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Our previous work identified specific expression of type IIB PKA in pancreatic beta cells. Based on these findings, we propose that type IIB PKA is involved in mediating the GPCR signalling in pancreatic beta cells.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>\n                      The glucagon-like peptide-1 (GLP-1) analogue liraglutide was administered to mice 30 min before glucose injection during an IPGTT, whereas the glucose levels and insulin levels were measured in wild-type and RII\u03b2-knockout mice. The isolated islets were subjected to both perifusion assay and static batch incubations following stimulation with liraglutide, glucagon and follicle-stimulating hormone (FSH). RNA-seq analysis was performed to identify molecular changes in islets with RII\u03b2 ablation. Both western blotting and quantitative PCR were employed to quantify the gene expression. Whole-cell patch-clamp recordings were conducted to measure K\n                      <jats:sub>ATP<\/jats:sub>\n                      and Ca\n                      <jats:sup>2+<\/jats:sup>\n                      currents. Insulin granule morphology and abundance were evaluated by electron microscopy and flow cytometry using EGFP-labelled Syncollin, respectively.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>\n                      RII\u03b2-knockout mice exhibited impaired glucose tolerance and attenuated insulin secretion in response to liraglutide. Islets isolated from RII\u03b2-knockout mice showed reduced insulin secretion following liraglutide stimulation. Similarly, RII\u03b2-ablated islets displayed decreased insulin secretion in response to both glucagon and FSH. Further mechanistic studies revealed that RII\u03b2 deficiency impaired liraglutide-mediated PKA signalling activation. Specifically, RII\u03b2-ablated beta cells exhibited reduced basal K\n                      <jats:sub>ATP<\/jats:sub>\n                      channel activity and lack of liraglutide-mediated channel inhibition. Multiple voltage-gated Ca\n                      <jats:sup>2+<\/jats:sup>\n                      channel genes were downregulated in RII\u03b2-ablated islets, leading to a mild reduction in basal Ca\n                      <jats:sup>2+<\/jats:sup>\n                      current and a significant decrease following liraglutide treatment. RII\u03b2-knockout beta cells also exhibited reduced insulin granule size, decreased total granule number and fewer granules docked at the plasma membrane.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusions\/interpretation<\/jats:title>\n                    <jats:p>Our results highlight type IIB PKA as a primary mediator of Gs-coupled receptor-potentiated insulin secretion, providing a new molecular framework for metabolic regulation research.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1007\/s00125-026-06781-8","type":"journal-article","created":{"date-parts":[[2026,6,23]],"date-time":"2026-06-23T17:21:11Z","timestamp":1782235271000},"page":"2585-2598","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Type IIB PKA serves as the primary effector of Gs-coupled receptor-potentiated insulin secretion in mice by orchestrating ion channels and granule phenotype"],"prefix":"10.1007","volume":"69","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-9341-2674","authenticated-orcid":false,"given":"Ying","family":"Liu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2453-2522","authenticated-orcid":false,"given":"Yunzhi","family":"Ni","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9012-1345","authenticated-orcid":false,"given":"Chuantong","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1239-2713","authenticated-orcid":false,"given":"Linling","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-9119-2745","authenticated-orcid":false,"given":"Yaojing","family":"Jiang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8446-4480","authenticated-orcid":false,"given":"Quanya","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8537-8701","authenticated-orcid":false,"given":"Bei","family":"Mao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3649-0497","authenticated-orcid":false,"given":"Chuxin","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhaoyun","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3600-2174","authenticated-orcid":false,"given":"Yehong","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0007-1879-838X","authenticated-orcid":false,"given":"Min","family":"He","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6897-4608","authenticated-orcid":false,"given":"Lei","family":"Xiao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1828-8765","authenticated-orcid":false,"given":"Yiming","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8321-1617","authenticated-orcid":false,"given":"Rui","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,6,23]]},"reference":[{"issue":"10","key":"6781_CR1","doi-asserted-by":"publisher","first-page":"2007","DOI":"10.1038\/s41591-022-02019-3","volume":"28","author":"M Van Name","year":"2022","unstructured":"Van Name M, Sherr J (2022) When insulin isn\u2019t enough: targeting glucagon in type 1 diabetes. 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Ye and W. Sun (Huashan Hospital of Fudan University, Shanghai) for their funding support and insightful discussions of this study.","order":1,"name":"Ethics","label":"Acknowledgements","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"The RNA-seq datasets have been submitted to NCBI Sequence Read Archive (SRA) and can be accessed via the following link:\n                      \n                      .","order":2,"name":"Ethics","label":"Data availability","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"This work was supported by Noncommunicable Chronic Diseases-National Science and Technology Major Project (grant no. 2023ZD0506800 to YML) and the National Natural Science Foundation of China (grant no. 82200949 to LF, grant no. 82300954 to Wanwan Sun).","order":3,"name":"Ethics","label":"Funding","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"The authors declare that there are no relationships or activities that might bias, or be perceived to bias, their work.","order":4,"name":"Ethics","label":"Authors\u2019 relationships and activities","group":{"name":"EthicsHeading","label":"Ethics"}},{"value":"RL designed the work. YL, YZN, CTX, YJJ, QYS, BM and CXH performed acquisition and analysis of data. RL, YML, LX, YHY, ZYZ, LLF and MH contributed to interpretation of data. RL drafted the manuscript. All authors reviewed the manuscript critically for important intellectual content and approved the final version. RL is the guarantor of this work.","order":5,"name":"Ethics","label":"Contribution statement","group":{"name":"EthicsHeading","label":"Ethics"}}]}}