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Here, a critical role of LGR4 is demonstrated in islet \u03b2 cell mass using a group of transgenic mice with LGR4 deficiency. Knock\u2010out of\n                    <jats:italic>Lgr4<\/jats:italic>\n                    in the pancreas and islet \u03b2 cells significantly reduced islet \u03b2 cell mass, and subsequently impaired glucose metabolism upon the challenge of a high\u2010fat diet. Deficiency of LGR4 in these mice or in cultured INS\u20101 cells showed a significant reduction in islet \u03b2 cell proliferation measured by Ki\u201067, EdU, and CCK\u20108 assay. Increase of islet \u03b2 cell proliferation induced by Rspondin\u2010LGR4 signaling occurred via Wnt\u2010\u03b2\u2010catenin\u2010\n                    <jats:italic>Ccnd1<\/jats:italic>\n                    axis. In addition, the deficiency of LGR4 in islet \u03b2 cells significantly increased apoptosis. Inhibition of RANKL\u2010RANK signaling by the TRAF\u2010STOP inhibitor significantly attenuated apoptosis of cultured INS\u20101 cells induced by deficiency of LGR4. Overall, this work shows that deficiency of LGR4 reduces islet \u03b2 cell mass via suppression of proliferation and concurrent increase of apoptosis. LGR4 in pancreatic islets is thus critical for the control of glucose homeostasis.\n                  <\/jats:p>","DOI":"10.1002\/advs.202508858","type":"journal-article","created":{"date-parts":[[2025,8,14]],"date-time":"2025-08-14T14:33:02Z","timestamp":1755181982000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Deficiency of Leucine\u2010Rich Repeat Containing G Protein\u2010Coupled Receptor 4 in Pancreas Reduces \u03b2 Cell Mass"],"prefix":"10.1002","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6112-1592","authenticated-orcid":false,"given":"Chao","family":"Luo","sequence":"first","affiliation":[{"name":"Department of Physiology and Pathophysiology School of Basic Medical Sciences State Key Laboratory of Vascular Homeostasis and Remodeling Peking University  Beijing 100191 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