A Role for Fatty Acids in Peripheral Neuropathy Associated with Type 2 Diabetes and Prediabetes

Significance: As the global prevalence of diabetes rises, diabetic complications are also increasing at an alarming rate. Peripheral neuropathy (PN) is the most prevalent complication of diabetes and prediabetes, and is characterized by progressive sensory loss resulting from nerve damage. While hyperglycemia is the major risk factor for PN in type 1 diabetes (T1D), the metabolic syndrome (MetS) underlies the onset and progression of PN in type 2 diabetes (T2D) and prediabetes. Recent Advances: Recent reports show that dyslipidemia, a MetS component, is strongly associated with PN in T2D and prediabetes. Dyslipidemia is characterized by an abnormal plasma lipid profile with uncontrolled lipid levels, and both clinical and preclinical studies implicate a role for dietary fatty acids (FAs) in PN pathogenesis. Molecular studies further show that saturated and unsaturated FAs differentially regulate the nerve lipid profile and nerve function. Critical Issues: We first review the properties of FAs and the neuroanatomy of the peripheral nervous system (PNS). Second, we discuss clinical and preclinical studies that implicate the involvement of FAs in PN. Third, we summarize the potential effects of FAs on nerve function and lipid metabolism within the peripheral nerves, sensory neurons, and Schwann cells. Future Directions: Future directions will focus on identifying molecular pathways in T2D and prediabetes that are modulated by FAs in PN. Determining pathophysiological mechanisms that underlie the injurious effects of saturated FAs and beneficial properties of unsaturated FAs will provide mechanistic targets for developing new targeted therapies to treat PN associated with T2D and prediabetes. Antioxid. Redox Signal. 37, 560–577.