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

Cheng, J.; Yang, Z.; Ge, X.-Y.; Gao, M.-X.; Meng, R.; Lin, J.-Y.; Tian, Z.-M.; Xu, Y.-F.; Yang, F.; Sun, J.-P.; Yu, X.

doi:10.1101/2020.12.18.423228

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bioRxiv · 10.1101/2020.12.18.423228

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

Cheng, J.·Yang, Z.·Ge, X.-Y.·Gao, M.-X.·Meng, R.·Lin, J.-Y.·Tian, Z.-M.·Xu, Y.-F.·Yang, F.·Sun, J.-P.·Yu, X.

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Abstract

Along with functionally intact insulin, diabetes-associated insulin peptides are secreted by {beta} cells(1-3). By screening the expression and functional characterization of olfactory receptors in pancreatic islets, we identified Olfr109 as the receptor to detect insulin peptides. Engagement of one insulin peptide, insB:9-23, with Olfr109 diminished insulin secretion through Gi-cAMP signalling and promoted macrophage proliferation. Remarkably, Olfr109 deficiency alleviated intra-islet inflammatory responses and improved glucose homeostasis in Akita- and HFD-fed mice. We further determined the binding mode between the 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 crosstalk with macrophages to increase intra-islet inflammation.

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Cheng, J., Yang, Z., Ge, X.-Y., Gao, M.-X., Meng, R., Lin, J.-Y., Tian, Z.-M., Xu, Y.-F., Yang, F., Sun, J.-P., Yu, X.. 2020-12-19. Autonomous sensing the insulin peptide by an olfactory G protein coupled receptor modulates glucose metabolism. https://doi.org/10.1101/2020.12.18.423228

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