MAFB is essential for the maintenance of adult human α-cell identity and glucagon secretion

Dysregulated hormone secretion and erosion of endocrine cell identity are features of type 1 and type 2 diabetes, but the transcriptional programs maintaining adult human islet identity and function remain poorly defined. The large MAF transcription factor MAFB is expressed in human α- and β-cells, marks their most functionally mature subpopulations, and is downregulated in diabetes, but its role in adult human islets has not been tested directly. Using shRNA-mediated MAFB knockdown (KD) in whole and CD26 ⁺ α-cell-enriched human pseudoislets, we found that whole pseudoislet MAFB KD impaired glucagon synthesis and secretion while only modestly reducing insulin content and cAMP-potentiated insulin release. Single-cell profiling detected no β-cell transcriptional response beyond MAFB KD itself, consistent with buffering by the related β-cell-enriched MAFA transcription factor. In contrast, α-cell-restricted MAFB KD unmasked a cell-autonomous requirement for MAFB in stimulus-secretion coupling. MAFB deficiency also destabilized α-cell identity, downregulating canonical α-cell and neuroendocrine secretory genes while ectopically inducing mesenchymal and extracellular matrix remodeling programs. In addition, MAFB-dependent downregulation of electron transport chain genes was confined to a large α-cell subcluster, manifesting as impaired islet-wide mitochondrial respiration within the broader α-cell population. Together, these findings identify MAFB as an essential adult human α-cell maintenance factor that links diabetes-associated downregulation to impaired glucagon secretion, α-cell identity erosion, and mitochondrial dysfunction.

What is already known about this subject? MAFB is expressed in adult human α- and β-cells, marks their most functionally mature subpopulations, and is downregulated in type 1 and type 2 diabetesIn human stem cell models, MAFB is essential for generating insulin-producing β-like cells, whereas glucagon-producing α-like cells are reduced but still formedNeither model addresses adult human islets: rodent MafB becomes α-cell restricted after birth, and stem cell models capture differentiation, not maintenance What is the key question? Is MAFB required to maintain identity and secretory function in adult human islet cells? What are the new findings? MAFB knockdown in primary human pseudoislets impaired glucagon synthesis and secretion but minimally affected β-cells, consistent with buffering by MAFAKnockdown in CD26+ α-cell-enriched pseudoislets revealed a cell-autonomous requirement for MAFB in stimulus-secretion coupling, and destabilized α-cell identity by inducing mesenchymal and extracellular matrix programsMAFB loss downregulated electron transport chain genes in the largest α-cell subcluster and reduced mitochondrial respiration How might this impact on clinical practice in the foreseeable future? Preserving MAFB activity in adult human α-cells may represent a strategy to limit α-cell dysfunction in diabetes.