Treatment for Diabetic Peripheral Neuropathy: What have we Learned from Animal Models?

Abstract

INTRODUCTION: Animal models have been widely used to investigate the etiology and potential treatments for diabetic peripheral neuropathy. What we have learned from these studies and the extent that this information has been adaptable to the human condition will be the subject of this review article. METHODS: A comprehensive search of the PubMed database was performed, and relevant articles on the topic were included in this review. RESULTS: Extensive study of diabetic animal models has shown that the etiology of diabetic peripheral neuropathy is complex, with multiple mechanisms affecting neurons, Schwann cells, and the microvasculature all contributing to the phenotypic nature of this most common complication of diabetes. Moreover, animal studies have demonstrated that the mechanisms related to peripheral neuropathy occurring in type 1 and type 2 diabetes are likely different, with hyperglycemia being the primary factor for neuropathology in type 1 diabetes and contributing to a lesser extent in type 2 diabetes, where insulin resistance, hyperlipidemia, and other factors may have a greater role. Two of the earliest mechanisms described from animal studies as a cause for diabetic peripheral neuropathy were the activation of the aldose reductase pathway and increased non-enzymatic glycation. However, continuing research has identified numerous other potential factors that may contribute to diabetic peripheral neuropathy, including; oxidative and inflammatory stress, dysregulation of protein kinase C and hexosamine pathways, and decreased neurotrophic support. In addition, recent studies have demonstrated that peripheral neuropathy-like symptoms are present in animal models representing pre-diabetes in the absence of hyperglycemia. CONCLUSIONS: This complexity complicates the identification of successful treatment of diabetic peripheral neuropathy and has likely been a factor in the poor outcome of translating successful treatments from animal studies to human clinical trials.