International Diabetes Federation. International diabetes federation: IDF Atlas. Brussels: Belgium; 2017. Available from: http://diabetesatlas.org/resources/2017-atlas.html. Accessed 29 April 2019.
Dyck PJ, Kratz KM, Karnes JL, Litchy WJ, Klein R, Pach JM, 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;43:817–24.
• Pop-Busui R, Boulton AJM, Feldman EJ, Bril V, Freeman R, Malik RA, et al. Diabetic neuropathy: a position statement by the American Diabetes Association. Diabetes Care. 2017;40:136–54 Recent position statement of Diabetic Neuropathy by the American Diabetes Association.
• Tesfaye S, Chaturvedi N, Eaton SE, Ward JD, Manes C, Ionescu-Tirgoviste C, et al. Vascular risk factors and diabetic neuropathy. N Engl J Med. 2005;352:341–50 Prospective epidemiological study showing that, apart from glycemic control, incident neuropathy is associated with modifiable cardiovascular risk factors.
• Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010;33:2285–93 Review by international panel of experts making recommendations in the clinical practice and research for DPN.
Sadosky A, Mardekian J, Parsons B, Hopps M, Bienen EJ, Markman J. Healthcare utilization and costs in diabetes relative to the clinical spectrum of painful diabetic peripheral neuropathy. J Diabetes Complicat. 2015;29:212–7.
Narres M, Kvitkina T, Claessen H, Droste S, Schuster B, Morbach S, et al. Incidence of lower extremity amputations in diabetic compared with the non-diabetic population: a systematic review. PLoS One. 2017;12:e0182081. https://doi.org/10.1371/journal.pone.0182081.
Daousi C, MacFarlane IA, Woodward A, Nurmikko TJ, Bundred PE, Benbow SJ. Chronic painful peripheral neuropathy in an urban community: a controlled comparison of people with and without diabetes. Diabet Med. 2004;21:976–82.
Van Acker K, Bouhassira D, De Bacquer D, Weiss S, Matthys K, Raemen H, 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;35:206–13.
Ziegler D, Rathmann W, Dickhaus T, Meisinger C, Mielck A, KORA Study Group. Neuropathic pain in diabetes, prediabetes and normal glucose tolerance: the MONICA/KORA Augsburg surveys S2 and S3. Pain Med. 2009;10:393–400.
Abbott CA, Malik RA, van Ross ER, Kulkarni J, Boulton AJ. Prevalence and characteristics of painful diabetic neuropathy in a large community-based diabetic population in the U.K. Diabetes Care. 2011;34:2220–4.
• Alleman CJ, Westerhout KY, Hensen M, Chambers C, Stoker M, Long S, et al. Humanistic and economic burden of painful diabetic peripheral neuropathy in Europe: a review of the literature. Diabetes Res Clin Pract. 2015;109:215–25 Review article of the epidemiology, humanistic burden and increasing healthcare costs associated with painful-DPN.
Binns-Hall O, Selvarajah D, Sanger D, Walker J, Scott A, Tesfaye S. One-stop microvascular screening service: an effective model for the early detection of diabetic peripheral neuropathy and the high-risk foot. Diabet Med. 2018;35:887–94.
Taylor-Stokes G, Pike J, Sadosky A, Chandran A, Toelle T. Association of patient-rated severity with other outcomes in patients with painful diabetic peripheral neuropathy. Diabetes Metab Syndr Obes. 2011;4:401–8.
Lauria G, Lombardi R. Small fiber neuropathy: is skin biopsy the holy grail? Curr Diab Rep. 2012;12:384–92.16.
Jensen TS, Backonja MM, Hernández Jiménez S, Tesfaye S, Valensi P, Ziegler D. New perspectives on the management of diabetic peripheral neuropathic pain. Diab Vasc Dis Res. 2006;3:108–19.
Sloan G, Shillo P, Selvarajah D, Wu J, Wilkinson ID, Tracey I, et al. A new look at painful diabetic neuropathy. Diabetes Res Clin Pract. 2018;144:177–91.
• Andersen ST, Witte DR, Dalsgaard EM, Andersen H, Nawroth P, Fleming T, 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;41:1068–75 Recent prospective study finding that cardiovascular risk factors are associated with incident DPN in T2DM.
Pop-Busui R, Lu J, Brooks MM, Albert S, Althouse AD, Escobedo J, 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;36:3208–15.
Callaghan BC, Gao LL, Li Y, Zhou X, Reynolds E, Banerjee M, et al. Diabetes and obesity are the main metabolic drives of peripheral neuropathy. Ann Clin Transl Neurol. 2018;5:397–40521.
•• Hébert HL, Veluchamy A, Torrance N, Smith BH. Risk factors for neuropathic pain in diabetes mellitus. Pain. 2017;158:560–8 Recent review of the risk factors for painful-DPN.
Elliott J. Female sex: an independent risk factor for the development of painful neuropathy? Diabetes. 2006;55(Supp 1) Abstract, number 794-P
•• Themistocleous AC, Ramirez JD, Shillo PR, Lees JG, Selvarajah D, Orengo C, et al. The pain in neuropathy study (PiNS): a cross-sectional observational study determining the somatosensory phenotype of painful and painless diabetic neuropathy. Pain. 2016;157:1132–45 Detailed cross-sectional study showing that the hyposensitivity sensory phenotype and increased severity of neuropathy are associated with painful-DPN.
Algeffari MA. Painful diabetic peripheral neuropathy among Saudi diabetic patients is common but under-recognized: multicenter cross-sectional study at primary health care setting. J Family Community Med. 2018;25:43–7.
Ziegler D, Landgraf R, Lobmann R, Reiners K, Rett K, Schnell O, et al. Painful and painless neuropathies are distinct and largely undiagnosed entities in subjects participating in an educational initiative (PROTECT study). Diabetes Res Clin Pract. 2018;139:147–54.
Pai YW, Lin CH, Lee IT, Chang MH, et al. Prevalence and biochemical risk factors of diabetic peripheral neuropathy with or without neuropathic pain in Taiwanese adults with type 2 diabetes mellitus. Diabetol Metab Syndr. 2018;12:11–6.
•• Raputova J, Srotova I, Vlckova E, Sommer C, Üçeyler N, Birklein F, et al. Sensory phenotype and risk factors for painful diabetic neuropathy: a cross-sectional observational study. Pain. 2017;158:2340–53 Another detailed cross-sectional study finding painful-DPN is associated with severity of neuropathy and thermal hyposensitivity.
•• Truini A, Spallone V, Morganti R, Tamburin S, Zenette G, Schenone A, et al. A cross-sectional study investigating frequency and features of definitely diagnosed diabetic painful polyneuropathy. Pain. 2018;159:2658–66 Large cross-sectional epidemiological study identifying female gender as the only risk factor associated with painful-DPN.
Abraham A, Barnett C, Katzberg HD, Lovblom LE, Perkins BA, Bril V. Sex differences in neuropathic pain intensity in diabetes. J Neurol Sci. 2018;388:103–6.
Sorge RE, Strath LJ. Sex differences in pain responses. Curr Opin Physiol. 2018;6:75–81.
Prabodha LBL, Sirisena ND, Dissanayake VHW. Susceptible and prognostic genetic factors associated with diabetic peripheral neuropathy: a comprehensive literature review. Int J Endocrinol. 2018;2018:8641942–9. https://doi.org/10.1155/2018/8641942.
Meng W, Deshmukh HA, Donnelly LA, Torrance N, Colhoun HM, Palmer CN, et al. A genome-wide association study provides evidence of sex-specific involvement of Chr1p35.1 (ZSCAN20-TLR12P) and Chr8p23.1 (HMGB1P46) with diabetic neuropathic pain. EBioMedicine. 2015;2:1386–93.
Meng W, Deshmukh HA, van Zuydam NR, Liu Y, Donnelly LA, Zhou K, et al. A genome-wide association study suggests an association of Chr8p21.3 (GFRA2) with diabetic neuropathic pain. Eur J Pain. 2015;19:392–9.
Li QS, Cheng P, Favis R, Wickenden A, Romano G, Wang H. SCN9A variants may be implicated in neuropathic pain associated with diabetic peripheral neuropathy and pain severity. Clin J Pain. 2015;31:976–82.
• Blesneac I, Themistocleous AC, Fratter C, Conrad LJ, Ramirez JD, Cox JJ, et al. Rare Nav1.7 variants associated with painful diabetic peripheral neuropathy. Pain. 2017;159:469–80 Study showing that rare sodium channel genetic variants contribute to neuropathic pain in some patients with DPN.
Faber CG, Hoeijmakers JG, Ahn HS, Cheng X, Han C, Choi JS, et al. Gain of function Naν1.7 mutations in idiopathic small fiber neuropathy. Ann Neurol. 2012;71:26–39.
Galer BS, Gianas A, Jensen MP. Painful diabetic polyneuropathy: epidemiology, pain description, and quality of life. Diabetes Res Clin Pract. 2000;47:123–8.
Gore M, Brandenburg NA, Dukes E, Hoffman DL, Tai KS, Stacey B. Pain severity in diabetic peripheral neuropathy is associated with patient functioning, symptom levels of anxiety and depression, and sleep. J Pain Symptom Manag. 2005;30:374–85.
Veves A, Young MJ, Manes C, Boulton AJ. Differences in peripheral and autonomic nerve function measurements in painful and painless neuropathy. A clinical study. Diabetes Care. 1994;17:1200–2.
Spallone V, Morganti R, D’Amato C, Cacciotti L, Fedele T, Maiello MR, et al. Clinical correlates of painful diabetic neuropathy and relationship of neuropathic pain with sensorimotor and autonomic nerve function. Eur J Pain. 2011;15:153–60.
Sorensen L, Molyneaux L, Yue DK. The level of small nerve fiber dysfunction dose not predict pain in diabetic neuropathy: a study using quantitative sensory testing. Clin J Pain. 2006;22:261–5.
Gandhi RA, Marques JL, Selvarajah D, Emery CJ, Tesfaye S. Painful diabetic neuropathy is associated with greater autonomic dysfunction than painless diabetic neuropathy. Diabetes Care. 2010;33:1585–90.
D’Amato C, Morganti R, Di Gennaro F, Marfia GA, Spallone V. A novel association between nondipping and painful diabetic polyneuropathy. Diabetes Care. 2014;37:2640–2.
Young RJ, Zhou TQ, Rodriguez E, Prescott RJ, Ewing DJ, Clarke BF. Variable relationship between peripheral somatic and autonomic neuropathy in patients with different syndromes of diabetic polyneuropathy. Diabetes. 1986;35:192–7.45.
Krämer HH, Rolke R, Bickel A, Birklein F. Thermal thresholds predict painfulness of diabetic neuropathies. Diabetes Care. 2004;27:2386–91.
Terkelsen AJ, Karlsson P, Lauria G, Freeman R, Finnerup NB, Jensen TS. The diagnostic challenge of small fibre neuropathy: clinical presentations, evaluations, and causes. Lancet Neurol. 2017;16:934–44.
•• Smith SM, Dworkin RH, Turk DC, Baron R, Polydefkis M, Tracey I, et al. The potential role of sensory testing, skin biopsy, and functional brain imaging as biomarkers in chronic pain clinical trials: IMMPACT Considerations. J Pain. 2017;18:757–77 Review of the role of sensory testing, skin biopsy and brain imaging as diagnostic, prognostic, predictive and pharmacodynamic biomarkers in analgesic treatment trials.
Üçeyler N, Vollert J, Broll B, Riediger N, Langjahr M, Saffer N, et al. Sensory profiles and skin innervation of patients with painful and painless neuropathies. Pain. 2018;159:1867–76.
Cheng HT, Dauch JR, Porzio MT, Yanik BM, Hsieh W, Smith AG, et al. Increased axonal regeneration and swellings in intraepidermal nerve fibers characterize painful phenotypes of diabetic neuropathy. J Pain. 2013;14:941–7.
• Bönhof GJ, Strom A, Püttgen S, Ringel B, Brüggemann J, Bódis K, et al. Patterns of cutaneous nerve fibre loss and regeneration in type 2 diabetes with painful and painless polyneuropathy. Diabetologia. 2017;60:2495–503 Study demonstrating measures of cutaneous nerve fibre regeneration are enhanced in painful-DPN.
Galosi E, La Cesa S, Di Stefano G, Karlsson P, Fasolino A, Leone C, et al. A pain in the skin. Regenerating nerve sprouts are distinctly associated with ongoing burning pain in patients with diabetes. Eur J Pain. 2018;22:1727–34.
Scheytt S, Riediger N, Braunsdorf S, Sommer C, Üçeyler N. Increased gene expression of growth associated protein-43 in skin of patients with early-stage peripheral neuropathies. J Neurol Sci. 2015;355:131–7.
Quattrini C, Tavakoli M, Jeziorska M, Kallinikos P, Tesfaye S, Finnigan J, et al. Surrogate markers of small fiber damage in human diabetic neuropathy. Diabetes. 2007;56:2148–54.
Cheung A, Podgomy P, Martinez JA, Chan C, Toth C. Epidermal axonal swellings in painful and painless diabetic peripheral neuropathy. Muscle Nerve. 2015;51:505–13.
Anand P, Terenghi G, Warner G, Kopelman P, Williams-Chestnut RE, Sinicropi DV. The role of endogenous nerve growth factor in human diabetic neuropathy. Nat Med. 1996;2:703–7.
Shillo P, Selvarajah D, Greig M, Wilkinson I, Yiangou Y, Donatien P, et al. Nerve and vascular biomarkers in skin biopsies differentiate painful from painless advanced diabetic peripheral neuropathy. Diabet Med. 2017;34(Supp 1):31–3.
Anand P, Bley K. Topical capsaicin for pain management: therapeutic potential and mechanism of action of the new high-concentration capsaicin 8% patch. Br J Anaesth. 2011;107:490–502.
Obreja O, Rukwied R, Nagler L, Schmidt M, Schmelz M, Namer B. Nerve growth factor locally sensitizes nociceptors in human skin. Pain. 2018;159:416–26.
Alam U, Jeziorska M, Petropoulos IN, Asghar O, Fadavi H, Ponirakis G, et al. Diagnostic utility of corneal confocal microscopy and intra-epidermal nerve fibre density in diabetic neuropathy. PLoS One. 2017;12:e0180175. https://doi.org/10.1371/journal.pone.0180175.
Malik RA, Kallinikos P, Abbott CA, van Schie CH, Morgan P, Efron N, et al. Corneal confocal microscopy: a non-invasive surrogate of nerve fibre damage and repair in diabetic patients. Diabetologia. 2003;46:683–8.
Jiang MS, Yuan Y, Gu ZX, Zhuang SL. Corneal confocal microscopy for assessment of diabetic peripheral neuropathy: a meta-analysis. Br J Opthalmol. 2016;100:9–14.
• Marshall AG, Lee-Kubli C, Azmi S, Zhang M, Ferdousi M, Mixcoatl-Zecuatl T, et al. Spinal disinhibition in experimental and clinical painful diabetic neuropathy. Diabetes. 2017;66:1380–90 Experimental and clinical study showing spinal inhibitory dysfunction may contribute to the pathogenesis of painful-DPN.
Kalteniece A, Ferdousi M, Petropoulos I, Azmi S, Adam S, Fadavi H, et al. Greater corneal nerve loss at the inferior whorl is related to the presence of diabetic neuropathy and painful diabetic neuropathy. Sci Rep. 2018;8:3283. https://doi.org/10.1038/s41598-018-21643-z.
Gasparotti R, Padua L, Briani C, Lauria G. New technologies for the assessment of neuropathies. Nat Rev Neurol. 2017;13:203–16.
Atherton DD, Facer P, Roberts KM, Misra VP, Chizh BA, Bountra C, et al. Use of the novel Contact Heat Evoked Potential Stimulator (CHEPS) for the assessment of small fibre neuropathy: correlations with skin flare responses and intra-epidermal nerve fibre counts. BMC Neurol. 2007;7:21. https://doi.org/10.1186/1471-2377-7-21.
Casanova-Molla J, Grau-Junyent JM, Morales M, Valls-Solé J. On the relationship between nociceptive evoked potentials and intraepidermal nerve fiber density in painful sensory polyneuropathies. Pain. 2011;152:410–8.
Chao CC, Tseng MT, Lin YJ, Yang WS, Hsieh SC, Lin YH, et al. Pathophysiology of neuropathic pain in type 2 diabetes: skin denervation and contact heat-evoked potentials. Hum Brain Mapp. 2013;34:2733–46.
Hansson P, Backonja M, Bouhassira D. Usefulness and limitations of quantitative sensory testing: clinical and research application in neuropathic pain states. Pain. 2007;129:256–9.
Cruccu G, Sommer C, Anand P, Attal N, Baron R, Garcia-Larrea L, et al. EFNS guidelines on neuropathic pain assessment: revised 2009. Eur J Neurol. 2010;17:1010–8.
Tsigos C, White A, Young RJ. Discrimination between painful and painless diabetic neuropathy based on testing of large somatic nerve and sympathetic nerve function. Diabet Med. 1992;9:359–65.
Krishnan ST, Quattrini C, Jeziorska M, Malik RA, Rayman G. Abnormal LDIflare but normal quantitative sensory testing and dermal nerve fiber density in patients with painful diabetic neuropathy. Diabetes Care. 2009;32:451–5.
Rolke R, Magerl W, Campbell KA, Schalber C, Caspari S, Birklein F, et al. Quantitative sensory testing: a comprehensive protocol for clinical trials. Eur J Pain. 2006;10:77–88.
•• Rolke R, Baron R, Maier C, Tölle TR, Treede RD, Beyer A, et al. Quantitative sensory testing in the German Research Network on Neuropathic Pain (DFNS): standardized protocol and reference values. Pain. 2006;123:231–43 QST protocol for the characterization the somatosensory phenotype of patients with neuropathic pain.
Umapathi T, Tan WL, Loke SC, Soon PC, Tavintharan S, Chan YH. Intraepidermal nerve fiber density as a marker of early diabetic neuropathy. Muscle Nerve. 2007;35:591–8.
Løseth S, Stålberg E, Jorde R, Mellgren SI. Early diabetic neuropathy: thermal thresholds and intraepidermal nerve fibre density in patients with normal nerve conduction studies. J Neurol. 2008;255:1197–202.
Ragé M, Van Acker N, Knaapen MW, Timmers M, Streffer J, Hermans MP, et al. Asymptomatic small fiber neuropathy in diabetes mellitus: investigations with intraepidermal nerve fiber density, quantitative sensory testing and laser-evoked potentials. J Neurol. 2011;258:1852–64.
Cameron NE, Eaton SE, Cotter MA, Tesfaye S. Vascular factors and metabolic interactions in the pathogenesis of diabetic neuropathy. Diabetologia. 2001;44:1973–88.
Tesfaye S, Harris ND, Wilson RM, Ward JD. Exercise-induced conduction velocity increment: a marker of impaired peripheral nerve blood flow in diabetic neuropathy. Diabetologia. 1992;35:155–9.
Tesfaye S, Harris N, Jakubowski JJ, Mody C, Wilson RM, Rennie IG, et al. Impaired blood flow and arterio-venous shunting in human diabetic neuropathy: a novel technique of nerve photography and fluorescein angiography. Diabetologia. 1993;36:1266–74.
Tesfaye S, Malik R, Harris N, Jakubowski JJ, Mody C, Rennie IG, et al. Arterio-venous shunting and proliferating new vessels in acute painful neuropathy of rapid glycaemic control (insulin neuritis). Diabetologia. 1996;39:329–35.
Archer AG, Roberts VC, Watkins PJ. Blood flow patterns in painful diabetic neuropathy. Diabetologia. 1984;27:563–7.
Eaton SE, Harris ND, Ibrahim S, Patel KA, Selmi F, Radatz M, et al. Increased sural nerve epineurial blood flow in human subjects with painful diabetic neuropathy. Diabetologia. 2003;46:934–9.
Tsigos C, Reed P, Weinkove C, White A, Young RJ. Plasma norepinephrine in sensory diabetic polyneuropathy. Diabetes Care. 1993;16:722–7.
Tack CJ, van Gurp PJ, Holmes C, Goldstein DS. Local sympathetic denervation in painful diabetic neuropathy. Diabetes. 2002;51:3545–53.
Quattrini C, Harris ND, Malik RA, Tesfaye S. Impaired skin microvascular reactivity in painful diabetic neuropathy. Diabetes Care. 2007;30:655–9.
Doupis J, Lyons TE, Wu S, Gnardellis C, Dinh T, Veves A. Microvascular reactivity and inflammatory cytokines in painful and painless peripheral diabetic neuropathy. J Clin Endocrinol Metab. 2009;94:2157–63.
Vas PR, Sharma S, Rayman G. Distal sensorimotor neuropathy: improvements in diagnosis. Rev Diabet Stud. 2015;12:29–47.
• Herder C, Kannenberg JM, Huth C, Carstensen-Kirbgerg M, Rathmann W, Koening W, et al. Proinflammatory cytokines predict the incidence and progression of distal sensorimotor polyneuropathy: KORA F4/FF4 Study. Diabetes Care. 2017;40:569–76 Prospective study finding IL-6 and TNF -α are associated with incident DPN.
Deguchi T, Hashiguchi T, Horinouchi S, Uto T, Oku H, Kimura K, et al. Serum VEGF increases in diabetic polyneuropathy, particularly in the neurologically active symptomatic stage. Diabet Med. 2009;26:247–52.
Quattrini C, Jeziorska M, Boulton AJ, Malik RA. Reduced vascular endothelial growth factor expression and intra-epidermal nerve fiber loss in human diabetic neuropathy. Diabetes Care. 2008;31:140–5.
Yuen KC, Baker NR, Rayman G. Treatment of chronic painful diabetic neuropathy with isosorbide dinitrate spray: a double-blind placebo-controlled cross-over study. Diabetes Care. 2002;25:1699–703.
Rayman G, Baker NR, Krishnan ST. Glyceryl trinitrate patches as an alternative to isosorbide dinitrate spray in the treatment of chronic painful diabetic neuropathy. Diabetes Care. 2003;26:2697–8.
Obrosova IG. Diabetic painful and insensate neuropathy: pathogenesis and potential treatments. Neurotherapeutics. 2009;6(4):638–47.
Dewanjee S, Das S, Das AK, Bhattacharjee N, Dihingia A, Dua TK. Molecular mechanism of diabetic neuropathy and its pharmacotherapeutic targets. Eur J Pharmacol. 2018;833:472–523.
Shamsaldeen YA, Mackenzie LS, Lione LA, Benham CD. Methylglyoxal, a metabolite increased in diabetes is associated with insulin resistance, vascular dysfunction and neuropathies. Curr Drug Metab. 2016;17:359–67.
Huang Q, Chen Y, Gong N, Wang YX. Methylglyoxal mediates streptozotocin-induced diabetic neuropathic pain via activation of the peripheral TRPA1 and Nav1.8 channels. Metabolism. 2016;65:463–74.
Bierhaus A, Fleming T, Stoyanov S, Leffler A, Babes A, Neacsu C, et al. Methylglyoxal modification of Nav1.8 facilitates nociceptive neuron firing and causes hyperalgesia in diabetic neuropathy. Nat Med. 2012;18:926–33.
Hansen CS, Jensen TM, Jensen JS, Nawroth P, Fleming T, Witte DR, et al. The role of serum methylglyoxal on diabetic peripheral and cardiovascular autonomic neuropathy: the ADDITION Denmark study. Diabetes Metab. 2015;32:778–85.
Zhou J, Zhou S. Inflammation: therapeutic targets for diabetic neuropathy. Mol Neurobiol. 2014;49:536–46.
Çakici N, Fakkel TM, van Neck JW, Verhagen AP, Coert JH. Systematic review of treatments for diabetic peripheral neuropathy. Diabet Med. 2016;33:1466–76.
Holick MF, Vitamin D. Deficiency. N Engl J Med. 2007;357:266–81.
Powanda MC. Is there a role for vitamin D in the treatment of chronic pain? Inflammopharmacology. 2014;22:327–32.
Danescu LG, Levy S, Levy J. Vitamin D and diabetes mellitus. Endocrine. 2009;35:11–7.
Mathieu C. Vitamin D and diabetes: where do we stand? Diabetes Res Clin Pract. 2015;108:201–9.
Fukuoka M, Sakurai K, Ohta T, Kiyoki M, Katayama I. Tacalcitol, an active vitamin D3, induces nerve growth factor production in human epidermal keratinocytes. Skin Pharmacol Appl Ski Physiol. 2001;14:226–33.
Riaz S, Malcangio M, Miller M, Tomlinson DR. A vitamin D(3) derivative (CB1093) induces nerve growth factor and prevents neurotrophic deficits in streptozotocin-diabetic rats. Diabetologia. 1999;42:1308–13.
Tague SE, Smith PG. Vitamin D receptor and enzyme expression in dorsal root ganglia of adult female rats: modulation by ovarian hormones. J Chem Neuroanat. 2011;41:1–12.
Tague SE, Clarke GL, Winter MK, McCarson KE, Wright DE, Smith PG. Vitamin D deficiency promotes skeletal muscle hypersensitivity and sensory hyperinnervation. J Neurosci. 2011;31:13728–38.
Esteghamati A, Fotouhi A, Faghihi-Kashani S, Hafezi-Nejad N, Heidari B, Sheikhbahaei S, et al. Non-linear contribution of serum vitamin D to symptomatic diabetic neuropathy: a case-control study. Diabetes Res Clin Pract. 2016;111:44–50.
• Shillo P, Selvarajah D, Greig M, Gandhi R, Rao G, Wilkinson ID, et al. Reduced vitamin D levels in painful diabetic peripheral neuropathy. Diabet Med. 2018;36:44–51. https://doi.org/10.1111/dme.13798. Cross-sectional study demonstrating that reduced serum 25-hydroxyvitamin D levels are associated with painful-DPN.
Lee P, Chen R. Vitamin D as an analgesic for patients with type 2 diabetes and neuropathic pain. Arch Intern Med. 2008;168:771–2.
Shehab D, Al-Jarallah K, Abdella N, Mojiminiyi OA, Al Mohamedy H. Prospective evaluation of the effect of short-term oral vitamin d supplementation on peripheral neuropathy in type 2 diabetes mellitus. Med Princ Pract. 2015;24:250–6.
Basit A, Basit KA, Fawwad A, Shaheen F, Fatima N, Petropoulos IN, et al. Vitamin D for the treatment of painful diabetic neuropathy. BMJ Open Diabetes Res Care. 2016;4:e000148. https://doi.org/10.1136/bmjdrc-2015-000148.
Pop-Busui R, Ang L, Holmes C, Gallgher K, Feldman E. Inflammation as a therapeutic target for diabetic neuropathies. Curr Diab Rep. 2016;16(3):29. https://doi.org/10.1007/s11892-016-0727-5.
Jin HY, Park TS. Role of inflammatory biomarkers in diabetic peripheral neuropathy. J Diabetes Investig. 2018;9:1016–8.
• Feldman EL, Nave KA, Jensen TS, Bennett DL. New horizons in diabetic neuropathy: mechanisms, bioenergetics, and pain. Neuron. 2017;93:1296–313 Review of the recent discoveries into the pathogenesis of DPN and painful-DPN.
• Herder C, Bongaerts BW, Rathmann W, Heier M, Kowall B, Koenig W, et al. Differential association between biomarkers of subclinical inflammation and painful polyneuropathy: results from the KORA F4 study. Diabetes Care. 2015;38:91–6 Study showing that biomarkers of subclinical and vascular inflammation are associated with painful-DPN.
• Bönhof GJ, Herder C, Strom A, Papanas N, Roden M, Ziegler D. Emerging biomarkers, tools, and treatments for diabetic polyneuropathy. Endocr Rev. 2018;40:153–92. https://doi.org/10.1210/er.2018-00107. Detailed review of the biomarkers and treatments for DPN.
Zhang C, Ward J, Dauch JR, Tanzi RE, Cheng HT. Cytokine-mediated inflammation mediates painful neuropathy from metabolic syndrome. PLoS One. 2018;13:e0192333. https://doi.org/10.1371/journal.pone.0192333.
Cheng HT, Dauch JR, Oh SS, Hayes JM, Hong Y, Feldman EL. p38 mediates mechanical allodynia in a mouse model of type 2 diabetes. Mol Pain. 2010;6:28. https://doi.org/10.1186/1744-8069-6-28.
Purwata TE. High TNF-alpha plasma levels and macrophages iNOS and TNF-alpha expression as risk factors for painful diabetic neuropathy. J Pain Res. 2011;4:169–75.
Uçeyler N, Rogausch JP, Toyka KV, Sommer C. Differential expression of cytokines in painful and painless neuropathies. Neurology. 2007;69:42–9.
Üçeyler N, Riediger N, Kafke W, Sommer C. Differential gene expression of cytokines and neurotrophic factors in nerve and skin of patients with peripheral neuropathies. J Neurol. 2015;262:203–12.
Empl M, Renaud S, Erne B, Fuhr P, Straube A, Schaeren-Wiemers N, et al. TNF-alpha expression in painful and nonpainful neuropathies. Neurology. 2001;56:1371–7.
Selvarajah D, Wilkinson ID, Emery CJ, Harris ND, Shaw PJ, Witte DR, et al. Early involvement of the spinal cord in diabetic peripheral neuropathy. Diabetes Care. 2006;29:2664–9.
Lee-Kubli C, Marshall AG, Malik RA, Calcutt NA. The H-reflex as a biomarker for spinal disinhibition in painful diabetic neuropathy. Curr Diab Rep. 2018;18:1. https://doi.org/10.1007/s11892-018-0969-5.
Lee-Kubli CA, Calcutt NA. Altered rate-dependent depression of the spinal H-reflex as an indicator of spinal disinhibition in models of neuropathic pain. Pain. 2014;155:250–60.
Fomberstein K, Qadri S, Ramani R. Functional MRI and pain. Curr Opin Anaesthesiol. 2013;26:588–93.
Tracey I. Imaging pain. Br J Anaesth. 2008;101:32–9.
Wager T, Atlas L, Lindquist M, Roy M, Woo C, Kross E. An fMRI-based neurologic signature of physical pain. N Engl J Med. 2013;368:1388–97.
Buonocore MH, Maddock RJ. Magnetic resonance spectroscopy of the brain: a review of physical principles and technical methods. Rev Neurosci. 2015;26:609–32.
Selvarajah D, Wilkinson ID, Emery CJ, Shaw PJ, Griffiths PD, Gandhi R, et al. Thalamic neuronal dysfunction and chronic sensorimotor distal symmetrical polyneuropathy in patients with type 1 diabetes mellitus. Diabetologia. 2008;51:2088–92.
Fischer TZ, Tan AM, Waxman SG. Thalamic neuron hyperexcitability and enlarged receptive fields in the STZ model of diabetic pain. Brain Res. 2009;1268:154–61.
Freeman OJ, Evans MH, Cooper GJ, Petersen RS, Gardiner NJ. Thalamic amplification of sensory input in experimental diabetes. Eur J Neurosci. 2016;44:1779–86.
Gandhi R, Selvarajah D, Wilkinson I, Emery C, Shaw PJ, Griffiths P, et al. Preservation of thalamic neuronal function may be a prerequisite for pain perception in diabetic neuropathy. Diabetologia. 2006;49(Supp 1):2088–92.
Shillo P, Selvarajah D, Greig M, Rao D, Edden R, Wilkinson I, et al. Painless diabetic peripheral neuropathy is characterised by reduced thalamic gamma-aminobutyric acid (GABA). Diabet Med. 2016;33(Supp 1):162.
• Selvarajah D, Wilkinson ID, Gandhi R, Griffiths PD, Tesfaye S. Microvascular perfusion abnormalities of the thalamus in painful but not painless diabetic polyneuropathy: a clue to the pathogenesis of pain in type 1 diabetes. Diabetes Care. 2011;34:718–20 Study demonstrating increased microvascular perfusion within the thalamus is associated with painful-DPN.
Cauda F, Sacco K, D'Agata F, Duca S, Cocito D, Geminiani G, et al. Low-frequency BOLD fluctuations demonstrate altered thalamocortical connectivity in diabetic neuropathic pain. BMC Neurosci. 2009;10:138. https://doi.org/10.1186/1471-2202-10-138.
Ossipov MH, Morimura K, Porreca F. Descending pain modulation and chronification of pain. Curr Opin Support Palliat Care. 2014;8:143–51.
Silva M, Amorim D, Almeida A, Tavares I, Pinto-Ribeiro F, Morgado C. Pronociceptive changes in the activity of rostroventromedial medulla (RVM) pain modulatory cells in the streptozotocin-diabetic rat. Brain Res Bull. 2013;96:39–44.
Morgado C, Terra PP, Tavares I. Neuronal hyperactivity at the spinal cord and periaqueductal grey during painful diabetic neuropathy: effects of gabapentin. Eur J Pain. 2010;14:693–9.
Greig M, Wilkinson ID, Shillo P, Selvarajah D, Gandhi R, Tesfaye S. Impaired hemodynamic response to thermal pain in patients with painful diabetic neuropathy. Diabetes. 2018;67(Supp 1):568–P. https://doi.org/10.2337/db18-568-P.
• Segerdahl AR, Themistocleous AC, Fido D, Bennett DL, Tracey I. A brain-based pain facilitation mechanism contributes to painful diabetic polyneuropathy. Brain. 2018;141:357–64 Study finding vlPAG altered function may contribute to neuropathic pain in painful-DPN.
Ashburner J, Friston KJ. Voxel-based morphometry—the methods. Neuroimage. 2000;11:805–21.
Selvarajah D, Wilkinson ID, Maxwell M, Davies J, Sankar A, Boland E, et al. Magnetic resonance neuroimaging study of brain structural differences in diabetic peripheral neuropathy. Diabetes Care. 2014;37:1681–8.
Selvarajah D, Heiberg-Gibbons F, Wilkinson ID, Gandhi R, Tesfaye S. A magnetic resonance imaging volumetry study of regional brain atrophy in diabetic peripheral neuropathy. Diabetes. 2018;67(Supp 1):550–P. https://doi.org/10.2337/db18-550-P.
Selvarajah D, Awadh M, Gandhi R, Wilkinson ID, Tesfaye S. Alterations in somatomotor network functional connectivity in painful diabetic neuropathy—a resting state functional magnetic resonance imaging study. Diabetes. 2018;67(Supp 1):61–OR. https://doi.org/10.2337/db18-61-OR.
Watanabe K, Hirano S, Kojima K, Nagashima K, Mukai H, Sato T, et al. Altered cerebral blood flow in the anterior cingulate cortex is associated with neuropathic pain. J Neurol Neurosurg Psychiatry. 2018;89:1082–7.
Selvarajah D, Gandhi R, Hunter M, Emery C, Griffiths P, Tesfaye S, et al. A functional magnetic resonance imaging study demonstrating alterations in brain responses to acute pain stimulation in diabetic neuropathy. Diabetologia. 2007;50(Supp 1):448–S9.
Tseng MT, Chiang MC, Chao CC, Tseng WY, Hsieh ST. fMRI evidence of degeneration-induced neuropathic pain in diabetes: enhanced limbic and striatal activations. Hum Brain Mapp. 2013;34:2733–46.
•• Tesfaye S, Selvarajah D, Gandhi R, Greig M, Shillo P, Fang F, et al. Diabetic peripheral neuropathy may not be as its name suggests: evidence from magnetic resonance imaging. Pain. 2016;157(Supp 1):S72–80 Review of the MRI studies into painful-DPN.