Pancreatic β-Cells Communicate With Vagal Sensory Neurons

Background And Aims: 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. Methods: We characterized the anatomical pattern of pancreatic sensory innervation by combining viral tracing, immunohistochemistry, and reporter mouse models. To assess the functional interactions of β-cells with vagal sensory neurons, we recorded Ca²⁺ responses in individual nodose neurons in vivo while selectively stimulating β-cells with chemogenetic and pharmacologic approaches. Results: We found that pancreatic islets are innervated by vagal sensory axons expressing Phox2b, substance P, calcitonin-gene related peptide, and the serotonin receptor 5-HT₃R. 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 β-cells and to pancreas infusion with serotonin, but were not sensitive to insulin. Responses to chemogenetic and pharmacologic stimulation of β-cells were blocked by a 5-HT₃R antagonist and were enhanced by increasing serotonin levels in β-cells. We further confirmed directly in living pancreas slices that sensory terminals in the islet were sensitive to serotonin. Conclusions: Our study establishes that pancreatic β-cells communicate with vagal sensory neurons, likely using serotonin signaling as a transduction mechanism. Serotonin is coreleased with insulin and may therefore convey information about the secretory state of β-cells via vagal afferent nerves.