High-fat diet-induced neuropathy of pre-diabetes and obesity : Effects of healthy diet and aldose reductase inhibition

• Published in: Diabetes (New York, N.Y.) Vol. 56; no. 10; pp. 2598 - 2608
• Main Authors: OBROSOVA, Irina G, ILNYTSKA, Olga, LYZOGUBOV, Valeriy V, PAVLOV, Ivan A, MASHTALIR, Nazar, NADLER, Jerry L, DREL, Viktor R
• Format: Journal Article
• Language: English
• Published: Alexandria, VA American Diabetes Association 01-10-2007
• Subjects: Aldehyde Reductase - antagonists & inhibitors; Aldose reductase; Animals; Antibodies; Biological and medical sciences; Body Temperature Regulation; Chemical properties; Diabetes; Diabetes research; Diabetes. Impaired glucose tolerance; Diabetic Neuropathies - chemically induced; Diabetic Neuropathies - prevention & control; Diabetic neuropathy; Diet; Dietary Fats - pharmacology; Disease Models, Animal; Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fatty Acids, Nonesterified - blood; Female; Glucose; Human subjects; Hyperglycemia; Imidazolidines - therapeutic use; Insulin; Laboratory animals; Medical sciences; Metabolic diseases; Metabolism; Mice; Mice, Inbred C57BL; Neurons, Afferent - physiology; Obesity; Obesity - physiopathology; Peripheral nerve diseases; Peripheral nervous system diseases; Physiology; Prediabetic State - physiopathology; Radioimmunoassay; Research design; Sensory Thresholds; Touch - physiology; United States; Endocrinopathy; Obesity; Nervous system diseases; Enzyme; Diabetes mellitus; Nutrition disorder; Neuropathy; Feeding; Diet; Aldehyde reductase; Oxidoreductases; Inhibition; Nutritional status
• ISSN: 0012-1797; 1939-327X
• DOI: 10.2337/db06-1176

Subjects with dietary obesity and pre-diabetes have an increased risk for developing both nerve conduction slowing and small sensory fiber neuropathy. Animal models of this type of neuropathy have not been described. This study evaluated neuropathic changes and their amenability to dietary and pharmacological interventions in mice fed a high-fat diet (HFD), a model of pre-diabetes and alimentary obesity.
Female C57BL6/J mice were fed normal diets or HFDs for 16 weeks.
HFD-fed mice developed obesity, increased plasma FFA and insulin concentrations, and impaired glucose tolerance. They also 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 HFD 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 x kg(-1) x day (-1)) corrected all functional changes of HFD-induced neuropathy.
Similar to human subjects with pre-diabetes and obesity, HFD-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.