title: 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.
authors.affiliation: Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA 70808, USA.
authors.forename: Sergey
authors.initials: S
authors.lastname: Lupachyk
authors.forename: Pierre
authors.initials: P
authors.lastname: Watcho
authors.forename: Alexander A
authors.initials: AA
authors.lastname: Obrosov
authors.forename: Roman
authors.initials: R
authors.lastname: Stavniichuk
authors.forename: Irina G
authors.initials: IG
authors.lastname: Obrosova
mesh_terms: D000200:Action Potentials; D000704:Analysis of Variance; D000818:Animals; D059305:Diet, High-Fat / Q000009:adverse effects; D004195:Disease Models, Animal; D004558:Electric Stimulation; D000091342:Endoplasmic Reticulum Chaperone BiP; D059865:Endoplasmic Reticulum Stress / Q000502:physiology*; D005227:Fatty Acids / Q000097:blood; D005951:Glucose Tolerance Test; D007328:Insulin / Q000097:blood; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009431:Neural Conduction; D010523:Peripheral Nervous System Diseases / Q000097:blood / Q000209:etiology*; D011236:Prediabetic State / Q000097:blood / Q000150:complications* / Q000209:etiology; D051381:Rats; D011924:Rats, Zucker; D012584:Sciatic Nerve / Q000378:metabolism / Q000473:pathology; D013116:Spinal Cord / Q000378:metabolism / Q000473:pathology
chemical_list: D000091342:Endoplasmic Reticulum Chaperone BiP; D005227:Fatty Acids; C000717248:Hspa5 protein, mouse; D007328:Insulin; D008055:Lipids
keywords: Diabetic peripheral neuropathy; Endoplasmic reticulum stress; Eukaryotic initiation factor-2α; High-fat diet fed mouse; Motor nerve conduction velocity; Prediabetic peripheral neuropathy; Salubrinal; Sensory nerve conduction velocity; Streptozotocin; Trimethylamine oxide; Unfolded protein response; Zucker (fa/fa) rat