Mechanisms of Nerve Injury in Diabetes: Dyslipidemia, Bioenergetics, and Oxidative Damage

Peripheral neuropathy (PN) is a common complication in patients with metabolic dysfunction, including obesity, prediabetes, and type 2 diabetes. Standard management consists of controlling hyperglycemia, which only modestly prevents PN development in obese and type 2 diabetes patients. Thus, PN still lacks effective disease-modifying treatments. The emergence of additional PN risk factors centered on the metabolic syndrome and its components, obesity and dyslipidemia, from multiple large diabetes clinical studies advocates a focus on lipid-centric pathomechanisms in addition to the traditional glucose-centric view of PN. This chapter will provide a brief overview of the clinical evidence that associates obesity and dyslipidemia with PN, followed by a generalized discussion of mitochondrial bioenergetics and dynamics as key and essential components of metabolism in the nerve. Next, preclinical and clinical studies that provide insight on the influence of bioenergetics failure, dyslipidemia specifically on lipogenesis, and impaired mitochondrial function and transport in the nerve will be covered. Emphasis will also be given to axo-glial metabolic communication and its role in preserving normal nerve bioenergetics, in light of the mounting interest of the noncell autonomous nature of PN. Finally, this chapter will conclude with the most promising therapeutic avenues for PN based on the lipid-centric view, particularly persons with type 2 diabetes.