Top

01-04-2024 | Diabetic Neuropathy | Neuropathic Pain (A Abd-Elsayed, Section Editor)

Diabetic Neuropathy: Pathophysiology Review

Authors: Natalie Strand, Meredith A. Anderson, Sumedha Attanti, Benjamin Gill, Christopher Wie, Azizat Dawodu, Robert Pagan-Rosado, Monica W. Harbell, Jillian A. Maloney

Published in: Current Pain and Headache Reports

Abstract

Purpose of Review

Diabetic neuropathy is a debilitating complication of diabetes mellitus that affects millions of individuals worldwide. It is characterized by nerve damage resulting from prolonged exposure to high blood glucose levels. Diabetic neuropathy may cause a range of symptoms, including pain, numbness, muscle weakness, autonomic dysfunction, and foot ulcers, potentially causing significant impairment to the quality of life for those affected. This review article aims to provide a comprehensive overview of the pathophysiology of diabetic neuropathy. The etiology of diabetic neuropathy will be discussed, including risk factors, predisposing conditions, and an overview of the complex interplay between hyperglycemia, metabolic dysregulation, and nerve damage. Additionally, we will explore the molecular mechanisms and pathways of diabetic neuropathy, including the impact of hyperglycemia on nerve function, abnormalities in glucose metabolism, the role of advanced glycation end products (AGEs), and inflammatory and immune-mediated processes. We will provide an overview of the various nerve fibers affected by diabetic neuropathy and explore the common symptoms and complications associated with diabetic neuropathy in the pain medicine field.

Recent Findings

This review highlights advances in understanding the pathophysiology of diabetic neuropathy as well as reviews potential novel therapeutic strategies and promising areas for future research.

Summary

In conclusion, this review article aims to shed light on the pathophysiology of diabetic neuropathy, its far-reaching consequences, and the evolving strategies for prevention and management. In understanding the mechanisms of diabetic neuropathy and the ongoing research in this area, healthcare professionals can better serve patients with diabetes, ultimately improving well-being and reducing complications.

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):817–24. https://doi.org/10.1212/wnl.43.4.817.CrossRefPubMed

Sloan G, Shillo P, Selvarajah D, et al. A new look at painful diabetic neuropathy. Diabetes Res Clin Pract. 2018;144:177–91. https://doi.org/10.1016/j.diabres.2018.08.020.CrossRefPubMed

Pop-Busui R, Boulton AJ, Feldman EL, et al. Diabetic neuropathy: a position statement by the american diabetes association. Diabetes Care. 2017;40(1):136–54. https://doi.org/10.2337/dc16-2042.CrossRefPubMed

Motataianu A, Maier S, Bajko Z, Voidazan S, Balasa R, Stoian A. Cardiac autonomic neuropathy in type 1 and type 2 diabetes patients. BMC Neurol. 2018;18(1):126. https://doi.org/10.1186/s12883-018-1125-1.CrossRefPubMedPubMedCentral

Ang L, Jaiswal M, Martin C, Pop-Busui R. Glucose control and diabetic neuropathy: lessons from recent large clinical trials. Curr Diab Rep. 2014;14(9):528. https://doi.org/10.1007/s11892-014-0528-7.CrossRefPubMedPubMedCentral

Koeppen BM, Stanton BA. Berne & Levy physiology. 8th ed. Philadelphia, PA: Elsevier; 2024.

Standring S. The anatomy of the peripheral nervous system. In: Standring S, editor. Gray’s anatomy. 42nd ed. Elsevier; 2021. p. 1464.e11-e55.

• Hansen CS, Maatta LL, Andersen ST, Charles MH. The epidemiology of diabetic neuropathy. In: Tesfaye S, Gibbons CH, Malik RA, Veves A, editors. Diabetic neuropathy: contemporary diabetes. Cham: Humana; 2023. p. 5–36. Notable for updates in the epidemiology of diabetic neuropathy.CrossRef

Feldman EL, Callaghan BC, Pop-Busui R, et al. Diabetic neuropathy. Nat Rev Dis Primers. 2019;5(1):41. https://doi.org/10.1038/s41572-019-0092-1.CrossRefPubMed

10.

Boulton AJ, Vinik AI, Arezzo JC, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. 2005;28(4):956–62. https://doi.org/10.2337/diacare.28.4.956.CrossRefPubMed

11.

• Sloan G, Selvarajah D, Tesfaye S. Pathogenesis, diagnosis and clinical management of diabetic sensorimotor peripheral neuropathy. Nat Rev Endocrinol. 2021;17(7):400–20. https://doi.org/10.1038/s41574-021-00496-z. Notable for up-to-date reviews regarding the clinical diagnostic tools for diabetic neuropathy.CrossRefPubMed

12.

Partanen J, Niskanen L, Lehtinen J, Mervaala E, Siitonen O, Uusitupa M. Natural history of peripheral neuropathy in patients with non-insulin-dependent diabetes mellitus. N Engl J Med. 1995;333(2):89–94. https://doi.org/10.1056/NEJM199507133330203.CrossRefPubMed

13.

Pop-Busui R, Lu J, Brooks MM, et al. Impact of glycemic control strategies on the progression of diabetic peripheral neuropathy in the bypass angioplasty revascularization investigation 2 diabetes (BARI 2D) cohort. Diabetes Care. 2013;36(10):3208–15. https://doi.org/10.2337/dc13-0012.CrossRefPubMedPubMedCentral

14.

Van Acker K, Bouhassira D, De Bacquer D, et al. Prevalence and impact on quality of life of peripheral neuropathy with or without neuropathic pain in type 1 and type 2 diabetic patients attending hospital outpatients clinics. Diabetes Metab. 2009;35(3):206–13. https://doi.org/10.1016/j.diabet.2008.11.004.CrossRefPubMed

15.

Jaiswal M, Lauer A, Martin CL, et al. Peripheral neuropathy in adolescents and young adults with type 1 and type 2 diabetes from the SEARCH for Diabetes in Youth follow-up cohort: a pilot study. Diabetes Care. 2013;36(12):3903–8. https://doi.org/10.2337/dc13-1213.CrossRefPubMedPubMedCentral

16.

Callaghan BC, Little AA, Feldman EL, Hughes RA. Enhanced glucose control for preventing and treating diabetic neuropathy. Cochrane Database Syst Rev. 2012;6(6):CD007543. https://doi.org/10.1002/14651858.CD007543.pub2.CrossRefPubMed

17.

Kazamel M, Stino AM, Smith AG. Metabolic syndrome and peripheral neuropathy. Muscle Nerve. 2021;63(3):285–93. https://doi.org/10.1002/mus.27086.CrossRefPubMed

18.

Callaghan BC, Gao L, Li Y, et al. Diabetes and obesity are the main metabolic drivers of peripheral neuropathy. Ann Clin Transl Neurol. 2018;5(4):397–405. https://doi.org/10.1002/acn3.531.CrossRefPubMedPubMedCentral

19.

Christensen DH, Knudsen ST, Gylfadottir SS, et al. Metabolic factors, lifestyle habits, and possible polyneuropathy in early type 2 diabetes: a nationwide study of 5,249 patients in the Danish centre for strategic research in type 2 diabetes (DD2) Cohort. Diabetes Care. 2020;43(6):1266–75. https://doi.org/10.2337/dc19-2277.CrossRefPubMed

20.

Callaghan BC, Xia R, Reynolds E, et al. Association between metabolic syndrome components and polyneuropathy in an obese population. JAMA Neurol. 2016;73(12):1468–76. https://doi.org/10.1001/jamaneurol.2016.3745.CrossRefPubMedPubMedCentral

21.

Andersen ST, Witte DR, Dalsgaard EM, et al. Risk factors for incident diabetic polyneuropathy in a cohort with screen-detected type 2 diabetes followed for 13 years: ADDITION-Denmark. Diabetes Care. 2018;41(5):1068–75. https://doi.org/10.2337/dc17-2062.CrossRefPubMed

22.

Wang CS, Pai YW, Lin CH, Lee IT, Chang MH. Renal impairment is one of appropriate predictors of future diabetic peripheral neuropathy: a hospital-based 6-year follow-up study. Sci Rep. 2022;12(1):5240. https://doi.org/10.1038/s41598-022-09333-3.CrossRefPubMedPubMedCentral

23.

Feldman EL, Nave KA, Jensen TS, Bennett DLH. New horizons in diabetic neuropathy: mechanisms, bioenergetics, and pain. Neuron. 2017;93(6):1296–313. https://doi.org/10.1016/j.neuron.2017.02.005.CrossRefPubMedPubMedCentral

24.

Lyssenko V, Vaag A. Genetics of diabetes-associated microvascular complications. Diabetologia. 2023;66(9):1601–13. https://doi.org/10.1007/s00125-023-05964-x.CrossRefPubMedPubMedCentral

25.

Kirthi V, Perumbalath A, Brown E, et al. Prevalence of peripheral neuropathy in pre-diabetes: a systematic review. BMJ Open Diabetes Res Care. 2021;9(1):2040. https://doi.org/10.1136/bmjdrc-2020-002040.CrossRef

26.

Shakher J, Stevens MJ. Update on the management of diabetic polyneuropathies. Diabetes Metab Syndr Obes. 2011;4:289–305. https://doi.org/10.2147/DMSO.S11324.CrossRefPubMedPubMedCentral

27.

Zochodne DW. The challenges of diabetic polyneuropathy: a brief update. Curr Opin Neurol. 2019;32(5):666–75. https://doi.org/10.1097/WCO.0000000000000723.CrossRefPubMed

28.

Hall BE, Macdonald E, Cassidy M, et al. Transcriptomic analysis of human sensory neurons in painful diabetic neuropathy reveals inflammation and neuronal loss. Sci Rep. 2022;12(1):4729. https://doi.org/10.1038/s41598-022-08100-8.CrossRefPubMedPubMedCentral

29.

Sies H, Jones DP. Reactive oxygen species (ROS) as pleiotropic physiological signalling agents. Nat Rev Mol Cell Biol. 2020;21(7):363–83. https://doi.org/10.1038/s41580-020-0230-3.CrossRefPubMed

30.

Volpe CMO, Villar-Delfino PH, Dos Anjos PMF, Nogueira-Machado JA. Cellular death, reactive oxygen species (ROS) and diabetic complications. Cell Death Dis. 2018;9(2):119. https://doi.org/10.1038/s41419-017-0135-z.CrossRefPubMedPubMedCentral

31.

• Bhatti JS, Sehrawat A, Mishra J, et al. Oxidative stress in the pathophysiology of type 2 diabetes and related complications: current therapeutics strategies and future perspectives. Free Radic Biol Med. 2022;184:114–34. https://doi.org/10.1016/j.freeradbiomed.2022.03.019. Notable for the overview of treatment options and what is potentially on the horizon in the future.CrossRefPubMed

32.

Dewanjee S, Das S, Das AK, et al. Molecular mechanism of diabetic neuropathy and its pharmacotherapeutic targets. Eur J Pharmacol. 2018;833:472–523. https://doi.org/10.1016/j.ejphar.2018.06.034.CrossRefPubMed

33.

Malone JI, Lowitt S, Korthals JK, Salem A, Miranda C. The effect of hyperglycemia on nerve conduction and structure is age dependent. Diabetes. 1996;45(2):209–15. https://doi.org/10.2337/diab.45.2.209.CrossRefPubMed

34.

Eid S, Sas KM, Abcouwer SF, et al. New insights into the mechanisms of diabetic complications: role of lipids and lipid metabolism. Diabetologia. 2019;62(9):1539–49. https://doi.org/10.1007/s00125-019-4959-1.CrossRefPubMedPubMedCentral

35.

Luna R, Talanki Manjunatha R, Bollu B, et al. A comprehensive review of neuronal changes in diabetics. Cureus. 2021;13(10):e19142. https://doi.org/10.7759/cureus.19142.CrossRefPubMedPubMedCentral

36.

Tesfaye S, Boulton AJ, Dyck PJ, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010;33(10):2285–93. https://doi.org/10.2337/dc10-1303.CrossRefPubMedPubMedCentral

37.

Sasaki H, Kawamura N, Dyck PJ, Dyck PJB, Kihara M, Low PA. Spectrum of diabetic neuropathies. Diabetol Int. 2020;11(2):87–96. https://doi.org/10.1007/s13340-019-00424-7.CrossRefPubMedPubMedCentral

38.

Schreiber AK, Nones CF, Reis RC, Chichorro JG, Cunha JM. Diabetic neuropathic pain: physiopathology and treatment. World J Diabetes. 2015;6(3):432–44. https://doi.org/10.4239/wjd.v6.i3.432.CrossRefPubMedPubMedCentral

39.

Herder C, Lankisch M, Ziegler D, et al. Subclinical inflammation and diabetic polyneuropathy: MONICA/KORA Survey F3 (Augsburg, Germany). Diabetes Care. 2009;32(4):680–2. https://doi.org/10.2337/dc08-2011.CrossRefPubMedPubMedCentral

40.

Jamwal S, Sharma S. Vascular endothelium dysfunction: a conservative target in metabolic disorders. Inflamm Res. 2018;67(5):391–405. https://doi.org/10.1007/s00011-018-1129-8.CrossRefPubMed

41.

Edwards JL, Vincent AM, Cheng HT, Feldman EL. Diabetic neuropathy: mechanisms to management. Pharmacol Ther. 2008;120(1):1–34. https://doi.org/10.1016/j.pharmthera.2008.05.005.CrossRefPubMedPubMedCentral

42.

Qureshi Z, Ali MN, Khalid M. An insight into potential pharmacotherapeutic agents for painful diabetic neuropathy. J Diabetes Res. 2022;2022:9989272. https://doi.org/10.1155/2022/9989272.CrossRefPubMedPubMedCentral

43.

Basem JI, Bah FN, Mehta ND. A brief review on the novel therapies for painful diabetic neuropathy. Curr Pain Headache Rep. 2023;27(9):299–305. https://doi.org/10.1007/s11916-023-01126-1.CrossRefPubMed

44.

Petersen EA, Stauss TG, Scowcroft JA, et al. Effect of high-frequency (10-kHz) spinal cord stimulation in patients with painful diabetic neuropathy: a randomized clinical trial. JAMA Neurol. 2021;78(6):687–98. https://doi.org/10.1001/jamaneurol.2021.0538.CrossRefPubMedPubMedCentral

45.

Callaghan BC, Gallagher G, Fridman V, Feldman EL. Diabetic neuropathy: what does the future hold? Diabetologia. 2020;63(5):891–7. https://doi.org/10.1007/s00125-020-05085-9.CrossRefPubMedPubMedCentral

46.

Hicks CW, Selvin E. Epidemiology of peripheral neuropathy and lower extremity disease in diabetes. Curr Diab Rep. 2019;19(10):86. https://doi.org/10.1007/s11892-019-1212-8.CrossRefPubMedPubMedCentral

47.

Petersen EA, Stauss TG, Scowcroft JA, et al. Durability of high-frequency 10-kHz spinal cord stimulation for patients with painful diabetic neuropathy refractory to conventional treatments: 12-month results from a randomized controlled trial. Diabetes Care. 2022;45(1):e3–6. https://doi.org/10.2337/dc21-1813.CrossRefPubMed

48.

Bodman MA, Varacallo M. Peripheral diabetic neuropathy. StatPearls [Internet]; 2023. Available at https://www.ncbi.nlm.nih.gov/books/NBK442009/.

Title: Diabetic Neuropathy: Pathophysiology Review
Authors: Natalie Strand
Meredith A. Anderson
Sumedha Attanti
Benjamin Gill
Christopher Wie
Azizat Dawodu
Robert Pagan-Rosado
Monica W. Harbell
Jillian A. Maloney
Publication date: 01-04-2024
Publisher: Springer US
Keywords: Diabetic Neuropathy
Diabetic Neuropathy
Hyperglycemia
Published in: Current Pain and Headache Reports
Print ISSN: 1531-3433
Electronic ISSN: 1534-3081
DOI: https://doi.org/10.1007/s11916-024-01243-5

At a glance: The STEP trials

Springer Medicine

Diabetic Neuropathy: Pathophysiology Review

Abstract

Purpose of Review

Recent Findings

Summary

At a glance: The STEP trials

Springer Medicine

Abstract

Purpose of Review

Recent Findings

Summary

Please log in to get access to this content