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Luciferase reporter assay was performed to identify miR binding sites in the 3\u2019-untranslated region (3\u2019 UTR) of PGC-1\u03b1. In &lt;i&gt;db\/db&lt;\/i&gt; mice, miRNA-encapsulated adenoviruses were administered and intraperitoneal glucose tolerance test and glucose stimulated insulin secretion tests were performed. For enhanced delivery to \u03b2-cells, we developed exendin-4 (Ex-4) coated cationic lipoparticles (CCLs) encapsulating miRNAs. The therapeutic potential of Ex-4-CCL-miRNA was further evaluated in insulin-producing cells derived from induced pluripotent stem cells.Results: By analyzing miRNA expression in primary rat islets exposed under hyperglycemic environment, we identified miR-374 as a potential target. &lt;i&gt;In vitro&lt;\/i&gt; experiments confirmed that miR-374 significantly suppressed PGC-1\u03b1 expression in \u03b2-cells and hepatocytes by binding to its 3\u2019-UTR. &lt;i&gt;In vivo&lt;\/i&gt; experiments using adenovirus-mediated miR-374 (Ad-miR-374) delivering directly to the pancreas and liver of &lt;i&gt;db\/db&lt;\/i&gt; mice demonstrated improved glycemic control, enhanced insulin secretion, and downregulated hepatic gluconeogenesis-related genes (&lt;i&gt;G6Pase, Pepck, PC&lt;\/i&gt;). To enhance the clinical applicability of miR-374, we developed Ex-4-CCLs. Ex-4-CCL-miR-374 successfully alleviated hyperglycemia, restored pancreatic islet function, and decreased gluconeogenesis gene expression in &lt;i&gt;db\/db&lt;\/i&gt; mice. Furthermore, Ex-4-CCL-miR-374 improved insulin secretory function in glucotoxicity-exposed human induced pluripotent stem cell-derived insulin producing cells.Conclusion: Based on these findings, we propose that Ex-4-CCL-miR-374 as a promising therapeutic approach to reverse \u03b2-cell dysfunction and improve hepatic insulin resistance in type 2 diabetes mellitus.<\/jats:p>","DOI":"10.4093\/dmj.2025.0287","type":"journal-article","created":{"date-parts":[[2025,11,3]],"date-time":"2025-11-03T07:56:16Z","timestamp":1762156576000},"page":"535-551","update-policy":"https:\/\/doi.org\/10.4093\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Targeting PGC-1\u03b1 by miRNA-374 Simultaneously Improve \u03b2-Cell Dysfunction and Suppress Hepatic Glucose Overproduction"],"prefix":"10.4093","volume":"50","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3806-4873","authenticated-orcid":true,"given":"Ji-Won","family":"Kim","sequence":"first","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea"},{"name":"Bio-Core Facility Center for Personalized Cell and Immune Therapy, Catholic Medical Center, The Catholic University of Korea, Seoul, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0533-9786","authenticated-orcid":true,"given":"Joonyub","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Young-Hye","family":"You","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chan-Hee","family":"Oh","sequence":"additional","affiliation":[{"name":"Department of Bio and Brain Engineering, Korea Advanced Institute of Science and Technology, Daejeon, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Heon-Seok","family":"Park","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, Department of Internal Medicine, College of Medicine, The Catholic University of Korea, Seoul, Korea"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eun Young","family":"Lee","sequence":"additional","affiliation":[{"name":"Division of Endocrinology and Metabolism, 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