Peripheral Diabetic Neuropathy

Earn CME/CE in your profession:

Continuing Education Activity

Peripheral neuropathy (PN) encompasses a broad range of clinical pathologies potentially presenting with peripheral nervous system dysfunction. Patients with PN often present with varying degrees of numbness, tingling, and/or burning in the extremities. While metabolic disorders represent the predominant etiology of extremity pain caused by an underlying PN clinical pathology, broad clinical consideration is given to a plethora of clinical conditions. Although there are many possible causes of peripheral neuropathy, the most prevalent subtype, diabetic peripheral neuropathy, can lead to major complications. The exact cause of diabetic peripheral neuropathy is not known. Mechanical compression (e.g., carpal tunnel), genetics, social and lifestyle factors such as chronic alcohol consumption and smoking have been implicated. This activity reviews the evaluation and management of diabetic neuropathy and the role of interprofessional team members in collaborating to provide well-coordinated care and enhance patient outcomes.


  • Review the pathophysiology of diabetic neuropathy.
  • Summarize the treatment of diabetic neuropathy.
  • Describe the potential complications of diabetic neuropathy.
  • Outline the management of diabetic neuropathy and the role of interprofessional team members in collaborating to provide well-coordinated care and enhance patient outcomes.


Peripheral neuropathy (PN) encompasses a broad range of clinical pathologies potentially presenting with peripheral nervous system dysfunction.[1] Patients with PN often present with varying degrees of numbness, tingling, and/or burning in the extremities.  While metabolic disorders represent the predominant etiology of extremity pain caused by an underlying PN clinical pathology, broad clinical consideration is given to a plethora of clinical conditions.

Although there are many possible causes of peripheral neuropathy, the most prevalent subtype, diabetic peripheral neuropathy, can lead to major complications. Early assessment of symptoms of peripheral polyneuropathy helps avoid neuropathic foot ulcers to ultimately combat potential morbidity and mortality resulting from the pathophysiologic poor wound healing potential, which can lead to limb compromise, local to systemic infection, septicemia, and even death.

The exact cause of diabetic peripheral neuropathy is not known. Proposed theories include metabolic, neurovascular, and autoimmune pathways have been proposed. Mechanical compression (e.g., carpal tunnel), genetics, social and lifestyle factors such as chronic alcohol consumption, and smoking all have been implicated. Perpetually high blood serum glucose appears to lead to damaged small blood vessels, which compromise oxygen and nutrients to the nerves. First, the distal sensory and autonomic nerve fibers are damaged; the damage then continues with proximal progression leading to a gradual loss of protective sensation in both the skin and foot joints. Half of the diabetic peripheral neuropathies may be asymmetric. If they are not recognized, and preventative foot care is not implemented, patients have an increased risk of injury due to their insensate feet.[2][3][4]


Metabolic disorders represent the most common clinical category of etiologies, causing extremity pain from underlying PN conditions.   

Several causes of PN exist, but diabetes mellitus (DM) is the most common etiology.  Other underlying etiologies worth considering include:

  • Alcohol use disorder
  • Nutritional deficiencies (e.g., low B12, high B6)
  • Guillain-Barre syndrome
  • Toxins (chemotherapy) and overdose
  • Hereditary or genetic conditions (e.g., Charcot Marie Tooth disease, amyloidosis, porphyria)
  • Infection (HIV)
  • Inflammatory conditions (Lupus, Rheumatoid arthritis)
  • Hypothyroidism
  • Malignancy

Risk factors for PN include:

  • Advanced age
  • Hypertension
  • Peripheral vascular disease
  • Smoking
  • Dyslipidemia
  • Poor glucose control
  • A long duration of diabetes
  • Heavy intake of alcohol
  • Positive HLA-DR3/4 genotype


At the time of diagnostic DM onset in patients, the literature reports about 10% to 20% of patients being concomitantly diagnosed with PN. However, studies analyzing patients with DM at an increasing duration of stages of the disease in terms of chronicity report increasing prevalence rates for the DM and PN association. After five years, 26% have peripheral neuropathy, and at ten years, 41% of patients with diabetes have neuropathy. The literature reports from 50% to 66% of patients with DM will eventually develop PN at some point during their lifetime.[5]

Clinically, about half of patients with diabetic PN can present with asymmetric sensory changes.[6][7] Obesity and genetic factors increase the risk of developing diabetes. Peripheral and autonomic neuropathies are one of the leading causes of morbidity in diabetes mellitus. At five years, the risk of death for patients with a diabetic foot ulcer is 2.5 times as high as the risk of death for a patient with diabetes who does not have a foot ulcer. The rate of emergency department visits for diabetic foot ulcers and associated infection exceeds the rates for congestive heart failure, renal disease, depression, and most forms of cancer.[8][9][10]


Diabetic peripheral neuropathy encompasses sensory, motor, and autonomic neuropathy. Implicated causes of peripheral nerve damage include oxidate stress damage, accumulation of sorbitol, and advanced glycosylation end products, as well as a disturbance of hexosamine, protein kinase C, and polymerase pathways. Neurovascular impairment with poor repair processes and endothelial dysfunction also have been implicated.[7]


Transient hyperglycemia is often tolerated by normal compensatory physiological function and homeostatic mechanisms of blood sugar control. However, in chronically elevated states, it can have toxic effects such as neuropathy. For patients diagnosed early with type 1 diabetes mellitus, tight glucose control can reduce the risk of diabetic peripheral neuropathy by 78%. [11]  In contrast, typically, with a later diagnosis of long-standing hyperglycemia or type 2 diabetes, tight glucose control only reduces the risk by 5% to 9%. [11]

History and Physical

Symptoms of burning, numbness, or tingling in the feet that tend to be worse at night are characteristic. Patients with pedal paresthesias and dysesthesia often describe a nonspecific constellation of symptoms resulting in difficulty with ambulation and other basic activities of daily living (ADL). The characteristic polyneuropathy and distal sensory peripheral neuropathy are present in about 80% of DM PN patients. This is often described as a "stocking-glove distribution," and it can take several years to develop.  [12]

Since the protective sensation is lost after sensory impairment, the standard Semmes-Weinstein 5.07 monofilament 10 grams of pressure protective sensation test may be accurately sensed even after a neurotrophic ulcer has developed. Simply timing the duration that a vibrating 128 Hz tuning fork is felt at the dorsal hallux interphalangeal joint (usually 18 seconds) can be used to detect sensory deficits earlier as well as quantify severity. Decreased light touch sensation or loss of ankle reflexes tend to occur earlier in the disease process, while the detectable loss of protective sensation tends to occur later in the disease, sometimes even after a neuropathic ulcer develops. Needle electromyography (EMG) and nerve conduction velocity testing can be both painful, expensive, and mainly test the large myelinated fibers. Epidermal nerve fiber density testing can be performed to evaluate the small unmyelinated fibers. [13]

Autonomic Symptoms

Autonomic neuropathy is also very common in diabetes and can affect the gastrointestinal, cardiovascular, and genitourinary organs. Typical symptoms include:

  • GI: Abdominal discomfort, dysphagia, nausea, fecal incontinence, constipation, diarrhea
  • Cardiac: Hypotension, sinus tachycardia, variable heart rate, syncope
  • Bladder: Weak urinary stream, straining to void, incomplete emptying of bladder, 
  • Skin: Heat intolerance, gustatory sweating, extreme diaphoresis
  • Nervous: Carpal tunnel syndrome, radiculopathy, lumbosacral, and cervical neuropathy. In addition, cranial nerves 3,4,6, and 7 may be affected.


The medical history review of systems and medications captures most of the causes of peripheral neuropathy. Electromyography and/or nerve conduction studies are suggested if there are severe or rapidly progressive symptoms or motor weakness. Minor symptoms may not need laboratory workup. Persistent unexplained symptoms may warrant laboratory investigation including serum glucose, hemoglobin A1c, complete blood count, erythrocyte sedimentation rate, rapid plasma reagin, serum electrophoresis, and vitamin B1, B6, and B12 level. A lower extremity neurological physical exam should be performed to include muscle strength, reflex evaluation, and sensation evaluation (light touch with a monofilament, vibratory sensation, and proprioception). A dermatological exam demonstrating dry/cracked skin may point to autonomic neuropathy, while pedal deformities (hammertoes) suggest motor neuropathy. [12] Measurement of epidermal nerve fiber density (ENFD) by skin biopsy can be considered in patients with idiopathic cases. The number and morphology of axons within the epidermis can be evaluated, and intraepidermal nerve fiber density is compared to age-dependent normal values.[14][15]

Treatment / Management

Many patients with neuropathy have mild to moderate numbness symptoms yet still retain protective sensation in their feet. They may only need reassurance and education as to the cause of the numbness. Periodic follow-up is important. With improved glycemic control, paresthesias and dysesthesias may diminish within one year. After peripheral arterial disease and radiculopathy are ruled out, painful symptoms that disturb sleep or activities of daily living can be treated with pregabalin, gabapentin, or anti-depressants. [16] These medications have been shown to reduce the symptoms by 30% to 50% in many patients. Some patients also respond to the over-the-counter antioxidant alpha-lipoic acid. Additionally, although classified as a medical food, the prescription containing L-methyl folate, pyridoxal 5'-phosphate, and methylcobalamin for the dietary management of endothelial dysfunction has been shown to improve nerve fiber density and monofilament sensation significantly. [17] Depletion of substance P with topical capsaicin cream may help some patients who can tolerate the initially increased burning.[18][19][20]  For patients with painful diabetic peripheral neuropathy, a capsaicin 8% patch in serial treatments can provide modest improvements in pain and sleep quality. [21][16]

Diabetic gastroparesis may be managed with erythromycin and metoclopramide. Tegaserod is a newer agent but is only available on an emergency basis because of serious adverse cardiac effects.

Some patients may benefit from the use of vitamins, especially zinc.

Erectile dysfunction is managed with phosphodiesterase inhibitors, but not everyone has a response. A penile prosthesis may be of benefit.

Orthostatic hypotension may be managed by increased salt and fluid intake and the use of compression stockings. If that fails, steroids may be required. Glycopyrrolate is used to manage sweating but often does not work.

  • All infected diabetic foot ulcers need debridement or amputation
  • Gastroparesis may be managed by a jejeunostomy tube, especially in patients losing weight.
  • A pancreas transplant is an option and has been shown to stabilize autonomic function.
  • Physical therapy is a must for all patients with PN, especially those with muscle pain and weakness. Also, occupational therapy may be necessary when there is a functional loss. Speech therapy is necessary to help patients with dysphagia and the risk of aspiration.

Differential Diagnosis

  • Alcohol-associated neuropathy
  • Nutritional linked neuropathy
  • Uremic neuropathy
  • Vasculitic linked neuropathy
  • Vitamin B-12 deficiency
  • Toxic metal neuropathy



  1. NO: No neuropathy
  2. N1a: Signs but no symptoms of neuropathy
  3. N2a: Mild polyneuropathy or autonomic neuropathy, patient able to walk on heels
  4. N2b: Severe polyneuropathy and patient unable to walk on heels
  5. N3: Disabling polyneuropathy


Poorly treated diabetics have higher morbidity and complication rates associated with PN compared to well-controlled diabetics. PN often leads to skin breakdown, infection, ulceration, and eventually to amputation. Further, the treatment of PN is not satisfactory, and adverse cardiac events are common. Less than a third of patients achieve good pain control. For most patients with PN, the quality of life is poor.


  • Amputations of the toes, foot, or leg
  • Infections of the foot
  • Dizziness falls
  • Diarrhea, failure to thrive, dehydration
  • Pain
  • Cardiovascular neuropathy can cause death

Deterrence and Patient Education

According to American Diabetes Association, people with diabetes should have a complete foot examination annually and a visual examination of the feet at each visit, which is usually every three to four months. Patients should be educated well on monitoring blood sugar levels and performing self-examination of their feet every day to look for ulcers, wounds, or any broken skin. They should also follow a diet plan as well as take medications on time as advised by the doctor. They should be made aware of the contribution role of alcohol and smoking in peripheral neuropathy and advised a plan to quit if required. Moreover, abnormally fitting shoes should not be worn by the patient.

Pearls and Other Issues

The lower extremities are especially prone to the repetitive microtrauma-induced complications of polyneuropathy. There is an increased propensity to develop not only recurrent neuropathic ulcers but Charcot neuroarthropathy and, to a lesser extent, motor neuropathy. Additionally, as patients age, their nails become dystrophic, and the face of decreased protective sensation, the risk of subungual ulcerations, gangrene, and osteomyelitis increases. Periodic pedal-focused examinations are essential. Professional foot care, along with therapeutic shoes and insoles, have helped to reduce the lower limb amputation rates in patients with diabetes mellitus.

Enhancing Healthcare Team Outcomes

Diabetic neuropathy affects many organ systems and is best managed by an interprofessional team. Because there is no cure for the disorder, the key is prevention. All people with diabetes should have a dietary consult and should be educated on what foods they should eat and what to avoid. The diet should be realistic and focused on lowering blood glucose levels. The patients should also enter a rehabilitation program or some exercise. Losing weight not only makes it easier to control blood sugars but also lowers blood pressure and lipids. A podiatry consult is vital as protection of the foot is necessary. Further, all people with diabetes should be informed about avoiding trauma and undergoing any invasive procedure on the feet without prior clearance from the endocrinologist. In addition, the patient should be told to avoid cold or hot temperatures.

A dedicated diabetic nurse should educate the patient about all aspects of diabetes and the importance of euglycemia. Patients should be taught how to monitor their blood glucose and how to use portable glucose monitors. The pharmacist should offer education about the medications, their benefits, and their adverse effects.

Compliance with diabetic medications is vital. Finally, patients who do develop neuropathy also tend to have nephropathy and retinopathy- hence, all people with diabetes should be referred to a nephrologist and ophthalmologist. There should be open communication between the interprofessional team so that all patients are provided the available standard of care with minimal morbidity. Foot and nail care nurses monitor patients, provide education, and inform the team of the patient's condition. Pharmacists educate patients about the use of medications and the importance of compliance. [22][23] [Level 5]


In general, patients with diabetes mellitus (DM) who are not compliant with treatment or are undertreated, usually tend to have a poorer outcome compared to patients who undergo treatment. The neuropathy frequently results in the breakdown of skin, ulceration, and eventually an infection. Amputation of the toes and limbs is not uncommon. However, the actual treatment of diabetic neuropathy is not perfect, and often most treatments do not work. Complete relief from symptoms of neuropathy is rare. Overall, the mortality rates are highest in patients with DM with autonomic neuropathy, especially those who have cardiac dysfunction. The overall mortality rates are 15% to 30% over ten years, but there is also significant morbidity from limb amputation. Other symptoms that make the quality of life poor include syncopal attacks, diarrhea, constipation, and continuous pain.[2][24] [Level 5]

Article Details

Article Author

Myron A. Bodman

Article Editor:

Matthew Varacallo


9/24/2022 8:28:42 AM



Wang Y,Li W,Peng W,Zhou J,Liu Z, Acupuncture for postherpetic neuralgia: Systematic review and meta-analysis. Medicine. 2018 Aug     [PubMed PMID: 30142834]


Zafeiri M,Tsioutis C,Kleinaki Z,Manolopoulos P,Ioannidis I,Dimitriadis G, Clinical Characteristics of Patients with co-Existent Diabetic Peripheral Neuropathy and Depression: A Systematic Review. Experimental and clinical endocrinology & diabetes : official journal, German Society of Endocrinology [and] German Diabetes Association. 2021 Feb     [PubMed PMID: 30257266]


Vinik AI,Casellini C,Parson HK,Colberg SR,Nevoret ML, Cardiac Autonomic Neuropathy in Diabetes: A Predictor of Cardiometabolic Events. Frontiers in neuroscience. 2018     [PubMed PMID: 30210276]


Sloan G,Shillo P,Selvarajah D,Wu J,Wilkinson ID,Tracey I,Anand P,Tesfaye S, A new look at painful diabetic neuropathy. Diabetes research and clinical practice. 2018 Sep 7     [PubMed PMID: 30201394]


Dyck PJ,Kratz KM,Karnes JL,Litchy WJ,Klein R,Pach JM,Wilson DM,O'Brien PC,Melton LJ 3rd,Service FJ, The prevalence by staged severity of various types of diabetic neuropathy, retinopathy, and nephropathy in a population-based cohort: the Rochester Diabetic Neuropathy Study. Neurology. 1993 Apr     [PubMed PMID: 8469345]


Djibril AM,Mossi EK,Djagadou AK,Balaka A,Tchamdja T,Moukaila R, [Epidemiological, diagnostic, therapeutic and evolutionary features of diabetic foot: a study conducted at the Medico-surgical Clinic, University Hospital Sylvanus Olympio in Lomé]. The Pan African medical journal. 2018     [PubMed PMID: 30123407]


Ghotaslou R,Memar MY,Alizadeh N, Classification, microbiology and treatment of diabetic foot infections. Journal of wound care. 2018 Jul 2     [PubMed PMID: 30016139]


Schröder K,Szendroedi J,Benthin A,Gontscharuk V,Ackermann P,Völker M,Steingrube N,Nowotny B,Ziegler D,Müssig K,Geerling G,Kuß O,Roden M,Guthoff R,GDS Cohort., German Diabetes Study - Baseline data of retinal layer thickness measured by SD-OCT in early diabetes mellitus. Acta ophthalmologica. 2019 Mar     [PubMed PMID: 30238609]


Moţăţăianu A,Maier S,Bajko Z,Voidazan S,Bălaşa R,Stoian A, Cardiac autonomic neuropathy in type 1 and type 2 diabetes patients. BMC neurology. 2018 Aug 27     [PubMed PMID: 30149797]


Doria M,Viadé J,Palomera E,Pérez R,Lladó M,Costa E,Huguet T,Reverter JL,Serra-Prat M,Franch-Nadal J,Mauricio D, Short-term foot complications in Charcot neuroarthropathy: A retrospective study in tertiary care centres in Spain. Endocrinologia, diabetes y nutricion. 2018 Aug 11     [PubMed PMID: 30108031]


Pop-Busui R,Boulton AJ,Feldman EL,Bril V,Freeman R,Malik RA,Sosenko JM,Ziegler D, Diabetic Neuropathy: A Position Statement by the American Diabetes Association. Diabetes care. 2017 Jan     [PubMed PMID: 27999003]


Sloan G,Selvarajah D,Tesfaye S, Pathogenesis, diagnosis and clinical management of diabetic sensorimotor peripheral neuropathy. Nature reviews. Endocrinology. 2021 Jul     [PubMed PMID: 34050323]


Sène D, Small fiber neuropathy: Diagnosis, causes, and treatment. Joint bone spine. 2018 Oct     [PubMed PMID: 29154979]


Chedid V,Brandler J,Vijayvargiya P,Park SY,Szarka LA,Camilleri M, Characterization of Upper Gastrointestinal Symptoms, Gastric Motor Functions, and Associations in Patients with Diabetes at a Referral Center. The American journal of gastroenterology. 2019 Jan     [PubMed PMID: 30166634]


Petropoulos IN,Ponirakis G,Khan A,Almuhannadi H,Gad H,Malik RA, Diagnosing Diabetic Neuropathy: Something Old, Something New. Diabetes & metabolism journal. 2018 Aug     [PubMed PMID: 30136449]


Vinik AI,Perrot S,Vinik EJ,Pazdera L,Jacobs H,Stoker M,Long SK,Snijder RJ,van der Stoep M,Ortega E,Katz N, Capsaicin 8% patch repeat treatment plus standard of care (SOC) versus SOC alone in painful diabetic peripheral neuropathy: a randomised, 52-week, open-label, safety study. BMC neurology. 2016 Dec 6;     [PubMed PMID: 27919222]


Fonseca VA,Lavery LA,Thethi TK,Daoud Y,DeSouza C,Ovalle F,Denham DS,Bottiglieri T,Sheehan P,Rosenstock J, Metanx in type 2 diabetes with peripheral neuropathy: a randomized trial. The American journal of medicine. 2013 Feb;     [PubMed PMID: 23218892]


Krishnasamy S,Abell TL, Diabetic Gastroparesis: Principles and Current Trends in Management. Diabetes therapy : research, treatment and education of diabetes and related disorders. 2018 Jul     [PubMed PMID: 29934758]


Garcia-Klepzig JL,Sánchez-Ríos JP,Manu C,Ahluwalia R,Lüdemann C,Meloni M,Lacopi E,De Buruaga VR,Bouillet B,Vouillarmet J,Lázaro-Martínez JL,Van Acker K, Perception of diabetic foot ulcers among general practitioners in four European countries: knowledge, skills and urgency. Journal of wound care. 2018 May 2     [PubMed PMID: 29738299]


Iqbal Z,Azmi S,Yadav R,Ferdousi M,Kumar M,Cuthbertson DJ,Lim J,Malik RA,Alam U, Diabetic Peripheral Neuropathy: Epidemiology, Diagnosis, and Pharmacotherapy. Clinical therapeutics. 2018 Jun     [PubMed PMID: 29709457]


Simpson DM,Robinson-Papp J,Van J,Stoker M,Jacobs H,Snijder RJ,Schregardus DS,Long SK,Lambourg B,Katz N, Capsaicin 8% Patch in Painful Diabetic Peripheral Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Study. The journal of pain. 2017 Jan     [PubMed PMID: 27746370]


Ferraresi R,Casini A,Caminiti M,Losurdo F,Clerici G, [Multidisciplinary approach to diabetic foot: a challenge of expertises]. Giornale italiano di cardiologia (2006). 2018 Sep     [PubMed PMID: 30087510]


Jiménez S,Rubio JA,Álvarez J,Lázaro-Martínez JL, Analysis of recurrent ulcerations at a multidisciplinary diabetic Foot unit after implementation of a comprehensive Foot care program. Endocrinologia, diabetes y nutricion. 2018 Oct     [PubMed PMID: 29914816]


Edwards RA,Bonfanti G,Grugni R,Manca L,Parsons B,Alexander J, Predicting Responses to Pregabalin for Painful Diabetic Peripheral Neuropathy Based on Trajectory-Focused Patient Profiles Derived from the First 4 Weeks of Treatment. Advances in therapy. 2018 Oct     [PubMed PMID: 30206821]