Imada Tasuku, Sasaki Shugo, Yamaguchi Hiroki, Ueda Ayaka, Kawamori Dan, Katakami Naoto, Shimomura Iichiro
Department of Metabolic Medicine, Osaka University Graduate School of Medicine, Osaka, Japan.
Medical Education Center, Faculty of Medicine, Osaka University, Osaka, Japan.
J Diabetes Investig. 2025 Apr;16(4):584-597. doi: 10.1111/jdi.14410. Epub 2025 Jan 20.
AIMS/INTRODUCTION: Metformin treatment for hyperglycemia in pregnancy (HIP) beneficially improves maternal glucose metabolism and reduces perinatal complications. However, metformin could impede pancreatic β cell development via impaired mitochondrial function. A new anti-diabetes drug imeglimin, developed based on metformin, improves mitochondrial function. Here we examine the effect of imeglimin on β cell differentiation using human induced pluripotent stem cell (iPSC)-derived pancreatic islet-like spheroid (SC-islet) models.
Human iPSCs are differentiated into SC-islets by three-dimensional culture with and without imeglimin or metformin. Differentiation efficiencies of SC-islets 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-islets. SC-islets were cultured with proinflammatory cytokines, in part mimicking the uterus environment in HIP.
Metformin perturbed SC-islet differentiation while imeglimin did not alter it. Furthermore, imeglimin enhanced the gene expressions of β cell lineage markers. Maintenance of mitochondrial function and optimization of TGF-β and Wnt signaling were considered potential mechanisms for augmented β cell maturation by imeglimin. In the presence of proinflammatory cytokines, imeglimin ameliorated β cell differentiation impaired by cytokines and metformin.
Imeglimin does not perturb differentiation of SC-islet cells and rather enhances gain in β cell identity gene sets in contrast to metformin. This may lead to the improvement of in vitro β cell differentiation protocols.
目的/引言：二甲双胍用于治疗妊娠期高血糖（HIP）可有益地改善母体葡萄糖代谢并减少围产期并发症。然而，二甲双胍可能通过损害线粒体功能来阻碍胰腺β细胞发育。一种基于二甲双胍研发的新型抗糖尿病药物依美格列明可改善线粒体功能。在此，我们使用人诱导多能干细胞（iPSC）衍生的胰岛样球体（SC-胰岛）模型研究依美格列明对β细胞分化的影响。
人iPSC通过在有或无依美格列明或二甲双胍的情况下进行三维培养分化为SC-胰岛。通过流式细胞术、免疫染色、定量PCR和胰岛素分泌测定分析SC-胰岛的分化效率。获取RNA测序和氧消耗率以进一步表征SC-胰岛。SC-胰岛与促炎细胞因子一起培养，部分模拟HIP中的子宫环境。
二甲双胍扰乱SC-胰岛分化，而依美格列明未改变其分化。此外，依美格列明增强了β细胞谱系标志物的基因表达。线粒体功能的维持以及TGF-β和Wnt信号通路的优化被认为是依美格列明增强β细胞成熟的潜在机制。在促炎细胞因子存在的情况下，依美格列明改善了细胞因子和二甲双胍损害的β细胞分化。
与二甲双胍相反，依美格列明不会扰乱SC-胰岛细胞的分化，反而增强了β细胞身份基因集的获得。这可能会导致体外β细胞分化方案的改进。
