The spectrum of neuropathy in diabetes and impaired glucose tolerance
Abstract
OBJECTIVE: To compare the neuropathy associated with impaired glucose tolerance (IGT) and diabetes mellitus (DM) determined by oral glucose tolerance testing (OGTT). METHODS: Patients with peripheral neuropathy of unknown cause were prescribed OGTT. Duration of neuropathic symptoms, neuropathic pain, neuropathy classification, nerve conduction test results, and intraepidermal nerve fiber densities (IENFD) were compared between IGT and DM groups. RESULTS: Seventy-three patients completed OGTT; 41 (56%) had abnormal results. Of these 41 patients, 26 had IGT and 15 had DM. Patients with IGT had less severe neuropathy than patients with diabetes, as measured by sural nerve amplitudes (p = 0.056), sural nerve conduction velocities (p = 0.03), and distal leg IENFD (p = 0.01). Patients with IGT had predominantly small fiber neuropathy, compared to patients with DM (p = 0.05), who had more involvement of large nerve fibers. CONCLUSIONS: The neuropathy associated with IGT is milder than the neuropathy associated with DM. Small nerve fibers are prominently affected and may be the earliest detectable sign of neuropathy in glucose dysmetabolism. OGTT is appropriate in patients with idiopathic neuropathy.
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Evidence is accumulating on increased prevalence of idiopathic polyneuropathy among prediabetic individuals, with IGT being more strongly related to painful than non-painful neuropathy.
“Finally, evidence is accumulating on increased prevalence of idiopathic polyneuropathy (eg, idiopathic sensory/painful neuropathy,73–78 and sensory/small fibre only neuropathy)73,75,78 among prediabetic individuals with IGT being more strongly related to painful than non-painful neuropathy.73,75,78”
From Prediabetes: a high-risk state for diabetes development (2012) · cites this paper as [78]
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“It may be difficult to estimate the duration of type 2 diabetes because of a delay in the diagnosis, and reduction of IENFs, although not necessarily to abnormal levels, is expected to occur before clinically definite diabetes mellitus [14, 17].”
BackgroundA controlled investigation of the cause of chronic idiopathic axonal polyneuropathy
Hughes, R. A. (2004) · Brain · doi:10.1093/brain/awh192 · Cited by 178 · see citing works
Painful Peripheral Neuropathies
Marchettini, P., Lacerenza, M. R., Mauri, E., & Marangoni, C. (2006) · Current Neuropharmacology · doi:10.2174/157015906778019536 · Cited by 173 · see citing works
Diabetic neuropathies: clinical manifestations and current treatment options
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Intraepidermal nerve fiber density as a marker of early diabetic neuropathy
Umapathi, T., Tan, W. L., Loke, S. C., Soon, P. C., Tavintharan, S., & Chan, Y. H. (2007) · Muscle & Nerve · doi:10.1002/mus.20732 · Cited by 167 · see citing works
Early detection of diabetic peripheral neuropathy with corneal confocal microscopy
Hossain, P. N., Sachdev, A., & Malik, R. A. (2005) · The Lancet · doi:10.1016/s0140-6736(05)67546-0 · Cited by 166 · see citing works
Impaired glucose tolerance and neuropathy
Smith, A. G., & Singleton, J. R. (2008) · The Neurologist · doi:10.1097/nrl.0b013e31815a3956 · Cited by 165 · see citing works
“IGT neuropathy patients have less severe neuropathy than those with diabetic neuropathy, but they have preferential involvement of small unmyelinated nerve fibers.(15) IGT and diabetic neuropathy patients share reduced cutaneous nerve fiber density.”
BackgroundThe Spectrum of Diabetic Neuropathies
Tracy, J. A., & Dyck, P. J. B. (2008) · Physical Medicine and Rehabilitation Clinics of North America · doi:10.1016/j.pmr.2007.10.010 · Cited by 164 · see citing works
Metabolic syndrome and peripheral neuropathy
Kazamel, M., Stino, A. M., & Smith, A. G. (2020) · Muscle & Nerve · doi:10.1002/mus.27086 · Cited by 164 · see citing works
“Of a cohort of 73 patients who underwent OGTT, 56% were found to have IFG, whereas 36% had IGT, with the IGT group showing preferential smallfiber involvement.(52)”
BackgroundCazzato, D., & Lauria, G. (2017) · Current Opinion in Neurology · doi:10.1097/wco.0000000000000472 · Cited by 160 · see citing works
Skin biopsy as a diagnostic tool in peripheral neuropathy
Lauria, G., & Devigili, G. (2007) · Nature Clinical Practice Neurology · doi:10.1038/ncpneuro0630 · Cited by 159 · see citing works
Assessing autonomic dysfunction in early diabetic neuropathy
Zilliox, L. A., Peltier, A., Wren, P. A., Anderson, A. L., Smith, A. G., Singleton, J. R., Feldman, E. L., Alexander, N. B., & Russell, J. W. (2011) · Neurology · doi:10.1212/wnl.0b013e3182120147 · Cited by 159 · see citing works
Prediabetes and associated disorders
Buysschaert, M., Medina, J. L., Bergman, M., Shah, A., & Lonier, J. (2014) · Endocrine · doi:10.1007/s12020-014-0436-2 · Cited by 159 · see citing works
Ahmad, J. (2015) · Diabetes & Metabolic Syndrome Clinical Research & Reviews · doi:10.1016/j.dsx.2015.04.002 · Cited by 156 · see citing works
Obesity and peripheral neuropathy risk: a dangerous liaison
Miscio, G., Guastamacchia, G., Brunani, A., Priano, L., Baudo, S., & Mauro, A. (2005) · Journal of the Peripheral Nervous System · doi:10.1111/j.1085-9489.2005.00047.x · Cited by 155 · see citing works
“Small nerve fibers are prominently affected and may be the earliest detectable sign of neuropathy in glucose dysmetabolism (Sumner et al., 2003).”
BackgroundEarly diabetic neuropathy: Triggers and mechanisms
Dobretsov, M. G. (2007) · World Journal of Gastroenterology · doi:10.3748/wjg.v13.i2.175 · Cited by 153 · see citing works
Incidence and prevalence of small-fiber neuropathy
Peters, M. J. H., Bakkers, M., Merkies, I. S. J., Hoeijmakers, J. G. J., van Raak, E. P. M., & Faber, C. G. (2013) · Neurology · doi:10.1212/wnl.0b013e3182a8236e · Cited by 151 · see citing works
Smith, S. M., Dworkin, R. H., Turk, D. C., Baron, R., Polydefkis, M. J., Tracey, I., Borsook, D., Edwards, R. R., Harris, R. E., Wager, T. D., et al. (2017) · Journal of Pain · doi:10.1016/j.jpain.2017.02.429 · Cited by 151 · see citing works
“biopsy detected neuropathy in individuals with impaired glucose tolerance or occult diabetes who had normal large fiber test results.(139,170,171,176) Patients with SFN followed for approximately 2.”
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A new simple method for assessing sudomotor function: Relevance in type 2 diabetes
Mayaudon, H., Miloche, P.-O., & Bauduceau, B. (2010) · Diabetes & Metabolism · doi:10.1016/j.diabet.2010.05.004 · Cited by 149 · see citing works
Myelinated nerve endings in human skin
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Lee, C. C., Perkins, B. A., Kayaniyil, S., Harris, S. B., Retnakaran, R. R., Gerstein, H. C., Zinman, B., & Hanley, A. J. (2015) · Diabetes Care · doi:10.2337/dc14-2585 · Cited by 147 · see citing works
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Burgess, J., Frank, B., Marshall, A. G., Khalil, R. S., Ponirakis, G., Petropoulos, I. N., Cuthbertson, D. J., Malik, R. A., & Alam, U. (2021) · Diagnostics · doi:10.3390/diagnostics11020165 · Cited by 149 · see citing works
“Sudoscan on the other hand, is an FDA approved point of care device [205] which has been advocated as a screening tool for DPN [206].”
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“This has been based on a number of observations, including: 1) findings of altered thermal thresholds in patients with normal NCSs (7,8); 2) reduced intraepithelial nerve fiber density (IENFD) at the ankle and IENFD ratios in diabetic patientswithout symptoms or signs of peripheral neuropathy and normal NCSs (8,11); a…”
BackgroundSmall fiber neuropathy: Getting bigger!
Chan, A. C. Y., & Wilder-Smith, E. P. (2016) · Muscle & Nerve · doi:10.1002/mus.25082 · Cited by 141 · see citing works
“showed that 56% of patients with idiopathic neuropathy had abnormal OGTT results, and the neuropathy associated with impaired glucose tolerance (IGT) is milder than the neuropathy associated with diabetes mellitus (DM).(49) However, Kassardjian et al.”
BackgroundTreatment of diabetic peripheral neuropathy: a review
Khdour, M. R. (2020) · Journal of Pharmacy and Pharmacology · doi:10.1111/jphp.13241 · Cited by 143 · see citing works
“The same is not the case for type-2 diabetes; several studies have demonstrated that aggressive glycaemic control has no meaningful impact on patient risk for polyneuropathy.([17,18]) A systemic review by Callaghan et al.”
BackgroundUse of Antiepileptic Drugs in the Treatment of Chronic Painful Diabetic Neuropathy
Vinik, A. I. (2005) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-2376 · Cited by 141 · see citing works
Azmi, S., Ferdousi, M., Petropoulos, I. N., Ponirakis, G., Alam, U., Fadavi, H., Asghar, O., Marshall, A., Atkinson, A. J., Jones, W., et al. (2015) · Diabetes Care · doi:10.2337/dc14-2733 · Cited by 148 · see citing works
England, J. D., Gronseth, G., Franklin, G. M., Carter, G. T., Kinsella, L. J., Cohen, J. A., Asbury, A. K., Szigeti, K., Lupski, J. R., Latov, N., et al. (2009) · PM&R · doi:10.1016/j.pmrj.2008.11.010 · Cited by 140 · see citing works
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Skin biopsy for the diagnosis of peripheral neuropathy
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Skin biopsy in the management of peripheral neuropathy
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Assessment of Epidermal Nerve Fibers
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“Differences between people with type I versus type II diabetes have not been identified although severity of IENF loss has been linked to the severity of glucose dysmetabolism (50).”
BackgroundInfluentialSelf-citationNew Insights Into Diabetic Polyneuropathy
Polydefkis, M. J. (2003) · JAMA · doi:10.1001/jama.290.10.1371 · Cited by 134 · see citing works
Self-citationThrainsdottir, S., Malik, R. A., Dahlin, L. B., Wiksell, P., Eriksson, K. F., Rosén, I., Petersson, J., Greene, D. A., & Sundkvist, G. (2003) · Diabetes · doi:10.2337/diabetes.52.10.2615 · Cited by 134 · see citing works
Dorsal root ganglia sensory neuronal cultures: a tool for drug discovery for peripheral neuropathies
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“The use of DRG sensory neurons has several advantages: i) they represent the main cellular target of diabetic neurotoxicity; ii) it is possible to enrich the neuronal population with nerve growth factor (NGF) dependent neurons that are often the most vulnerable ones clinically [34] and in animal models of type I diabe…”
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Biological and medical physics, biomedical engineering
Herman, I. P. (2014) · Cited by 136 · see citing works
Body Mass Index, Weight Gain, and Incident Urinary Incontinence in Middle-Aged Women
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Diagnosing Diabetic Neuropathy: Something Old, Something New
Petropoulos, I. N., Ponirakis, G., Khan, A., Almuhannadi, H., Gad, H., & Malik, R. A. (2018) · Diabetes & Metabolism Journal · doi:10.4093/dmj.2018.0056 · Cited by 134 · see citing works
“[42] found a reduction in IENFD, sural nerve amplitude and conduction velocity in patients with IGT and DM, with more marked abnormalities in patients with DM with a predominantly small fiber neuropathy in the IGT group.”
BackgroundSmall-Fiber Neuropathy/Neuronopathy Associated With Celiac Disease
Brannagan, T. H., Hays, A. P., Chin, S. S., Sander, H. W., Chin, R. L., Magda, P., Green, P. H. R., & Latov, N. (2005) · Archives of Neurology · doi:10.1001/archneur.62.10.1574 · Cited by 5 · see citing works
“There is likely a spectrum of fiber involvement with CD as occurs with diabetes mellitus.(9) In our previous study, we noted that 8% of the patients in our center with symptoms of neuropathy and normal results of sensory nerve conduction studies that suggested small-fiber neuropathy had CD.”
Background
- Authors
- Sumner, C. J., Sheth, S., Griffin, J. W., Cornblath, D. R., & Polydefkis, M.
- Affiliations
- Johns Hopkins University (US)
- Venue
- Neurology
- Published
- 2003-01-14
- Volume
- 60
- Issue
- 1
- Pages
- 108-111
- ISSN
- 0028-3878 (ISSN-L)
- 1526-632X
- OpenAlex
- W1978686107
- Cited by
- 708
- References
- 25
- Citations by year
- 2026: 9 · 2025: 18 · 2024: 11 · 2023: 13 · 2022: 19 · 2021: 21 · 2020: 30 · 2019: 26 · 2018: 27 · 2017: 35 · 2016: 37 · 2015: 42 · 2014: 53 · 2013: 43 · 2012: 40
- FWCI
- 21.43
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Neurology (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5k23ns041374-04)
- National Institute of Neurological Disorders and Stroke (K23NS41374-01)
- Topics
- Health Sciences › Medicine › Neurology › Peripheral Neuropathies and Disorders
- Health Sciences › Medicine › Physiology › Pain Mechanisms and Treatments
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Hereditary Neurological Disorders
- Keywords
- diabetic peripheral neuropathy, impaired glucose tolerance, oral glucose tolerance test, small fiber neuropathy, intraepidermal nerve fiber density, nerve conduction velocity, sural nerve, neuropathic pain, neuropathy classification
- MeSH terms
- Adult, Aged, Aged, 80 and over, Blood Glucose, Cell Count, Diabetic Nephropathies, Electrodiagnosis, Electromyography, Epidermis, Female, Glucose Tolerance Test, Humans, Male, Middle Aged, Nerve Fibers, Neural Conduction, Pain Measurement, Peripheral Nervous System Diseases, Sural Nerve, Cell Size
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