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

Cell Metab. 2022 Feb 1;34(2):240-255.e10. doi: 10.1016/j.cmet.2021.12.022.


Along with functionally intact insulin, diabetes-associated insulin peptides are secreted by β 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 β cell-macrophage circuit and a β-arrestin-1-mediated CCL2 pathway, as evidenced by β-arrestin-1-/- mouse models. Systemic Olfr109 deficiency or deficiency induced by Pdx1-Cre+/-Olfr109fl/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 β 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.

Keywords: GPCR; diabetes; insulin secretion; olfactory receptor.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blood Glucose / metabolism
  • Diet, High-Fat
  • Glucose / metabolism
  • Insulin / metabolism
  • Insulin-Secreting Cells* / metabolism
  • Islet Amyloid Polypeptide / metabolism
  • Islets of Langerhans* / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Receptors, G-Protein-Coupled / metabolism


  • Blood Glucose
  • Insulin
  • Islet Amyloid Polypeptide
  • Receptors, G-Protein-Coupled
  • Glucose