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However, metformin could impede pancreatic \u03b2 cell development via impaired mitochondrial function. A new anti\u2010diabetes drug imeglimin, developed based on metformin, improves mitochondrial function. Here we examine the effect of imeglimin on \u03b2 cell differentiation using human induced pluripotent stem cell (iPSC)\u2010derived pancreatic islet\u2010like spheroid (SC\u2010islet) models.<\/jats:p><\/jats:sec><jats:sec><jats:title>Materials and Methods<\/jats:title><jats:p>Human iPSCs are differentiated into SC\u2010islets by three\u2010dimensional culture with and without imeglimin or metformin. Differentiation efficiencies of SC\u2010islets were analyzed by flow cytometry, immunostaining, quantitative PCR, and insulin secretion assay. RNA sequencing and oxygen consumption rate were obtained for further characterization of SC\u2010islets. SC\u2010islets were cultured with proinflammatory cytokines, in part mimicking the uterus environment in HIP.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>Metformin perturbed SC\u2010islet differentiation while imeglimin did not alter it. Furthermore, imeglimin enhanced the gene expressions of \u03b2 cell lineage markers. Maintenance of mitochondrial function and optimization of TGF\u2010\u03b2 and Wnt signaling were considered potential mechanisms for augmented \u03b2 cell maturation by imeglimin. In the presence of proinflammatory cytokines, imeglimin ameliorated \u03b2 cell differentiation impaired by cytokines and metformin.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>Imeglimin does not perturb differentiation of SC\u2010islet cells and rather enhances gain in \u03b2 cell identity gene sets in contrast to metformin. This may lead to the improvement of <jats:italic>in vitro<\/jats:italic> \u03b2 cell differentiation protocols.<\/jats:p><\/jats:sec>","DOI":"10.1111\/jdi.14410","type":"journal-article","created":{"date-parts":[[2025,1,20]],"date-time":"2025-01-20T08:56:51Z","timestamp":1737363411000},"page":"584-597","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["Imeglimin, unlike metformin, does not perturb differentiation of human induced pluripotent stem cells towards pancreatic \u03b2\u2010like cells and rather enhances gain in \u03b2 cell identity gene sets"],"prefix":"10.1111","volume":"16","author":[{"given":"Tasuku","family":"Imada","sequence":"first","affiliation":[{"name":"Department of Metabolic Medicine Osaka University Graduate School of Medicine  Osaka 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