SENSORY NEURON INSULIN SIGNALING AND ITS ROLE IN DIABETIC NEUROPATHY

Abstract

Diabetes is a global concern; approximately 366 million people are currently diagnosed worldwide. Complications of diabetes are numerous and can cause damage to almost every organ system in the body. Neuropathy is the most common complication associated with diabetes and severely impacts patients' quality of life. Diabetic neuropathy (DN) most commonly present as a distal symmetric polyneuropathy with a dichotomous presentation of either peripheral insensitivity or chronic pain. Eventually, patients can develop injury unawareness and foot ulcers, often resulting in amputation. Clearly establishing the mechanisms of diabetes-induced nerve damage will drive the development of more targeted and appropriate treatments. The pathogenesis of DN is multifactorial and the majority of research currently focuses on the toxic pathways induced by hyperglycemia. Interestingly though, insulin has been recently characterized to have direct effects on sensory neurons and is now believed to be a neurotrophic factor that is required for proper development, growth, and maintenance of the nervous system. Here, we tested the hypothesis that reduced sensory neuron insulin signaling contributes to DN pathogenesis via disrupted neurotrophic support. Results demonstrate that PI3K-Akt pathway activation in sensory neurons is insulin dose dependent and that insulin supplementation increases neurite outgrowth, establishing that sensory neurons are insulin responsive. These responses are blunted in type 2 diabetic mice, indicating that sensory neurons demonstrate signs of insulin resistance similar to muscle, liver, and adipose. However, sensory neuron insulin receptor knockout (SNIRKO) mice that maintain euglycemia do not display signs of DN. Suggesting that a disruptions solely in sensory neuron insulin signaling does not cause DN. Surprisingly though, SNIRKO mice are hyperinsulinemic and pancreatic islets from SNIRKO mice display increased insulin content, suggesting a possible feedback mechanism between sensory neuron insulin signaling and insulin production. These results are consistent with a recently described novel pathway of pancreatic beta cell regulation via sensory neuron neuropeptides. In conclusion, while sensory neurons are insulin responsive, reductions in sensory neuron insulin signaling without hyperglycemia does not cause signs of DN and it is most likely the combination of reduced insulin support and glucose neurotoxicity. Furthermore, the generation of SNIRKO mice has outlined a possible feedback mechanism through which sensory neurons modulate insulin production that could possible aid in establishing new therapeutic avenues for the treatment of diabetes