{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,24]],"date-time":"2026-02-24T10:20:52Z","timestamp":1771928452575,"version":"3.50.1"},"reference-count":60,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T00:00:00Z","timestamp":1769990400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:p>\n                    The core pathophysiological mechanism of type 2 diabetes mellitus (T2DM) is closely associated with gut microbiota dysbiosis and its consequential impairment of enteroendocrine glucagon-like peptide-1 (GLP-1) secretion. T2DM mouse model was established using high-fat diet (HFD) feeding combined with streptozotocin (STZ) administration. Diabetic mice received 30 or 60\u00a0mg\/kg of leonurine (LEO) via daily gavage for 12 weeks. Gut microbiota composition was profiled by metagenomic sequencing, fecal short chain fatty acids (SCFAs) concentrations were quantified via enzyme-linked immunosorbent assay (ELISA), and GLP-1 expression was assessed using oral glucose tolerance tests (OGTT), ELISA, and immunofluorescence.\n                    <jats:italic>In vitro<\/jats:italic>\n                    , high-glucose (25\u00a0mM)-challenged GLUTag enteroendocrine cells were employed to delineate the butyrate\u2013mitochondrial pyruvate carrier 2 (MPC2) regulatory network using qPCR and Western blotting. LEO intervention significantly ameliorated glucose intolerance in diabetic mice and elevated GLP-1 levels in serum and colonic tissues. Metagenomic analysis revealed that LEO (60\u00a0mg\/kg) remodeled gut microbiota structure, markedly enhancing \u03b1-diversity and specifically enriching butyrate-producing\n                    <jats:italic>Alistipes<\/jats:italic>\n                    . Mechanistically, butyrate activated MPC2 expression, effectively restoring cristae architecture defects observed by transmission electron microscopy, thereby promoting GLP-1 secretion. Crucially, MPC2 knockdown abrogated the secretagogue effect of butyrate on GLP-1 in GLUTag cells. LEO alleviates T2DM by remodeling the gut microbiota ecosystem, enhancing butyrate biosynthesis, and activating an MPC2-dependent mitochondrial energy metabolism pathway to reverse GLP-1 secretory dysfunction in intestinal L\u00a0cells. This study establishes MPC2-mediated mitochondrial functional repair as a core mechanism through which microbial metabolites regulate enteroendocrine hormone secretion, identifying a novel therapeutic target within the \u201cgut\u2013islet axis\u201d for diabetes intervention. Future studies should identify its active constituents, elucidate downstream effectors, and validate this mechanism in germ-free models.\n                  <\/jats:p>","DOI":"10.3389\/fphar.2026.1747267","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T11:04:05Z","timestamp":1770030245000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Leonurine ameliorates experimental type 2 diabetes through gut microbiota remodeling, enhanced butyrate production, and MPC2 activation to restore GLP-1 secretion"],"prefix":"10.3389","volume":"17","author":[{"given":"Yaoyuan","family":"Zhang","sequence":"first","affiliation":[{"name":"Department of General Practice, The Fifth Affiliated Hospital of Southern Medical University","place":["Guangzhou, Guangdong, China"]},{"name":"Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University","place":["Guilin, Guangxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wanyi","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of General Practice, The Fifth Affiliated Hospital of Southern Medical University","place":["Guangzhou, Guangdong, China"]},{"name":"Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University","place":["Guilin, Guangxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xinyuan","family":"Yu","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Institute of Traditional Chinese Medicine & Natural Products, College of Pharmacy, Jinan University","place":["Guangzhou, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jianhua","family":"Feng","sequence":"additional","affiliation":[{"name":"Department of General Practice, The Fifth Affiliated Hospital of Southern Medical University","place":["Guangzhou, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Abdul","family":"Sammad","sequence":"additional","affiliation":[{"name":"Department of General Practice, The Fifth Affiliated Hospital of Southern Medical University","place":["Guangzhou, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zhenbo","family":"Wang","sequence":"additional","affiliation":[{"name":"Department of General Practice, The Fifth Affiliated Hospital of Southern Medical University","place":["Guangzhou, Guangdong, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kai","family":"Yin","sequence":"additional","affiliation":[{"name":"Department of General Practice, The Fifth Affiliated Hospital of Southern Medical University","place":["Guangzhou, Guangdong, China"]},{"name":"Guangxi Key Laboratory of Diabetic Systems Medicine, Guilin Medical University","place":["Guilin, Guangxi, China"]}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2026,2,2]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"678","DOI":"10.1080\/13813455.2023.2258559","article-title":"Berberine-induced glucagon-like peptide-1 and its mechanism for controlling type 2 diabetes mellitus: a comprehensive pathway review","volume":"130","author":"Araj-Khodaei","year":"2024","journal-title":"Arch. 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