High-Fat Diet–Induced Neuropathy of Pre-Diabetes and Obesity

Abstract

OBJECTIVE-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.RESEARCH DESIGN AND METHODS-Female C57BL6/J mice were fed normal diets or HFDs for 16 weeks.RESULTS-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 ⅐ kg Ϫ1 ⅐ day Ϫ1 ) corrected all functional changes of HFD-induced neuropathy.CONCLUSIONS-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. Diabetes 56: [2598][2599][2600][2601][2602][2603][2604][2605][2606][2607][2608] 2007 O ver the last decade, profound changes in the quality, quantity, and source of food consumed in many developed countries combined with a decrease in levels of physical activity have led to an increase in the prevalence of diabetes and its complications (1). Furthermore, some manifestations of peripheral diabetic neuropathy (PDN) and cardiovascular disease in overweight and obese subjects develop at the stage of impaired glucose tolerance (IGT), preceding overt diabetes (2-4). A high BMI is a well-recognized risk factor for median nerve sensory conduction slowing and carpal tunnel syndrome (5-7). Furthermore, nondiabetic obese subjects have been reported to display significantly decreased compound muscle action potential amplitude of tibial and peroneal nerves and decreased sensory action potential amplitude of median, ulnar, and sural nerves compared with nondiabetic individuals (8). In the same study, warm and cold sensations from the index and little fingers, warm sensation from the big toe, and thermal and pain thresholds from the little finger directly correlated with the insulin sensitivity index, which was reduced in obese subjects. A higher prevalence...

Insulin Resistance Prevents AMPK-induced Tau Dephosphorylation through Akt-mediated Increase in AMPKSer-485 Phosphorylation

“…However, as the diabetic phenotype continues to deteriorate the mice prone to a spontaneous death, so we harvested the mice at 24 weeks. Mice fed with high fat diet usually display signs of prediabetes starting around 16 weeks of age (37,38). Their blood glucose level and body weight continue to increase up to a year (39).…”

Schwann cell interactions with axons and microvessels in diabetic neuropathy

“…Nerve biopsy samples from patients with diabetes reveal overall fibre loss; degenerating fibres and clusters of regenerating axons are both present. Reduced axonal diameters, which suggest impaired maturation or atrophy, are frequently reported in rat models of diabetes, but are not a notable feature in many mouse models or humans with dia betes 23,24 . Whether axonopathy or Schwannopathy develops first in diabetic neuropathy 25 has long been debated, and a single nerve biopsy sample is not sufficient to determine whether Schwann cells undergo independent structural damage during diabetes or are responding to axonal degeneration.…”

“…Accumulation of triglycerides, cholesterol and free fatty acids in blood plasma in diabetes seems to drive lipid-mediated neuropathology via mechanisms that are incompletely understood but might involve oxidative and inflammatory pathways in Schwann cells 86 . In rodents, a high-fat diet causes accumulation of oxidized lipids and activation of lipoxygenases in peripheral nerves, suggestive of a prediabetic condition 24 . Moreover, accumulation of oxidized LDLs in peripheral nerves promotes oxidative stress that has been associated with a low nerve conduction velocity and sensory deficits 87 .…”

Diabetic Painful and Insensate Neuropathy: Pathogenesis and Potential Treatments

“…Obrosova, unpublished data), as well as in two animal models of prediabetes and obesity, Zucker fatty rats 55 and high-fat diet-fed C57Bl/6J mice. 56 Data for leptin receptor-deficient (db/db) mice 57,58 and Zucker diabetic fatty rats 59,60 are contradictory, and both normal and reduced thermal sensation in these two animal models have been reported. Surprisingly, a number of mechanisms contributing to increased thermal sensitivity in the rat models with relatively short-term duration of diabetes were also implicated in development of thermal hypoalgesia in rats with diabetes of longer duration or diabetic mice.…”

“…59 Finally, thermal hypoalgesia associated with alimentary obesity and glucose intolerance can be cured by switching from high-fat to normal-fat diet. 56 Thus, both dietary and pharmacological approaches should be developed for treatment of this disorder in human subjects with diabetes mellitus.…”