Diabetic neuropathy, once well established, is poorly reversible in human trials. Sensitive diagnostic measures are necessary to identify patients with very early axonal injury who may be better candidates for intervention or even preventative therapy. The Cutaneous Measures of Diabetic Neuropathy (CMND) study extensively characterizes peripheral nerve function in 221 diabetic subjects, with longitudinal follow-up. CMND shows that early diabetic neuropathy is characterized by progressive small fiber loss, and identifies skin biopsy with intraepidermal nerve fiber density (IENFD) as a sensitive, quantitative surrogate measure of neuropathy severity. IENFD closely correlates with clinical and electrodiagnostic measures of neuropathy, and declines significantly over two years in diabetic subjects, including those without neuropathy symptoms. We have shown that metabolic improvement achieved through individualized diet and exercise counseling for subjects with early neuropathy associated with impaired glucose tolerance significantly improves measures of small fiber neuropathy, including pain and IENFD. We hypothesize that 1) early IENFD decline predicts future development of clinically meaningful diabetic neuropathy, and 2) correction of IENFD decline with aggressive lifestyle intervention based on the impaired glucose tolerance neuropathy studies will successfully result in weight loss, improved metabolic parameters, and reduced risk of diabetic neuropathy development or slowing of its progression.
Aim 1 will follow CMND diabetic subjects for an additional four years to determine the magnitude of early decline in IENFD that predicts future development of symptomatic distal polyneuropathy.
Aim 2 will randomize 175 additional diabetic subjects without neuropathy symptoms to determine if two years of aggressive diet and exercise counseling reduces IENFD progression, or incidence of symptomatic neuropathy.
Both Aims will examine if metabolic syndrome, obesity or specific baseline metabolic parameters, insulin resistance (HOMA-IR) or adipokine levels predict rate of IENFD decline or risk of future neuropathy development.

Public Health Relevance

Injury to the very longest peripheral nerves due to diabetes (diabetic neuropathy) is very common. The earlier diabetic neuropathy can be identified, the more effective treatment is likely to be. This proposal will test a method to count nerves in skin to see if it predicts future diabetic neuropathy, and tests the effect of diet and exercise on preventing nerve injury.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project (R01)
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Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
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Jones, Teresa L Z
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University of Utah
Schools of Medicine
Salt Lake City
United States
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Stino, Amro M; Smith, Albert G (2017) Peripheral neuropathy in prediabetes and the metabolic syndrome. J Diabetes Investig 8:646-655
Kluding, Patricia M; Singleton, J Robinson; Pasnoor, Mamatha et al. (2017) Activity for Diabetic Polyneuropathy (ADAPT): Study Design and Protocol for a 2-Site Randomized Controlled Trial. Phys Ther 97:20-31
Singleton, J Robinson; Marcus, Robin L; Lessard, Margaret K et al. (2015) Supervised exercise improves cutaneous reinnervation capacity in metabolic syndrome patients. Ann Neurol 77:146-53
Kinard, Krista I; Smith, A Gordon; Singleton, J Robinson et al. (2015) Chronic migraine is associated with reduced corneal nerve fiber density and symptoms of dry eye. Headache 55:543-9
Baets, Jonathan; Duan, Xiaohui; Wu, Yanhong et al. (2015) Defects of mutant DNMT1 are linked to a spectrum of neurological disorders. Brain 138:845-61
Singleton, J Robinson; Smith, A Gordon; Marcus, Robin L (2015) Exercise as Therapy for Diabetic and Prediabetic Neuropathy. Curr Diab Rep 15:120
Tavakoli, Mitra; Ferdousi, Maryam; Petropoulos, Ioannis N et al. (2015) Normative values for corneal nerve morphology assessed using corneal confocal microscopy: a multinational normative data set. Diabetes Care 38:838-43
Smith, A Gordon; Lessard, Margaret; Reyna, Sandra et al. (2014) The diagnostic utility of Sudoscan for distal symmetric peripheral neuropathy. J Diabetes Complications 28:511-6
Frech, Tracy M; Smith, Gordon; Reily, Melissa et al. (2013) Peripheral neuropathy: a complication of systemic sclerosis. Clin Rheumatol 32:885-8
Smith, A Gordon; Singleton, J Robinson (2013) Obesity and hyperlipidemia are risk factors for early diabetic neuropathy. J Diabetes Complications 27:436-42

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