Imeglimin, unlike metformin, does not perturb differentiation of human induced pluripotent stem cells towards pancreatic ß-like cells and rather enhances gain in ß cell identity gene sets

Aims/Introduction: Metformin treatment for hyperglycemia in pregnancy (HIP) beneficially improves maternal glucose metabolism and reduces perinatal complications. However, metformin could impede pancreatic ß 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 ß cell differentiation using human induced pluripotent stem cell (iPSC)-derived pancreatic islet-like spheroid (SC-islet) models. Materials and Methods: 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. Results: Metformin perturbed SC-islet differentiation while imeglimin did not alter it. Furthermore, imeglimin enhanced the gene expressions of ß cell lineage markers. Maintenance of mitochondrial function and optimization of TGF-ß and Wnt signaling were considered potential mechanisms for augmented ß cell maturation by imeglimin. In the presence of proinflammatory cytokines, imeglimin ameliorated ß cell differentiation impaired by cytokines and metformin. Conclusions: Imeglimin does not perturb differentiation of SC-islet cells and rather enhances gain in ß cell identity gene sets in contrast to metformin. This may lead to the improvement of in vitro ß cell differentiation protocols. Overall design: mRNA profiles of human iPSC-derived ß-like cell spheroids treated with and without compounds at differentiation day 22