From Candy to Chemotherapy: Characterizing Sensory Neuropathy Associated with Prediabetes and Paclitaxel Treatment

Abstract

Peripheral neuropathy is one of the major co-morbidities associated with diabetes mellitus. Neurotoxic chemotherapies including paclitaxel also display significant risk of development of peripheral neuropathy. It is hypothesized that paclitaxel might also affect sensory neurons innervating the pancreas parenchyma, including the islets, disrupting insulin production. Overall, we evaluated several different aspects of somatic and visceral neuropathy in both animal models and human patients. In mice, we evaluated the effects of paclitaxel treatment on C57BL/6 mice as well as the use of ketogenic diet as a neuroprotective agent. We showed that paclitaxel caused mechanical allodynia as well as a reduction in pancreatic islet innervation. Paclitaxel also caused high fat diet-fed mice to develop increased weight gain and insulin instability. Consumption of a ketogenic diet prevented the paclitaxel-associated weight gain and fat deposition in male mice but did not appear to have an effect on glucose or insulin levels. In human patients, we evaluated the evaluated the lifestyle, metabolic, and epidermal changes in prediabetic patients with and without neuropathy through an ongoing clinical study. Prediabetic patients with neuropathy displayed a reduced intraepidermal nerve fiber density, higher neuropathy screening instrument scores, as well as lower LDL levels compared to prediabetic patients without neuropathy and healthy controls. Both pre-diabetes and chemotherapy lead to sensory nerve damage, and our results demonstrate that additional sensory nerve populations such as pancreatic afferents should be considered in the clinical evaluation of patients due to a more insidious presentation and long-term consequences on metabolic health.