169-OR: Magnetogenetic Stimulation of Pancreatic Nerves Regulates Blood Glucose

There is substantial evidence that neural regulation plays a critical role in glucose metabolism and hormone release. Targeting neural populations innervating the pancreas could provide an alternative therapy for diabetes. However, our understanding of the precise physiological roles of pancreatic nerves is incomplete because we lack tools to study these populations in a non-invasive, targeted, temporally controlled manner. Here, we developed and validated a novel magnetogenetic neuromodulatory construct in vitro and in vivo then targeted defined pancreatic nerves to assess their roles in glucose metabolism and hormone secretion. The construct, coding for TRPV1 ion channel fused to a nanobody binding endogenous ferritin (NbTRPV1), was transfected into neural cell lines and primary neurons. Magnetic stimulation significantly increased intracellular calcium in cells expressing NbTRPV1. For in vivo delivery, the construct was packaged into AAV and infused into the pancreas through the pancreatic duct, using serotypes and promoters to target β cells or pancreatic nerves. Ex vivo calcium imaging confirmed magnet activation of pancreas-projecting neurons expressing NbTRPV1. In vivo, targeting NbTRPV1 to β cells improved glucose tolerance in male and female mice, validating the efficacy of this construct to regulate cell activity in the pancreas of freely moving mice. Magnet treatment of ChAT-CRE mice expressing NbTRPV1 in parasympathetic pancreatic neurons significantly improved glucose tolerance and increased insulin secretion. Conversely, targeting vagal sensory nerves from the pancreas in Advillin-iCRE mice impaired glucose tolerance with no significant effect on hormone secretion. These data demonstrate for the first time a method for remote, temporally controlled, targeted modulation of pancreatic islets and nerves to regulate blood glucose. This approach can be used to study the contribution of pancreatic nerves in a wide range of diseases, from diabetes to pancreatic cancer.