ABSTRACT
Type 2 diabetes (T2D) affects approximately 537 million people worldwide. Peripheral neuropathy (PN) is the
most common complication of diabetes, affecting 60% of individuals with T2D. Glycemic control is the only PN
treatment, but it often fails to restore nerve function in T2D. Dyslipidemia is an independent risk factor for PN,
but there is a gap in our understanding of how it leads to nerve damage. Thus, there is a critical need to
understand mechanisms by which dyslipidemia promotes nerve injury in T2D to develop targeted, mechanism-
based therapies. The American Diabetes Association recommends diet and exercise to correct lipid profiles
and prevent PN in T2D. In addition to clinical data on exercise benefits in PN, we discovered that a dietary
reversal (DR) paradigm restores the nerve lipidome and nerve function in an established nongenetic model of
T2D and PN. These animals are fed a high fat diet (HFD) and treated with low dose streptozotocin (STZ) to
mirror the human condition. What remains unknown is the cellular and molecular mechanisms underlying the
restoration of nerve function. One mechanism by which diet and/or exercise mediate their beneficial effects in
metabolically active tissues is through the release of extracellular vesicles (EVs). EVs mediate intercellular
communication by transferring cargo containing proteins, lipids, and miRNA that support ATP production in
recipient tissues during bioenergetic stress. With respect to the peripheral nervous system, Schwann cells
(SCs) maintain nerve health through orchestrated metabolic communication via homeostatic EV transfer from
SCs to axons. We recently discovered that SC dysfunction promotes secretion of pathologic EVs carrying miR-
15b, a regulator of lipid metabolism, ATP levels, and neurodegeneration, leading to axonal damage and PN.
Our objective is to uncover the mechanisms underlying DR- and exercise- mediated improvements in PN,
focusing on SC-derived EVs, SC single-cell transcriptomics, and the overall effect on nerve lipid metabolism,
bioenergetics, and function. We hypothesize that following diet and/or exercise, SCs transfer homeostatic EVs
to axons and improve PN by normalizing nerve lipid metabolism and bioenergetics. To test this hypothesis, we
will 1) assess the effects of DR, voluntary exercise in a running wheel (Ex), and DR/Ex on T2D-induced SC
injury and nerve function to determine how T2D and/or the intervention(s) impact the SC-specific
transcriptome, SC EV cargo, and SC-axon crosstalk; 2) interrogate the effect of SC-derived EVs on neuronal
health in an in vitro PN model to identify mechanisms of EV-mediated SC-axon crosstalk through miRNA
changes, uncovering the contribution of SC-axon coupling to nerve damage and PN, and 3) determine how
SC-derived EVs contribute to PN in T2D mice to determine the roles of EVs and miR-15b in SC-axon crosstalk
and PN and confirm whether EVs and miR-15b are suitable for therapeutic targeting in PN. These studies will
have a significant impact by advancing our understanding of nerve injury mechanisms in T2D and identifying
SC-specific therapies for PN.
