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Endoplasmic reticulum stress contributes to prediabetic peripheral neuropathy.

Abstract
Growing evidence suggests that prediabetes and metabolic syndrome are associated with increased risk for the development of microvascular complications including retinopathy, nephropathy, and, most commonly, peripheral painful neuropathy and/or autonomic neuropathy. The etiology of these disabling neuropathies is unclear, and several clinical and experimental studies implicated obesity, impaired fasting glycemia/impaired glucose tolerance, elevated triglyceride and non-esterified fatty acids, as well as oxidative-nitrative stress. Endoplasmic reticulum stress resulting from abnormal folding of newly synthesized proteins and leading to the impairment of metabolism, transcriptional regulation, and gene expression, is emerging as a key mechanism of metabolic diseases including obesity and diabetes. We evaluated the role for this phenomenon in prediabetic neuropathy using two animal models i.e., Zucker (fa/fa) rats and high-fat diet fed mice which displayed obesity and impaired glucose tolerance in the absence of overt hyperglycemia. Endoplasmic reticulum stress manifest in upregulation of the glucose-regulated proteins BiP/GRP78 and GRP94 of unfolded protein response was identified in the sciatic nerve of Zucker rats. A chemical chaperone, trimethylamine oxide, blunted endoplasmic reticulum stress and alleviated sensory nerve conduction velocity deficit, thermal and mechanical hypoalgesia, and tactile allodynia. A selective inhibitor of eukaryotic initiation factor-2α dephosphorylation, salubrinal, improved glucose intolerance and alleviated peripheral nerve dysfunction in high-fat diet fed mice. Our findings suggest an important role of endoplasmic reticulum stress in the neurobiology of prediabetic peripheral neuropathy, and identify a new therapeutic target.
AuthorsSergey Lupachyk, Pierre Watcho, Alexander A Obrosov, Roman Stavniichuk, Irina G Obrosova
JournalExperimental neurology (Exp Neurol) Vol. 247 Pg. 342-8 (Sep 2013) ISSN: 1090-2430 [Electronic] United States
PMID23142188 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)
CopyrightCopyright © 2013 Elsevier Inc. All rights reserved.
Chemical References
  • Endoplasmic Reticulum Chaperone BiP
  • Fatty Acids
  • Hspa5 protein, mouse
  • Insulin
  • Lipids
Topics
  • Action Potentials
  • Analysis of Variance
  • Animals
  • Diet, High-Fat (adverse effects)
  • Disease Models, Animal
  • Electric Stimulation
  • Endoplasmic Reticulum Chaperone BiP
  • Endoplasmic Reticulum Stress (physiology)
  • Fatty Acids (blood)
  • Glucose Tolerance Test
  • Insulin (blood)
  • Lipids (blood)
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Neural Conduction
  • Peripheral Nervous System Diseases (blood, etiology)
  • Prediabetic State (blood, complications, etiology)
  • Rats
  • Rats, Zucker
  • Sciatic Nerve (metabolism, pathology)
  • Spinal Cord (metabolism, pathology)

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