The mechanisms that lead to painful or insensate symptoms in diabetic neuropathy (DN) are poorly understood. Many variables likely play a role in the development of these diverse symptoms, including reduced neurotrophic supply, abnormal insulin support, and oxidative stress. These symptoms may also underlie peripheral axon damage amongst select sensory neuronal subpopulations. Our long-term goal is to understand the etiology of painful and/or insensate complications of DN in relation to insulin support, oxidative stress, and peripheral axon degeneration. The central hypothesis of this proposal is that unique genetic differences underlie the differential progression and severity of diabetic neuropathy. Exploring these genetic differences will help identify mechanisms involved in the pathogenesis of diabetic neuropathy.
Aim 1 will characterize the progression of painful and insensate neuropathy in type 1 (STZ- A/J vs. STZ-C57Bl/6) and type 2 (ob/ob vs. db/db) mouse models of diabetes and test whether neurotrophins can alleviate the diabetes-induced abnormalities in mechanical sensitivity.
Aim 2 will test whether insulin support plays a critical role in the progression of painful or insensate neuropathy amongst these variant mouse models of diabetes.
Aim 3 will examine the role of oxidative stress in the development of painful or insensate neuropathy in these diabetic mice.
Aim 4 will determine whether differential damage to epidermal axons is important factor in developing painful or insensate diabetic neuropathy. Collectively, these studies will identify three possible mechanisms responsible for the variable progression of symptoms experienced within human patients and identify new therapeutic targets aimed at the severity of symptoms amongst diabetic patients.

Public Health Relevance

This proposal will elucidate mechanisms related to the development of painful versus nonpainful symptoms in mouse models of diabetic neuropathy. The role of neurotrophins, insulin support, oxidative stress, and axonal degeneration will be investigated to identify mechanisms that lead to the neural complications associated with diabetes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Research Project (R01)
Project #
5R01NS043314-09
Application #
8322109
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Gwinn, Katrina
Project Start
2002-04-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
9
Fiscal Year
2012
Total Cost
$321,563
Indirect Cost
$107,188
Name
University of Kansas
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
016060860
City
Kansas City
State
KS
Country
United States
Zip Code
66160
Guilford, B L; Ryals, J M; Lezi, E et al. (2017) Dorsal Root Ganglia Mitochondrial Biochemical Changes in Non-diabetic and Streptozotocin-Induced Diabetic Mice Fed with a Standard or High-Fat Diet. J Neurol Neurosci 8:
Cooper, Michael A; Ryals, Janelle M; Wu, Pau-Yen et al. (2017) Modulation of diet-induced mechanical allodynia by metabolic parameters and inflammation. J Peripher Nerv Syst 22:39-46
Grote, Caleb W; Wright, Douglas E (2016) A Role for Insulin in Diabetic Neuropathy. Front Neurosci 10:581
Cooper, Michael A; Kluding, Patricia M; Wright, Douglas E (2016) Emerging Relationships between Exercise, Sensory Nerves, and Neuropathic Pain. Front Neurosci 10:372
Kluding, Patricia M; Pasnoor, Mamatha; Singh, Rupali et al. (2015) Safety of aerobic exercise in people with diabetic peripheral neuropathy: single-group clinical trial. Phys Ther 95:223-34
Katz, N K; Ryals, J M; Wright, D E (2015) Central or peripheral delivery of an adenosine A1 receptor agonist improves mechanical allodynia in a mouse model of painful diabetic neuropathy. Neuroscience 285:312-23
Biessels, G J; Bril, V; Calcutt, N A et al. (2014) Phenotyping animal models of diabetic neuropathy: a consensus statement of the diabetic neuropathy study group of the EASD (Neurodiab). J Peripher Nerv Syst 19:77-87
Wilson, Natalie M; Wright, Douglas E (2014) Experimental motor neuropathy in diabetes. Handb Clin Neurol 126:461-7
Groover, Anna L; Ryals, Janelle M; Guilford, Brianne L et al. (2013) Exercise-mediated improvements in painful neuropathy associated with prediabetes in mice. Pain 154:2658-67
Guilford, B L; Wright, D E (2013) Chewing the fat: genetic approaches to model dyslipidemia-induced diabetic neuropathy in mice. Exp Neurol 248:504-8

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