Impact of intermittent fasting on prediabetes-induced neuropathy : insights on a novel mechanistic pathway

Abstract

Background: Prediabetes, also known as intermediate hyperglycemia, is an alarming precursor of type 2 diabetes mellitus, which is fraught with complications. Peripheral neuropathy is one major complication that is a cause of disability worldwide. A growing body of literature links prediabetes, obesity and metabolic syndrome to the risk of both diabetic peripheral neuropathy (DPN) and cryptogenic sensory peripheral neuropathy (CSPN). Lifestyle changes are key in the management of prediabetes. Recent data suggest that intermittent fasting is the cornerstone in the management of obesity, however, its role in prediabetic complications is not well described. Furthermore, the mechanism of action by which intermittent fasting exert its metabolic role remains to be poorly investigated. Reactive oxygen species production (ROS) has been described as the final common signaling pathway orchestrating the onset and development of complications. Moreover, increasing evidence in both experimental and clinical studies suggests that oxidative stress plays a major role in the pathogenesis of diabetes and its different complications. Cytochromes P450 monooxygenases, especially those involved in the epoxygenase pathways controlling EETs production, are considered to be a negative regulator of ROS production. Nevertheless, this role has not been fully interrelated to peripheral neuropathy. Aim: In this study we investigated the influence of intermittent fasting on prediabetes-induced peripheral neuropathy. Furthermore, we explored the cellular and molecular mechanistic pathways by which intermittent fasting exerts its effect. Methods: C57-BL6 mice were recruited and prediabetes was induced by high calories-high fat diet feeding. After 8 weeks of high calories-high fat diet feeding, mice were exposed to a protocol of alternate day fasting. They were divided as follows: 1control mice (14.1 kcalpercent fat), 2control prediabetic mice (60 kcalpercent fat), prediabetic mice that underwent an alternate day fasting protocol with different types of d