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Selective activation of TRPV1+ sensory neurons in the pancreas halts islet autoimmunity and restore normoglycemia in Diabetic Non‐Obese Diabetic (NOD) mice

Hyperglycemia, as a result of autoimmune destruction of insulin‐producing beta cells, is the clinical outcome in human type‐1 diabetics and in the NOD mouse model. Our lab recently reported that NOD mice possess a hypo‐functional mutation in the Transient Receptor Potential Vanilloid 1 (TRPV1), which is expressed on a major subset of sensory neurons and is associated with increased beta cell stress and T‐cell autoimmunity. Here, we demonstrate that TRPV1+ sensory innervations in the pancreas receive input from cutaneous thoracic 8–11 nerves on the chest wall. Stimulation of intercostal nerves by surgical transection or the application of a TRPV1 agonist directly on the axons triggers the release of vasodilatory neuropeptides (ex. Substance P) in the pancreas, as indicated by an increase in Evans Blue plasma extravasation. Surprisingly, nerve stimulation induces an acute (6–12 hr post) wave of T‐cell apoptosis in islet infiltrates and pancreas‐draining lymph node (pLN) in NOD.BDC2.5 T‐cell receptor transgenics and NOD wild‐type mice. Further analysis reveals a skewing of the ratio between pathogenic and regulatory T‐cells in the pLN to a more protective phenotype. Lastly, nerve stimulation restores long‐term normoglycemia in diabetic NOD mice, especially during the early phase of overt disease. Stimulation of TRPV+ neurons may be a novel therapy in Type‐1 Diabetes. Y.C. is supported by a CIHR studentship.