Autonomous sensing of the insulin peptide by an olfactory G protein-coupled receptor modulates glucose metabolism

Along with functionally intact insulin, diabetes-associated insulin peptides are secreted by beta cells. By screening the expression and functional characterization of olfactory receptors (ORs) in pancreatic islets, we identified Olfr109 as the receptor that detects insulin peptides. The engagement of one insulin peptide, insB:9-23, with Olfr109 diminished insulin secretion through Gi-cAMP signaling and promoted islet-resident macrophage proliferation through a beta cell-macrophage circuit and a beta-arrestin-1-mediated CCL2 pathway, as evidenced by beta-arrestin-1(-/-) mouse models. Systemic Olfr109 deficiency or deficiency induced by Pdxl-Cre(+/-) Olfr109(fl/fl) specifically alleviated intra-islet inflammatory responses and improved glucose homeostasis in Akita- and high-fat diet (HFD)-fed mice. We further determined the binding mode between insB:9-23 and Olfr109. A pepducin-based Olfr109 antagonist improved glucose homeostasis in diabetic and obese mouse models. Collectively, we found that pancreatic beta cells use Olfr109 to autonomously detect self-secreted insulin peptides, and this detection arrests insulin secretion and crosstalks with macrophages to increase intra-islet inflammation.