Diabetic peripheral neuropathy (DPN)

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 widely^1,2,7,10

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%)

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.

Footnotes

CI, confidence interval.

Gylfadottir SS et al. J Diabetes Investig. 2019;10:1148–57.
Gylfadottir SS et al. Pain. 2020;161:574–83.
Boulton AJ et al. Diabet Med. 1998;15:508–14.
Pop-Busui R et al. Diabetes Care. 2017;40:136–54.
Pop-Busui R et al. Diagnosis and treatment of painful diabetic peripheral neuropathy. Arlington (VA): American Diabetes Association; 2022. https://www.ncbi.nlm.nih.gov/books/NBK580224/. Accessed May 19, 2025.
Gandhi M et al. Drugs Context. 2022;11:2021-10-2.
Elafros MA et al. Lancet Neurol. 2022;21:922–36.
Tesfaye S et al. J Diabetes Complications. 2023;37:108417.
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Centers for Disease Control and Prevention. National Diabetes Statistics Report. 2024. https://www.cdc.gov/diabetes/php/data-research/index.html. Accessed May 19, 2025.
Bodman MA et al. Diabetic Peripheral Neuropathy [Internet]. Treasure Island (FL): StatPearls Publishing; 2025. Available from: https://www.ncbi.nlm.nih.gov/books/NBK442009/. Accessed May 19, 2025.
Miranda-Massari JR et al. Curr Clin Pharmacol. 2011;6:260–73.
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Symptoms of diabetic peripheral neuropathy

Diabetic peripheral neuropathy is commonly defined by the presence of peripheral nerve dysfunction in people with diabetes after exclusion of other causes.^1,2

Diabetic peripheral neuropathy symptoms and signs vary depending on the type of nerve fibers affected.³ While pain is a common symptom, not all patients experience it, and some individuals may be asymptomatic.³

Small-fiber symptoms and signs

Small-fiber damage can cause pain, which may manifest as stabbing, burning or electric shock-like sensations.³ It often emerges during the early stages of diabetic peripheral neuropathy and tends to worsen at night.³

Pain may be accompanied by dysesthesias, such as hyperalgesia and allodynia.³ Hyperalgesia refers to abnormally increased pain sensitivity to a stimulus that normally provokes pain,^4,5 while allodynia refers to pain due to a stimulus that does not normally provoke pain.^4,5

Upon clinical examination, patients may also display characteristic signs of small-fiber damage such as reduced or absent response to thermal discrimination and pinprick sensation testing.³

Learn more about diagnostic assessments of peripheral nerve dysfunction in people with diabetes after exclusion of other causes.^1,2

Large-fiber symptoms and signs

Damage to large fibers can result in symptoms such as numbness and tingling sensations without pain.³ In advanced stages of diabetic peripheral neuropathy, patients may also experience poor balance and muscle weakness.^3,6

Clinical signs of large fiber damage include impaired proprioception and reduced or absent response to several diagnostic tests such as ankle reflexes, vibration perception, and 10-g monofilament sensation.³

Asymptomatic diabetic peripheral neuropathy

Up to 50% of patients with diabetic peripheral neuropathy may be asymptomatic or reluctant to report symptoms.³

Some patients, initially aware of neuropathic symptoms, may become asymptomatic with time due to severe sensory loss in nerve fibers, which can result in insensate feet.³

Distal to proximal progression of diabetic peripheral neuropathy

Progression of diabetic peripheral neuropathy most often starts in the toes and gradually moves proximally. Once established in the lower limbs, it can begin to affect upper limbs as well.⁸

A distal-to-proximal loss of sensory fibers (axonal loss), with accompanying “stocking and glove” pattern of symptoms, are the hallmark of diabetic peripheral neuropathy.^3,8

Distal-to-proximal progression of diabetic peripheral neuropathy<sup>3,8</sup>

Distal-to-proximal progression of diabetic peripheral neuropathy^3,8

Recognition of early symptoms and signs, and timely interventions are crucial to preventing the progression of diabetic peripheral neuropathy and complications.⁹ Learn more about diagnosising diabetic peripheral neuropathy.

Footnotes

Boulton AJ et al. Diabet Med. 1998;15:508–14.
Pop-Busui R et al. Diabetes Care. 2017;40:136–54.
Pop-Busui R et al. Diagnosis and treatment of painful diabetic peripheral neuropathy. Arlington (VA): American Diabetes Association; 2022. https://www.ncbi.nlm.nih.gov/books/NBK580224/. Accessed May 21, 2025.
Bannister K et al. Annu Rev Pharmacol Toxicol. 2020;60:257–74.
International Association for the Study of Pain (IASP). 2021. Terminology. https://www.iasp-pain.org/resources/terminology/. Accessed May 21, 2025.
Feldman EL et al. Nat Rev Dis Primers. 2019;5:42.
de Souza RJ et al. J Diabetes Complications. 2015;29:811–7.
Tesfaye S, Selvarajah D. Diabetes Metab Res Rev. 2012;28(Suppl 1):8–14
Gandhi M et al. Drugs Context. 2022;11:2021-10-2.

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Diagnosing diabetic peripheral neuropathy

Recognition of early signs and/or symptoms and timely intervention are crucial for preventing progression of diabetic peripheral neuropathy and complications (e.g. foot ulcerations and amputations), particularly as up to 50% of patients may be asymptomatic.^1,2

Challenges associated with diagnosis of diabetic peripheral neuropathy

Pain and other symptoms and/or signs of diabetic peripheral neuropathy significantly diminish patient quality of life, affecting physical, psychological, and social well-being.^3–6 Yet, diabetic peripheral neuropathy is frequently under- and misdiagnosed.^6,7

It can be a clinical challenge to diagnose patients with diabetic peripheral neuropathy as⁸:

Diagnostic recommendations

According to the American Academy of Clinical Endocrinology (AACE) and American Diabetes Association (ADA), diabetic peripheral neuropathy is a clinical diagnosis based on exclusion of other causes.^2,8

Screening via clinical history and physical examination is recommended to rule out nondiabetic neuropathies in all patients with diabetes^2,8:

Assessments for diabetic peripheral neuropathy should include a careful history and a combination of tests, such as^2,8,9:

According to AACE, assessments should follow the typical diabetic peripheral neuropathy pattern by starting distally and moving proximally until a sensory threshold is identified.⁸

Large-fiber function may be assessed through vibration sensation, light-touch sensation or ankle reflex testing<sup>9,10</sup><br> Small-fiber function may be evaluated with pinprick sensation and temperature discrimination tests.<sup>9,10</sup>

Large-fiber function may be assessed through vibration sensation, light-touch sensation or ankle reflex testing^9,10
Small-fiber function may be evaluated with pinprick sensation and temperature discrimination tests.^9,10

Diabetic foot exams should be performed to detect deformities and identify risks for complications such as ulceration and amputations.^2,8

Multiple other screening tools are available to aid diagnosis of diabetic peripheral neuropathy, including the Michigan Neuropathy Screening Instrument (MNSI) and the Douleur Neuropathique en 4 (DN4) questionnaire, along with other patient-reported outcome measures.¹¹

Diagnosis of atypical diabetic peripheral neuropathy

Presence of atypical symptoms may contribute to under- and misdiagnosis of diabetic peripheral neuropathy and includes^2,8:

Electrophysiological testing, skin biopsies, or referral to a neurologist may be considered when clinical features of diabetic peripheral neuropathy are atypical or when the diagnosis is unclear.^8,12

Electrophysiological testing, such as nerve conduction studies, may be used to measure large-fiber function.¹¹During nerve conduction studies, surface electrodes are used to stimulate nerves at several points of the limb and measure the response¹³
Skin biopsy of the distal leg (lower calf and ankle) to quantify intraepidermal nerve fiber density is not an appropriate screening tool due to its invasive nature but has utility as a diagnostic tool and clinical endpoint in research environments¹²

Pain and other symptoms of diabetic peripheral neuropathy may be addressed with appropriate disease management strategies and therapeutic targets. Learn more.

Footnotes

Gandhi M et al. Drugs Context. 2022;11:2021-10-2.
Pop-Busui R et al. Diabetes Care. 2017;40:136–54.
Tesfaye S et al. J Diabetes Complications. 2023;37:108417.
Tölle T et al. J Diabetes Complications. 2006;20:26–33.
Gao Y et al. Nurs Open. 2023;10:3164–77.
Abd-Elsayed AA et al. J Pain Res. 2023;16:2269–85.
Wang W et al. Diabetes Educ. 2011;37:536–48.
Blonde L et al. Endocr Pract. 2022;28:923–1049.
Gylfadottir SS et al. J Diabetes Invest. 2019;10:1148–57.
Pop-Busui R et al. Diagnosis and treatment of painful diabetic peripheral neuropathy. Arlington (VA): American Diabetes Association; 2022. https://www.ncbi.nlm.nih.gov/books/NBK580224/. Accessed May 21, 2025.
Petropoulos IN et al. Diabetes Metab J. 2018;42:255–69.
Yang H et al. Front Endocrinol (Lausanne). 2020;10:929.
Huynh W, Kiernan MC. Aust Fam Physician. 2011;40:693–7.

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Management of painful diabetic peripheral neuropathy

Diabetic peripheral neuropathy is commonly defined by the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after exclusion of other causes.^1,2 Up to 30% of patients with diabetic peripheral neuropathy are affected by neuropathic pain, which is commonly reported in the feet and known as painful diabetic peripheral neuropathy.^3,4,5

Multifactorial management of painful diabetic peripheral neuropathy

A multifactorial treatment approach is often needed to manage painful diabetic peripheral neuropathy and may include glycemic control, management of metabolic syndrome components such as dyslipidemia or obesity, and neuropathic pain management with pharmacological and/or non-pharmacological treatments.^6–8

With glycemic control, various studies have shown that^7,9:

Management of metabolic syndrome may include addressing dyslipidemia, obesity, and hypertension.^6–8 Lifestyle interventions such as implementation of healthy eating plans, increased physical activity, and reduction of sedentary behavior can play a key role in the management of metabolic syndrome.^6,7

Neuropathic pain management may involve oral and/or topical pharmacological treatment options, and non-pharmacological therapies such as neuromodulatory techniques, and/or lifestyle interventions.^5,6 Combination therapy with multiple pharmacological agents and/or non-pharmacological methods may also be used.^5,6

Management of painful diabetic peripheral neuropathy requires a multidisciplinary approach combining coordinated care from specialists in neurology, endocrinology, podiatry, pain management, and primary care physicians.^6,8,10

Several factors contribute to management choices for painful diabetic peripheral neuropathy, including comorbidities, contraindications or physical limitations, drug-drug interactions, potential for adverse events, patient education and preferences, and/or cost.^6,8

Treatment landscape and guidelines for painful diabetic peripheral neuropathy

Currently available FDA-approved pharmacological treatments to manage neuropathic pain in patients with painful diabetic peripheral neuropathy are the oral drugs pregabalin,¹¹ duloxetine,¹² and tapentadol extended-release (ER),¹³ and one topical agent, the capsaicin 8% topical system.^14,a

FDA-approved or cleared non-pharmacological treatments for painful diabetic peripheral neuropathy include several spinal cord stimulation devices^15,16 and one magnetic peripheral nerve stimulation device.^17,a

Several US expert groups have published guidelines for the management of painful diabetic neuropathy, including:

Recommendations may vary across expert groups and contain not only FDA-approved or cleared treatments for painful diabetic peripheral neuropathy, but also off-label treatment options such as gabapentin, serotonin and norepinephrine reuptake inhibitors (other than duloxetine), tricyclic antidepressants, sodium channel blockers, lidocaine patches and plasters, or transcutaneous electrical stimulation.^5,6,20–22

Although tapentadol ER has a US indication for painful diabetic peripheral neuropathy,¹³ current guidelines from the ASPN, ADA, AACE, and AAN do not recommend opioids for the treatment of painful diabetic peripheral neuropathy due to the high risk of addiction and other complications.^5,6,20–22

Emerging therapeutic options and US initiatives

Ongoing research is being conducted to investigate new therapeutic options to address painful diabetic peripheral neuropathy.¹⁶ Furthermore, US initiatives, such as the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) Diabetic Foot Consortium and the National Institute of Health (NIH) Helping to End Addiction Long-term (HEAL) Initiative, also seek to improve care for diabetic foot ulcers and pain management by supporting clinical research in these areas.^23,24

Effective management of painful diabetic peripheral neuropathy requires a multidisciplinary and multifactorial approach. Understanding diabetic peripheral neuropathy, recognizing the symptoms, and ensuring timely diagnosis are critical steps to enhance patient outcomes.

Footnotes

^aInformation is current as of May 2025.

AACE, American Association of Clinical Endocrinologists; AAN, American Academy of Neurology; ADA, American Diabetes Association; ASPN, American Society of Pain and Neuroscience; FDA, Food and Drug Administration; US, United States of America.

Boulton AJ et al. Diabet Med. 1998;15:508–14.
Gylfadottir SS et al. J Diabetes Investig. 2019;10:1148–57.
Elafros MA et al. Lancet Neurol. 2022;21:922–36.
Tesfaye S et al. J Diabetes Complications. 2023;37:108417.
Pop Busui R et al. Diagnosis and treatment of painful diabetic peripheral neuropathy. Arlington (VA): American Diabetes Association; 2022. https://www.ncbi.nlm.nih.gov/books/NBK580224/. Accessed May 20, 2025.
Blonde L et al. Endocr Pract. 2022;28:923–1049.
Feldman EL et al. Nat Rev Dis Primers. 2019;5:42.
Gandhi M et al. Drugs Context. 2022;11:2021-10-2.
Grisold A et al. Curr Opin Endocrinol Diabetes Obes. 2017;24:103–11.
Adams AS et al. Healthc (Amst). 2017;5:171–3.
Pfizer. US Prescribing Information: Pregabalin capsules and oral solution. Updated May 2018.
Eli Lilly and Company. US Prescribing Information: Duloxetine hydrochloride delayed release capsules. Updated: October 2010.
Collegium Pharmaceutical, Inc. US Prescribing Information: Tapentadol extended release tablets. Updated: October 2019.
Averitas Pharma. US Prescribing Information: Capsaicin 8% topical system. Updated: July 2024.
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