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High Fat Diet- Induced Neuropathy of Prediabetes and Obesity: Effects of "Healthy" Diet and Aldose Reductase Inhibition

¹Pennington Biomedical Research Center, Louisiana State University System, Baton Rouge, LA
² Division of Endocrinology and Metabolism, University of Virginia Health Science System, Charlottesville, VA

Correspondence: obrosoig{at}pbrc.edu

Key Words: aldose reductase • dietary intervention • intraepidermal nerve fiber density • neuropathy of prediabetes and obesity • motor and sensory nerve conduction deficits • oxidative-nitrosative stress • tactile allodynia • thermal hypoalgesia

Subjects with dietary obesity and prediabetes have increased risk for developing both nerve conduction slowing and small sensory fiber neuropathy. Animal model of this type of neuropathy has not been described. This study evaluated neuropathic changes and their amenability to dietary and pharmacological interventions in mice fed high-fat diet, a model of prediabetes and alimentary obesity. Female C57Bl6/J mice were fed normal or high fat diets for 16 weeks. High fat diet fed mice developed obesity, increased plasma FFA and insulin concentrations, and impaired glucose tolerance. They had motor and sensory nerve conduction deficits, tactile allodynia and thermal hypoalgesia, in the absence of intraepidermal nerve fiber loss or axonal atrophy. Despite the absence of overt hyperglycemia, the mice displayed augmented sorbitol pathway activity in the peripheral nerve, as well as 4-hydroxynonenal adduct, nitrotyrosine and poly(ADP-ribose) accumulation and 12/15-lipoxygenase overexpression in peripheral nerve and dorsal root ganglion neurons. A 6-week feeding with normal chow after 16 weeks on high fat diet alleviated tactile allodynia and essentially corrected thermal hypoalgesia and sensory nerve conduction deficit without affecting motor nerve conduction slowing. Normal chow containing the aldose reductase inhibitor fidarestat (16 mg kg^-1d^-1) corrected all functional changes of high fat diet-induced neuropathy. In conclusion, similarly to human subjects with prediabetes and obesity, high fat diet fed mice develop peripheral nerve functional but not structural, abnormalities, and, therefore, are a suitable model for evaluating dietary and pharmacological approaches to halt progression and reverse diabetic neuropathy at the earliest stage of the disease.

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