ABSTRACT The long-term goal of this project is to identify how diet influences neuropathic pain. Painful diabetic neuropathy (PDN) is a common symptom of diabetes in which poor glucose regulation causes sensory afferent dysfunction, affecting 50% of diabetic patients within 25 years of their diagnosis. However, the mechanism by which dietary hyperglycemia causes sensory neuron dysfunction and eventual neurodegeneration is not completely known. This represents a significant gap in knowledge and an important unmet need, since type-2 diabetics are expected to represent the largest neuropathic pain population by 2030. Preliminary studies indicate that hyperglycemic conditions disrupt sensory neuronal autophagy, a process by which organelles and proteins are metabolized and recycled. Multiple studies in central nervous system structures have identified that autophagy is critical to neuronal health, such that inhibition of this process causes neurodegeneration. The objective of this proposal is to identify that hyperglycemic inhibition of autophagy produces painful diabetic neuropathy symptoms. Based on our preliminary findings and existing literature, our central hypothesis is that hyperglycemia inhibits autophagy in sensory neurons. This hypothesis will be addressed through two specific aims that (1) quantify the contribution of AMPK/mTOR signaling to hyperglycemic inhibition of autophagy and (2) determine whether increasing autophagy improves PDN in type-2 diabetes. The proposed study is innovative because it utilizes transgenic technology to manipulate autophagy in sensory neurons of rodents exposed to a translationally relevant model of type-2 diabetes. The contribution of this research is significant because it advances our understanding of mechanisms that contribute to type-2 diabetic neuropathic pain and perhaps other neuropathic conditions.