Over the course of disease progression, half of adults with type II diabetes also develop diabetic peripheral neuropathy (DPN), peripheral nerve damage precipitated by the downstream metabolic effects of hyperglycemia, insulin resistance, and dyslipidemia. This multifactorial pathogenesis of DPN leads to various structural and physiological changes within the nerve, ultimately causing nerve fiber death and manifesting in symptoms such as pain, paresthesia, numbness, and temperature sensitivity in the extremities. If left unregulated, more severe outcomes including foot ulceration and amputation can also occur. Furthermore, by the time symptoms of DPN are present, nerve damage is largely irreversible, making early detection and intervention essential. Methods of early diagnosis have greatly improved the prognosis of DPN by evaluating end-organ small nerve fiber loss. However, other than nerve biopsies, which often result in further impairment, there are no clinical tests that are able to assess early pathology within the nerve itself. In this dissertation I propose the evaluation of peripheral nerve extracellular matrix (ECM) remodeling with mechanical properties, such as stiffness, as a novel method of early detection in DPN.

Alterations within the ECM of biological tissues are known to occur early in diabetes and are frequently observed in the histopathology and genetic profiling of DPN. As peripheral nerve ECM is composed primarily of collagen and other fibrillar proteins with stiffnesses orders of magnitude greater than nerve as a whole, changes to the ECM are likely correlated with changes in nerve stiffness. In this dissertation, although I found no differences in ex vivo sciatic nerve stiffness or ECM structure between diabetic mice and controls, I believe differences could still be significant at more distal locations or in sensory nerves as they are typically the first to be affected by DPN. Indirect evaluation of peripheral nerve stiffness was also assessed in vivo with a more clinically applicable approach using ultrasound shear wave (SW) elastography, a non-invasive technique that measures SW velocity through soft tissue. However, while it has previously been shown that nerve SW velocity is greater in patients with DPN, it remains unknown what SW velocity is truly measuring. In passive skeletal muscle for instance, SW velocity is highly correlated with stiffness, but also tension. In this project, I seek to characterize the individual effects of both of stiffness and tension on SW velocity, as knowing these relationships is crucial to determining the best clinical applications for ultrasound SW elastography and for interpreting results. My findings in unimpaired feline nerves suggest that SW velocity can be used to predict both stiffness and tension, but that the relationship is stronger between tension and SW velocity. Finally, I underscore the physiologically relevant effects of tension on young adult and unimpaired feline nerve SW velocity in this dissertation by indirectly by manipulating limb position.