The role the nervous system plays in modulating islet inflammation and diabetes pathogenesis has barely been examined. Recent papers suggest that changes in sensory innervation initiate autoimmune diabetes in mice, which is in line with the notion that sensory neurons contribute to inflammation in several chronic disorders. Thus, the local interactions between the immune system and nerves in the islet may be crucial for the progression of diabetes. We propose that pathological activation of sensory nerves creates a chronic inflammatory milieu in the islet that ultimately leads to autoimmunity in susceptible individuals. Excessive activation of sensory nerves, as it may occur during hyperglycemic stress or infection with diabetogenic viruses, may lead to deranged secretion of neurotransmitters that alters vascular and macrophage functions, promoting inflammation. Studies, however, are limited by the difficulty to visualize and manipulate these processes in vivo and longitudinally in the hardly accessible pancreatic islets. Here we propose to identify the pattern of sensory innervation of the pancreatic islet in health and diabetes, using techniques our laboratory developed recently. At the successful completion, this project will provide fundamental knowledge about how the sensory innervation of the islet changes during diabetes progression. This in turn will provide the basis for functional and interventional studies to understand the role of sensory nerves in diabetes pathogenesis.