{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,19]],"date-time":"2026-02-19T02:06:42Z","timestamp":1771466802192,"version":"3.50.1"},"reference-count":48,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T00:00:00Z","timestamp":1744156800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82360035 82260854 82060738"],"award-info":[{"award-number":["82360035 82260854 82060738"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Pharmacol."],"abstract":"<jats:sec><jats:title>Introduction<\/jats:title><jats:p>Traditional Chinese Medicine (TCM) theory posits that type 2 diabetes mellitus (T2DM) characterized by Qi and Yin deficiency, is associated with elevated blood lipid levels. The Xinmaitong formula (XMT) is a folk remedy believed to lower blood lipid levels. However, the functional components and molecular mechanisms through which XMT exerts its anti-diabetic effects remain to be elucidated. This study aimed to investigate the therapeutic effects and potential mechanisms of XMT in the treatment of T2DM, focusing on the glucagon-like peptide-1 receptor (GLP-1R) signaling pathway.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>A TCM formula that promotes GLP-1R expression was screened using a GLP-1R promoter-dependent luciferase reporter gene vector (PGL3-GLP-1R-luc). The T2DM mouse model was established using a high-fat diet and streptozotocin (STZ). Blood glucose levels were measured using a glucometer and oral glucose tolerance test (OGTT). Serum biochemical parameters and insulin levels were also assessed. Organ pathology in mice was evaluated using hematoxylin and eosin (H&amp;amp;E) staining. Immunofluorescence (IF) was employed to observe changes in insulin and GLP-1R expression in the pancreas of mice. The effects of medicated serum on Min6 cell growth were examined using a methyl thiazolyl tetrazolium (MTT) assay. A Min6 cell injury model was established to detect cAMP and Ca<jats:sup>2+<\/jats:sup> concentrations. Ultra high-performance liquid chromatography-mass spectrometry (UHPLC-MS) was used to identify blood-absorbed components of XMT.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Luciferase reporter constructs driven by GLP-1R promoter response elements analysis identified that TCM formula XMT promoted GLP-1R expression. <jats:italic>In vivo<\/jats:italic> experiments demonstrated that XMT significantly reduced fasting blood glucose levels in T2DM mice and improved OGTT results. It also exhibited protective effects on islet tissues, notably increasing GLP-1R expression and insulin secretion in the pancreas. Biochemical markers indicated no significant adverse effects on liver or kidney function following XMT administration. After treatment with palmitic acid (PA), GLP-1R expression in Min6 cells was significantly decreased. However, treatment with XMT upregulated GLP-1R expression. Additionally, cyclic adenosine monophosphate (cAMP) and Ca<jats:sup>2+<\/jats:sup> exhibited substantial improvements, and the key pancreatic growth protein PDX1 was activated.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>XMT exerts hypoglycemic effects by upregulating GLP-1R gene expression, enhancing GLP-1R protein synthesis, and subsequently promoting cAMP release. This process activates Ca<jats:sup>2+<\/jats:sup> influx in pancreatic \u03b2-cells, triggering insulin exocytosis from islet cells.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fphar.2025.1575450","type":"journal-article","created":{"date-parts":[[2025,4,9]],"date-time":"2025-04-09T05:22:45Z","timestamp":1744176165000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":1,"title":["Therapeutic effects and mechanisms of Xinmaitong formula for type 2 diabetes mellitus via GLP-1R signaling"],"prefix":"10.3389","volume":"16","author":[{"given":"Weidong","family":"Pu","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yang","family":"Pan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kang","family":"Yang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jian","family":"Gao","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fen","family":"Tian","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jingrui","family":"Song","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yubing","family":"Huang","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yanmei","family":"Li","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1965","published-online":{"date-parts":[[2025,4,9]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"103627","DOI":"10.1016\/j.drudis.2023.103627","article-title":"Mechanistic insights into the beneficial effects of curcumin on insulin resistance: opportunities and challenges","volume":"28","author":"Balakumar","year":"2023","journal-title":"Drug Discov. 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