biostudies-literatureQiu XZhejiang Provincial Postdoctoral Science FoundationNational Key R&D Program of ChinaShuguang ProjectNatural Science Fund for Excellent Young Scholars of ChinaChina Postdoctoral Science FoundationNational Natural Science Foundation of ChinaShanghai Research Center for Endocrine and Metabolic DiseasesMajor Natural Science Project of the Scientific Research and Innovation Plan of Shanghai Municipal Commission of EducationInnovative research team of high-level local universities in ShanghaiZhejiang Provincial Natural Science FoundationConstruction Fund of Medical Key Disciplines of Hangzhoue177980https://www.ebi.ac.uk/biostudies/studies/S-EPMC12646663biostudies-literatureUnknown135(23)Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of β cell dysfunction in diabetes. Epigenetic mechanisms govern cellular glucose sensing and GSIS by β cells, but they remain incompletely defined. Here, we found that BAF60a functions as a chromatin regulator that sustains biphasic GSIS and preserves β cell function under metabolic stress conditions. BAF60a was downregulated in β cells from obese and diabetic mice, monkeys, and humans. β cell-specific inactivation of BAF60a in adult mice impaired GSIS, leading to hyperglycemia and glucose intolerance. Conversely, restoring BAF60a expression improved β cell function and systemic glucose homeostasis. Mechanistically, BAF60a physically interacted with Nkx6.1 to selectively modulate chromatin accessibility and transcriptional The Journal of clinical investigationBAF60a-dependent chromatin remodeling preserves β cell function and contributes to the therapeutic benefits of GLP-1R agonists.PMC126466632023ZKZD17LHDMD24H030001,LZ21H070001,LHDMD22H02001SHSMU-ZDCX2021270081722012No.2025HZZD06ZJ202211721SG112022ZZ010022018YFA0800403,2021YFC27019032022M72328482425012,92457301,32471170,91857110,81722012,82325010,82300893,82500965Shi MZhang RDing WQiu XWang QPiao HLZheng MGuo GChen WWang WMeng ZXWang RRJin LPan XYan JLi CYan SChen HLiang BZhang WHu CLuo PYang YJi XZhang ZFu HZhu LYan DWu QQZhu SfalseBAF60a-dependent chromatin remodeling preserves β cell function and contributes to the therapeutic benefits of GLP-1R agonists.Impaired glucose-stimulated insulin secretion (GSIS) is a hallmark of β cell dysfunction in diabetes. Epigenetic mechanisms govern cellular glucose sensing and GSIS by β cells, but they remain incompletely defined. Here, we found that BAF60a functions as a chromatin regulator that sustains biphasic GSIS and preserves β cell function under metabolic stress conditions. BAF60a was downregulated in β cells from obese and diabetic mice, monkeys, and humans. β cell-specific inactivation of BAF60a in adult mice impaired GSIS, leading to hyperglycemia and glucose intolerance. Conversely, restoring BAF60a expression improved β cell function and systemic glucose homeostasis. Mechanistically, BAF60a physically interacted with Nkx6.1 to selectively modulate chromatin accessibility and transcriptional 2025-01-01T00:00:00Z2025 Dec2026-06-05T19:13:04.449Z2026-05-20T03:14:51.705ZS-EPMC126466634105224610.1172/JCI177980