Abstract Diabetic neuropathy (DN) is characterized by the retraction of sensory axon terminals in the periphery from their targets with a “glove and stocking” pattern. The mechanisms of DN remain though, unclear, impairing successful therapeutic interventions. Unlike type 1 diabetes, type 2 diabetes is accompanied by a systemic metabolic dysfunction that may contribute to the development of DN. Many patients develop neuropathy while pre-diabetic and hyperlipidemia, hyperglycemia, and insulin resistance all impair membrane integrity, axon growth, and mitochondrial motility in sensory neurons. Another important hallmark of the metabolic syndrome is systemic low-grade inflammation involving inflammatory macrophages. Macrophages are major players in Wallerian degeneration and have roles in debris clearance as well as recovery from sciatic nerve injury and regeneration. Whether macrophages in the sciatic nerve contribute or react to diabetic neuropathy is unexplored. I find in preliminary data that pre-diabetic mice exhibit heat hyposensitivity and decreased skin innervation, especially for CGRP+ fibers. I also find that pre-diabetic mice have an increased sciatic nerve inflammation reminiscent of the immediate response to sciatic nerve injury including, CCL2 upregulation and CD68 increase in macrophages. Here, I propose to study if and how sciatic nerve macrophages contribute to diabetic neuropathy or react o axon degeneration. I hypothesize that SCN macrophages contribute to the pathogenesis of type 2 diabetic neuropathy. In the first aim, I will determine whether CCL2-driven recruitment of macrophages to the nerve contributes to the onset of heat hyposensitivity. In the second aim, I will determine whether the sustained increase in CD68+ macrophages/CCL2 signaling in the sciatic nerve contributes to the sustained denervation of the skin of pre-diabetic mice and whether the denervation can be rescued by CCR2 blockade. Finally, I will determine whether small unmyelinated c-fibers undergo injury transcriptional reprogramming and to what extent low-grade inflammation contributes to the DRG neuron transcriptional changes. This study will improve our understanding of if and how the immune system is involved in the development of peripheral neuropathies, which remains largely unknown. In addition, this study will also determine how similar diabetic neuropathy is to sciatic nerve injury models in terms of transcriptional reprogramming. The proposed work could open new therapeutic avenues for pre-diabetic neuropathy, a significant clinical challenge that is only increasing, and will improve our knowledge of how sensory neurons respond to metabolic dysfunction.