Determination of peripheral neuropathy in high‐fat diet fed low‐dose streptozotocin‐treated female C57Bl/6J mice and Sprague–Dawley rats

Abstract

Aims/IntroductionPeripheral neuropathy is a common complication of diabetes and also occurs in 30% of human obese individuals with impaired glucose tolerance. Even though peripheral neuropathy affects both sexes, most pre‐clinical studies have been carried out using male rodents. The aim of the present study was to create diet‐induced obesity and type 2 diabetes in female rats and mice in order to examine the development of peripheral neuropathy.Materials and MethodsAt 12 weeks‐of‐age, rats and mice were separated into three groups. Two groups or rats and mice were fed a 60‐kcal% high‐fat diet for 12 weeks (rats) or 8 weeks (mice). To induce type 2 diabetes, one group of high‐fat diet‐fed rats and mice were treated with a low dose of streptozotocin. Analyses of multiple neural end‐points were carried out 12 weeks later.ResultsGlucose utilization was impaired in diet‐induced obese female rats and mice, as was a number of neurological end‐points including nerve conduction velocity, intraepidermal and subepithelial corneal nerve fiber densities, and thermal and mechanical sensitivity. When female diet‐induced obese rats or mice were made hyperglycemic, glucose utilization and sensory nerve density of the skin and cornea, as well as thermal and mechanical sensitivity, were more significantly impaired compared with diet‐induced obese female rodents.ConclusionsThese studies show that diet‐induced obese and type 2 diabetic female rodents develop peripheral neuropathy that is similar to that occurring in male rodents. However, for female rats, more aggressive treatment is required to induce dietary obesity.

Evidence of Altered Peripheral Nerve Function in a Rodent Model of Diet-Induced Prediabetes

“…In this study, no difference was observed between groups in tactile sensitivity, contrasting previous studies in rodents that have reported decreased mechanical paw withdrawal threshold following HFD feeding [32,49,56,57]. However, in those studies, increased tactile sensitivity was accompanied by changes in NCV measures while in our rats NCVs were not affected.…”

Amelioration of Both Central and Peripheral Neuropathy in Mouse Models of Type 1 and Type 2 Diabetes by the Neurogenic Molecule NSI-189

“…This finding was apparent in two separate studies using two different methods of corneal nerve quantification. There are multiple reports of corneal nerve depletion in rodent models of type 1 diabetes (13,45,46) and also in a model of type 2 diabetes produced by a high-fat diet to promote insulin resistance combined with low-dose STZ to reduce insulin levels (47). As corneal nerve loss is prevented by topical insulin in type 1 diabetic mice (45), it is plausible that the extreme hyperinsulinemia of db/db mice is sufficient to protect corneal nerves or promote sprouting from surviving fibers.…”

Diet-Induced Rodent Models of Diabetic Peripheral Neuropathy, Retinopathy and Nephropathy

“…Hence, animal models of diet-induced obesity (DIO) based on purified high fat or high fat/sugar diets (alone or combined with STZ-induced diabetic conditions) have been broadly used to replicate experimental DPN, as summarized in Table 1. Typically, chronic HFD/HFSD paradigms are key determinants for the progressive manifestation of behavioral and NCV's deficits as well as nerve structural impairments [21,44]. In fact, adult C57BL/6J mice fed a HFSD (24% from fat, 41% from carbohydrates (CH)) for 12 weeks display glucose intolerance as well as impairments in aforementioned neurological end-points, including behavioral (hindpaw thermal nociceptive response), NCV's (motor sciatic-posterior tibial nerve conduction and sensory digital nerve conduction velocities), as well as anatomic IENFD loss (immunoreactive hindpaw IEFND profile) [42,46].…”

“…Nevertheless, when hyperglycemia was induced in female obese rats (30 mg/kg STZ, i.p. ), sensory nerve density of the skin and cornea as well as thermal and mechanical sensitivity were more significantly impaired, likely reflecting the progressive nature of DPN evolution [44]. It is worth emphasizing the distinct sensitivity to pain between male and female rodents [47], as well as the effect of dietary salt supplementation on DPN hallmarks [45].…”