Molecules and Cells

Korean Society for Molecular and Cellular Biology (한국분자세포생물학회)
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ER stress and unfolded protein response (UPR) signaling modulate GLP-1 receptor signaling in the pancreatic islets

  • Yurong Gao (Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST)) ;
  • Hanguk Ryu (Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST)) ;
  • Hyejin Lee (Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST)) ;
  • Young-Joon Kim (Department of Life Sciences, Gwangju Institute of Science and Technology (GIST)) ;
  • Ji-Hye Lee (Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST)) ;
  • Jaemin Lee (Department of New Biology, Daegu Gyeongbuk Institute of Science and Technology (DGIST))
  • Received : 2023.08.14
  • Accepted : 2023.10.26
  • Published : 2024.01.31
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Abstract

Insulin is essential for maintaining normoglycemia and is predominantly secreted in response to glucose stimulation by β-cells. Incretin hormones, such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide, also stimulate insulin secretion. However, as obesity and type 2 diabetes worsen, glucose-dependent insulinotropic polypeptide loses its insulinotropic efficacy, whereas GLP-1 receptor (GLP-1R) agonists continue to be effective owing to its signaling switch from Gs to Gq. Herein, we demonstrated that endoplasmic reticulum (ER) stress induced a transition from Gs to Gq in GLP-1R signaling in mouse islets. Intriguingly, chemical chaperones known to alleviate ER stress, such as 4-PBA and TUDCA, enforced GLP-1R's Gq utilization rather than reversing GLP-1R's signaling switch induced by ER stress or obese and diabetic conditions. In addition, the activation of X-box binding protein 1 (XBP1) or activating transcription factor 6 (ATF6), 2 key ER stress-associated signaling (unfolded protein response) factors, promoted Gs utilization in GLP-1R signaling, whereas Gq employment by ER stress was unaffected by XBP1 or ATF6 activation. Our study revealed that ER stress and its associated signaling events alter GLP-1R's signaling, which can be used in type 2 diabetes treatment.

Keywords

Acknowledgement

This study was supported by a grant from the Korean Diabetes Association to J.L. (G.D.H., 2023F-1) and the Daegu Gyeongbuk Institute of Science and Technology R&D Program and Basic Science Research Program through the National Research Foundation of Korea funded by the Ministry of Science and ICT and Ministry of Education to J.L. (22-CoE-BT-04, NRF-2019R1A4A102972413, and NRF-2020M3A9D8038660), Y.-J.K (2019R1A4A102972413), and J.-H.L. (NRF-2019R1A6A3A01094138).

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