An Overview of Diabetic Peripheral Neuropathy
Symptoms of diabetic peripheral neuropathy include lower-extremity weakness, in addition to tingling, pain and burning.
Diabetic peripheral neuropathy is a common complication of both type 1 and type 2 diabetes. The overall annual incidence of this condition is approximately 2%, according to the Diabetes Control and Complications Trial.1
Another study estimated that 7% of patients had neuropathy at the time they received a diagnosis of diabetes and that 50% of patients with diabetes for longer than 25 years had peripheral neuropathy.2 A later American study revealed similar findings, estimating that 47% of patients with diabetes eventually develop some sort of peripheral neuropathy.3
Diabetic peripheral neuropathy is a significant source of morbidity and mortality and is implicated in approximately 50% to 75% of nontraumatic amputations.4 It has been defined as "the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes."5
This article presents an overview of diabetic peripheral neuropathy, but it is important to remember that diabetes is not always the cause of nerve dysfunction in patients with diabetes in whom it develops. This article reviews the entities to be considered in the differential diagnosis when a patient with diabetes undergoes an evaluation for peripheral neuropathy; in addition, we review the risk factors for this condition, as well as pathophysiology, signs and symptoms, diagnosis, screening, and treatment of diabetic peripheral neuropathy.
In making a diagnosis of diabetic peripheral neuropathy, it is important that the examiner consider a variety of entities because in 10% to 26% of patients with diabetes who experience peripheral neuropathy, another underlying cause may be present.6 Making the proper diagnosis requires a careful clinical evaluation and laboratory testing. Electrodiagnostic studies or nerve biopsy may be needed if the diagnosis remains unclear. Potential non-diabetic causes of peripheral neuropathy are listed in Table 1; however, this list is not exhaustive.
Mechanisms underlying the development of diabetic peripheral neuropathy commonly cited in the literature include the polyol pathway, advanced glycation end products, and oxidative stress. In this section, each of these mechanisms is described briefly.
Polyol pathway. With prolonged hyperglycemia, excess glucose moves into the polyol pathway, where it is converted to sorbitol and fructose. The accumulation of sorbitol and fructose contributes to the structural breakdown of nerves, leading to the development of peripheral neuropathy.7
Advanced glycation end products. Also with prolonged hyperglycemia, the reaction of excess glucose with proteins, nucleotides, and lipids results in the production of advanced glycation end products. These play a role in disrupting nerve cell metabolism, leading to the development of peripheral neuropathy.8
Oxidative stress. Oxidative stress and the production of free radicals also are involved in the development of peripheral neuropathy. Free radicals may damage blood vessels, leading to ischemia in the nerve cells, and facilitate the production of advanced glycation end products, which in turn contribute to the development of peripheral neuropathy.9
Signs and symptoms
The peripheral nervous system can be damaged by diabetes in numerous ways. Most commonly, patients with diabetes experience peripheral neuropathy. Symptoms typically include lower-extremity weakness, in addition to tingling, pain, burning, and electrical and stabbing sensations with or without numbness.
Patients may describe a sensation that feels like socks bunching up in their shoes. These symptoms usually begin in the feet and move proximally (stocking-and-glove distribution). The symptoms present symmetrically and appear sensory in nature.
Over time, allodynia (painful sensations in response to innocuous stimuli) and hyperalgesia (increased sensitivity to painful stimuli) may develop.10 Diabetic peripheral neuropathy is insidious in nature and can lead to foot ulceration. These ulcerations can be slow to heal, become infected, and lead to amputation. Unfortunately, patients with peripheral neuropathy may not report their symptoms, and often, fewer than half of patients are treated for their pain. Table 2 provides an overview of some of the common signs and symptoms of diabetic peripheral neuropathy.
A variety of risk factors for the development of diabetic neuropathy are known (Table 3). According to the Diabetes Control and Complications Trial,1 hyperglycemia is one of the most significant risk factors. Others include a long duration of diabetes, large total exposure to hyperglycemia, male sex, advanced age, elevated lipid levels, elevated blood pressure, kidney disease, cigarette smoking, overweight, increased height, and a high level of exposure to other potentially neurotoxic agents, such as ethanol. Genetic factors, such as the HLA-DR3/4 phenotype and apolipoprotein E genotype, are also associated with a risk for diabetic peripheral neuropathy.
There are many important physical examination components to consider in the evaluation of a patient with diabetes. According to the American Diabetes Association 2016 Standards of Medical Care in Diabetes,11 patients with type 2 diabetes should undergo screening for peripheral neuropathy at the time of diagnosis, and patients with type 1 diabetes should be screened 5 years after diagnosis.
Following the initial screening, all patients with diabetes should be monitored on an annual basis for this condition. Screening should focus on sensory function, including pinprick, temperature, and vibratory perception (128-Hz tuning fork), or pressure sensation (10-g monofilament at distal halluces).12
Two simple screening tests, including the Michigan neuropathy screening instrument and the United Kingdom screening test, are available for routine clinical practice.13 Patients with diabetes should be educated regarding the importance of vigilant examination and care of their lower extremities. They should be taught to perform daily foot checks and note the development of calluses, ulcers, or deformation. Proper footwear, including socks, should be reviewed in an effort to prevent calluses or ulcers. Additionally, these patients should be taught about proper toenail trimming and dry skin management. Referral to a podiatrist should be considered if lower-extremity deformities are present or if assistance with toenail trimming is needed.
A diagnosis of diabetic peripheral neuropathy is commonly considered on the basis of a patient's presenting signs and symptoms, medical history, and physical examination findings. A diagnosis of diabetic peripheral neuropathy can be confirmed after electrodiagnostic, sensory, and autonomic function testing. Diagnostic tests commonly performed during an evaluation for diabetic peripheral neuropathy are summarized in Table 4.
Diabetic peripheral neuropathy can be difficult to treat. At the current time, adequate glycemic control and pain management are the only effective treatment strategies.10 Observational studies have shown that neuropathic symptoms are mitigated with glucose optimization but may not necessarily be reversed.12
Diligent adjustment of diabetes medications is vital in the treatment of peripheral neuropathy. To manage the chronic pain associated with diabetic peripheral neuropathy, practitioners should consider a variety of antidepressants and anticonvulsants, including amitriptyline, duloxetine, venlafaxine, gabapentin, valproate, and pregabalin, as well as opioid therapy.
The US Food and Drug Administration has approved duloxetine and pregabalin for the treatment of pain associated with diabetic peripheral neuropathy; however, there is no defined treatment of choice. Direct comparisons of agents have not been conducted, and a patient's therapy should be switched if the pain does not decrease.14
In addition to maintaining glycemic control and managing pain, practitioners should attempt to control factors that may increase the likelihood of peripheral neuropathy. Therefore, patients with diabetes are encouraged to maintain a healthy body weight, exercise as tolerated, eliminate cigarette smoking and alcohol consumption, and treat blood pressure and lipids to goal.
The American Academy of Neurology provides guidelines regarding the pharmacologic and nonpharmacologic treatment of painful diabetic neuropathy.15 These level A and level B recommendations for the treatment of painful diabetic neuropathy are summarized in Table 5.
As previously mentioned in the section on pathophysiology, hyperglycemia-related oxidative stress and the production of free radicals can contribute to the development of peripheral neuropathy. Alpha-lipoic acid, an antioxidant, has been shown to be a powerful scavenger of free radicals in peripheral nerves. Studies have examined the use of alpha-lipoic acid in treating the symptoms of diabetic peripheral neuropathy, and some have found that patients with diabetic peripheral neuropathy who were given 600 mg of intravenous alpha-lipoic acid daily for 3 weeks experienced a decrease in pain, numbness, and paresthesia.16-18 More research is needed to determine the efficacy of alpha-lipoic acid in reducing the symptoms of diabetic neuropathy.
History and presentation
A patient, aged 79 years, was given a diagnosis of type 2 diabetes approximately 20 years ago. Her condition was originally managed with oral agents, but she was transitioned to a regimen of multiple daily injections of insulin glargine and insulin aspart approximately 8 years ago. Her hemoglobin A1c level has ranged from 7.9% to 8.2% over the last few years.
Diabetes-related comorbidities and complications include retinopathy, obesity with a body mass index (BMI) of 39, hypertension, hyperlipidemia, chronic kidney disease (stage 3A), sleep apnea, and diabetic peripheral neuropathy. Between visits with her endocrinologist, she has worked closely with a diabetes educator for assistance with adjusting her insulin dose. The patient was not aware of her hypoglycemia condition in the past but notes that since she has been participating in insulin education and having regular contact with her diabetes educator, her episodes of hypoglycemia have become less frequent. Her husband has been educated regarding the use of glucagon.
The patient's main concern at today's visit is increased sensations of burning and pain in her lower extremities, which she notes have worsened in the last 2 to 3 months. Her primary care provider has referred her to a neurologist to confirm the diagnosis of diabetic peripheral neuropathy.
Previously, she preferred nonpharmacologic methods, including ice/heat and exercise, to relieve her symptoms. After the pain and burning sensations worsened, she tried topical capsaicin cream at the recommendation of her pharmacist but found that to be of minimal benefit. She denies issues with lower-extremity ulcerations and states that she assesses her feet on a daily basis, using lotion to manage dry skin. Today, she is inquiring about additional treatment options for improving the management of her diabetic peripheral neuropathy.
Assessment and plan
For this patient, the importance of glycemic control and adherence to her schedule of multiple daily insulin injections was stressed. She was referred to a diabetes educator, who provided ongoing support and showed her how to adjust her insulin doses to achieve her glycemic goal. It was recommended that the patient initiate gabapentin at a dosage of 300 mg by mouth once daily. She was instructed to take this medication at bedtime because of its common side effect of drowsiness. She also received written instructions to increase the dose gradually to 1800 mg, to be divided into 3 doses taken throughout the day. The patient was reminded that this medication can take up to 12 weeks to take effect.
Diabetic peripheral neuropathy is a prevalent disorder that is hard to treat. It is often underreported and undertreated. The costs associated with diabetic peripheral neuropathy are high. Potentially 25% of the cost of diabetes care in the United States is associated with neuropathy, ranging from $4.6 billion to $13.7 billion annually.10
To improve outcomes, patients with diabetes should be screened for peripheral neuropathy on an annual basis. A diagnosis of diabetic peripheral neuropathy is often suspected on the basis of symptoms, medical history, and physical examination findings. It is important to consider a variety of conditions in the differential diagnosis because a patient's neuropathy may have an underlying cause other than diabetes. Glycemic control and pain management are the cornerstones of treatment, with several classes of drugs considered effective in the treatment of diabetic peripheral neuropathy.
Jennifer A. Grenell, APRN, CNP, and Anne E. Turner, PA-C, practice in the Department of Endocrinology at the Mayo Clinic in Rochester, Minn., and specialize in diabetes management.
- Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329(14):977-986.
- Pirart J. Diabetes mellitus and its degenerative complications: a prospective study of 4400 patients observed between 1947 and 1973. Diabetes Metab. 1977;3(2):97-107.
- Dyck PJ, Kratz KM, Karnes JL, et al. 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;43(4):817-824.
- Vinik AI, Park TS, Stansberry KB, Pittenger GL. Diabetic neuropathies. Diabetologia. 2000;43(8):957-973.
- Boulton AJ, Gries FA, Jervell JA. Guidelines for the diagnosis and outpatient management diabetic peripheral neuropathy. Diabet Med. 1998;15(6):508-514.
- Vinik AI. New methods to assess diabetic neuropathy for clinical research. Paper presented at: 60th Scientific Sessions of the American Diabetes Association; June 9-13, 2000; San Antonio, TX.
- Carrington AL, Litchfield JE. The aldose reductase pathway and nonenzymatic glycation in the pathogenesis of diabetic neuropathy: a critical review for the end of the 20th century. Diabetes Rev. 1999;7:275-299.
- Ryle C, Donaghy M. Nonenzymatic glycation of peripheral nerve proteins in human diabetics. J Neurol Sci. 1995;129(1):62-68.
- Figueroa-Romero C, Sadidi M, Feldman EL. Mechanisms of disease: the oxidative stress theory of diabetic neuropathy. Rev Endocr Metab Disord. 2008;9(4):301-314.
- Callaghan BC, Cheng HT, Stables CL, Smith AL, Feldman EL. Diabetic neuropathy: clinical manifestations and current treatments. Lancet Neurol. 2012;11(6):521-534.
- American Diabetes Association. Standards of medical care in diabetes-2016. Diabetes Care. 2016;39(suppl 1):S1-S112.
- Boulton AJ, Vinik AI, Arezzo JC, et al.. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. 2005;28(4):956-962.
- Feldman EL. Clinical manifestations and diagnosis of diabetic polyneuropathy. UpToDate website. http://www.uptodate.com/contents/clinical-manifestations-and-diagnosis-of-diabetic-polyneuropathy. Updated March 24, 2015. Accessed October 28, 2016.
- Powers AC. Diabetes mellitus: complications. In: Kasper D, Fauci A, Hauser S, Longo D, Jameson J, Loscalzo J (eds). Harrison's Principles of Internal Medicine. 19th ed. New York, NY: McGraw-Hill; 2015:chap 419.
- American Academy of Neurology (AAN). Treatment of painful diabetic neuropathy. https://www.aan.com/Guidelines/home/GetGuidelineContent/480. Published 2011. Accessed October 28, 2016.
- Ziegler D, Gries FA. Alpha-lipoic acid in the treatment of diabetic peripheral and cardiac autonomic neuropathy. Diabetes. 1997;46(suppl 2):S62-S66.
- Morelli V, Zoorob RJ. Alternative therapies: part I. Depression, diabetes, obesity. Am Fam Physician. 2000;62(5):1051-1060.
- Ziegler D, Nowak H, Kempler P, Vargha P, Low PA. Treatment of symptomatic diabetic polyneuropathy with the antioxidant alpha-lipoic acid: a meta-analysis. Diabetic Med. 2004;21(2):114-121.