Destroying visceral sensory nerves impacts pancreatic islet function, glucose metabolism and diabetes onset, but how islet endocrine cells interact with sensory neurons has not been studied.We characterized the anatomical pattern of pancreatic sensory innervation by combining viral tracing, immunohistochemistry, and reporter mouse models. To assess the functional interactions of beta cells with vagal sensory neurons, we recorded Ca2+ responses in individual nodose neurons in vivo while selectively stimulating beta cells with chemogenetic and pharmacologic approaches.We found that pancreatic islets are innervated by vagal sensory axons expressing Phox2b, substance P, calcitonin-gene related peptide, and the serotonin receptor 5HT3R. Centrally, vagal neurons projecting to the pancreas terminate in the commissural nucleus of the solitary tract. Nodose neurons responded in vivo to chemogenetic stimulation of beta cells and to pancreas infusion with serotonin, but were not sensitive to insulin. Responses to chemogenetic and pharmacological stimulation of beta cells were blocked by a 5HT3R antagonist and were enhanced by increasing serotonin levels in beta cells. We further confirmed directly in living pancreas slices that sensory terminals in the islet were sensitive to serotonin.Our study establishes that pancreatic beta cells communicate with vagal sensory neurons, likely using serotonin signaling as a transduction mechanism. Serotonin is co-released with insulin and may therefore convey information about the secretory state of beta cells via vagal afferent nerves.

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