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.