Influence of intermittent fasting on prediabetes-induced neuropathy: Insights on a novel mechanistic pathway

Maya Dannawi; Mansour E Riachi; Antony F Haddad; Mohamed El Massry; Mary Haddad; Pamela Moukarzel; Frédéric Harb; Hilda E Ghadieh; Assaad A Eid

doi:10.1016/j.metop.2022.100175

Influence of intermittent fasting on prediabetes-induced neuropathy: Insights on a novel mechanistic pathway

Metabol Open. 2022 Mar 13:14:100175. doi: 10.1016/j.metop.2022.100175. eCollection 2022 Jun.

Authors

Maya Dannawi^{1

2}, Mansour E Riachi^{1

2}, Antony F Haddad^{1

2}, Mohamed El Massry^{1

2}, Mary Haddad^{1

2}, Pamela Moukarzel^{1

2}, Frédéric Harb³, Hilda E Ghadieh^{1

2}, Assaad A Eid^{1

2}

Affiliations

¹ Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine and Medical Center, American University of Beirut, Beirut, Lebanon.
² AUB Diabetes, American University of Beirut, Faculty of Medicine, Medical Center, Lebanon.
³ Department of Life and Earth Sciences, Faculty of Sciences, Lebanese University, Fanar, Lebanon.

Abstract

Aims: Peripheral neuropathy (PN) is correlated with obesity and metabolic syndrome. Intermittent fasting (IF) has been described as the cornerstone in the management of obesity; however, its role in prediabetic complications is not well elucidated. Cytochromes P450 Monooxygenases (CYP450) are major sources of Reactive Oxygen Species (ROS) that orchestrate the onset and development of diabetic complications. One of the CYP-metabolites, Expoxyecosatetraenoic Acids (EETs), are considered to be negative regulators of ROS production. In this study, we elucidated the role of IF on ROS production and investigated its influence on prediabetes-induced PN.

Methods: C57/BL6 control mice, prediabetic, prediabetic that underwent alternate day fasting with different diet composition, and prediabetic mice treated with EET-metabolizing sEH-inhibitor, AUDA. Body mass composition, metabolic, behavioral, and molecular tests were performed.

Results: High-fat diet (HFD) led to an increase in NADPH-induced ROS production; that was due to an alteration in the epoxygenase pathway assessed by the decrease in CYP1a1/1a2 expression. IF reinstated the homeostatic levels of EETs in HFD-fed mice. Moreover, treatment with AUDA mimicked the beneficial effect observed with IF.

Conclusion: IF and EETs bioavailability have a protective role in prediabetes-induced PN, suggesting a novel interventional strategy in the management of prediabetes and its associated complications.

Keywords: Diabetes; Diabetic peripheral neuropathy; Intermittent fasting; Oxidative stress; Reactive oxygen species.