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

By Jie Cheng, Zhao Yang, Xiao-Yan Ge, Ming-Xin Gao, Ran Meng, Jing-Yu Lin, Zhao-Mei Tian, Yun-Fei Xu, Fan Yang, Jin-Peng Sun, Xiao Yu

Posted 19 Dec 2020
bioRxiv DOI: 10.1101/2020.12.18.423228

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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