Taurine and Painful Diabetic Neuropathy Diabetic neuropathy (DN) commonly complicates diabetes and can lead to lower limb amputations. In diabetes, neuropathic pain reduces quality of life, contributes to depression, limits exercise and impairs metabolic control thereby contributing to excess cardiovascular risk. Currently there are no treatments for DN other than improved metabolic control and conventional treatment for painful neuropathy can be cardiotoxic and have low efficacy. The etiology of pain complicating diabetes is poorly understood but may result from dysfunction of pain signaling pathways at multiple levels including cutaneous nociceptors, afferent neurons and spinal and supraspinal pathways. Taurine is a ubiquitous a amino acid, which functions as an antioxidant, regulator of glucose sensitive signal transduction pathways and analgesic such that its depletion in diabetes may contribute to the development of DN and pain. We have identified taurine depletion in the peripheral nerve of diabetic rodents and shown that taurine repletion alleviates hyperalgesia and prevents nerve metabolic, vascular and functional deficits. This proposal extends these observations and aims to explore the ability of taurine treatment alone to decrease pain and in combination with D-L-a-lipoic acid to improve nerve structure and function in patients with DN. The overall hypothesis is that taurine depletion contributes to the development of painful DN. The rationale is based on: (a) evidence implicating oxidative stress, altered neuronal calcium signaling and neuronal hyperexcitability in the development of painful DN (b) the emerging role of taurine as an important endogenous antioxidant, calcium regulator, neurotrophin, modulator of neuronal hyperexcitability and analgesic and (c) our data implicating an important role for taurine depletion and oxidative stress in the pathogenesis of experimental DN. The experimental approach will be to utilize biochemical, electrophysiological and imaging techniques to test the following aims: 1. Determine whether neuropathic pain complicating diabetes can be ameliorated by therapy with taurine. 2. Determine whether nerve functional and structural deficits complicating diabetes can be ameliorated by combination therapy with taurine and D-L-a-Iipoic acid. These studies will test a novel mechanistically based therapeutic approach to a common disabling and often-refractory complication of diabetes.

Agency
National Institute of Health (NIH)
Institute
National Center for Complementary & Alternative Medicine (NCCAM)
Type
Research Project (R01)
Project #
1R01AT002146-01A1
Application #
6870898
Study Section
Clinical Neuroplasticity and Neurotransmitters Study Section (CNNT)
Program Officer
Klein, Marguerite
Project Start
2004-09-29
Project End
2005-06-30
Budget Start
2004-09-29
Budget End
2005-06-30
Support Year
1
Fiscal Year
2004
Total Cost
$336,600
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
Askwith, Trevor; Zeng, Wei; Eggo, Margaret C et al. (2012) Taurine reduces nitrosative stress and nitric oxide synthase expression in high glucose-exposed human Schwann cells. Exp Neurol 233:154-62
Zeng, Wei; Tahrani, Abd; Shakher, Jayadave et al. (2011) Effects of a synthetic retinoid on skin structure, matrix metalloproteinases, and procollagen in healthy and high-risk subjects with diabetes. J Diabetes Complications 25:398-404
Kellogg, Aaron P; Converso, Kimber; Wiggin, Tim et al. (2009) Effects of cyclooxygenase-2 gene inactivation on cardiac autonomic and left ventricular function in experimental diabetes. Am J Physiol Heart Circ Physiol 296:H453-61
Askwith, Trevor; Zeng, Wei; Eggo, Margaret C et al. (2009) Oxidative stress and dysregulation of the taurine transporter in high-glucose-exposed human Schwann cells: implications for pathogenesis of diabetic neuropathy. Am J Physiol Endocrinol Metab 297:E620-8
Pop-Busui, Rodica; Oral, Elif; Raffel, David et al. (2009) Impact of rosiglitazone and glyburide on nitrosative stress and myocardial blood flow regulation in type 2 diabetes mellitus. Metabolism 58:989-94
Kellogg, Aaron P; Wiggin, Tim D; Larkin, Dennis D et al. (2007) Protective effects of cyclooxygenase-2 gene inactivation against peripheral nerve dysfunction and intraepidermal nerve fiber loss in experimental diabetes. Diabetes 56:2997-3005
Stevens, M J; Li, F; Drel, V R et al. (2007) Nicotinamide reverses neurological and neurovascular deficits in streptozotocin diabetic rats. J Pharmacol Exp Ther 320:458-64
Li, Fei; Abatan, Omorodola I; Kim, Howard et al. (2006) Taurine reverses neurological and neurovascular deficits in Zucker diabetic fatty rats. Neurobiol Dis 22:669-76
Stevens, Martin J (2005) Oxidative-nitrosative stress as a contributing factor to cardiovascular disease in subjects with diabetes. Curr Vasc Pharmacol 3:253-66