasoconstriction and associated vascular abnormalities restrict blood supply to the periphery​.13 ​These vascular effects lead to diminished oxygen tension and hypoxia, which in turn contribute to nerve damage.13,14

A self-perpetuating cycle of nerve damage and poor circulation is established.13,14 Microcirculatory dysfunction is therefore likely associated with peripheral nerve dysfunction.14

Structural and chemical changes of epidermal nerve fibers in people with diabetic peripheral neuropathy

Epidermal nerve fiber density in patients with diabetic peripheral neuropathy is reduced compared to healthy individuals.15,16

Remaining nerve fibers may become hypersensitive to stimuli due to physical and chemical changes, potentially leading to increased pain response.16

Damage to and loss of these nerve fibers are associated with pain and other symptoms experienced by patients with diabetic peripheral neuropathy.5,16

Understanding the epidemiology and pathophysiology of diabetic peripheral neuropathy is crucial for diagnosis, symptom management, and understanding the impact on patient quality of life.

Symptoms

Footnotes

CI, confidence interval.

N/A 05 25 0007 | June 2025