AFF3 and BACH2 are master regulators of metabolic inflexibility, β/α-cell transition, and dedifferentiation in type 2 diabetes

ABSTRACT Type 2 Diabetes is associated with defective insulin secretion, reduced β-cell mass, and increased glucagon production. Cell lineage-tracing in rodents and human autopsy surveys support the notion of β-cell dedifferentiation as a unifying mechanism for these abnormalities. Yet, mechanistic determinants of human β-cell failure remain elusive. Using regulatory-network-based single-cell analysis of human islets, we identify aberrant, diabetes-enriched transitional states characterized by metabolic inflexibility, α/β-transition, and endocrine progenitor/stem cell features. A coordinated transcription factor hierarchy mediating cell state transition emerged and was validated using barcoded guide-based, single-cell gene transfer and calcium flux measures in primary human islet cells. Specifically, two master regulators and associated epigenetic drivers emerged, one (AFF3) controlling β- to α-like-cell reprogramming, the other (BACH2) transition to a dedifferentiated endocrine progenitor-like cell. The findings provide mechanistic insight into diabetic islet cell dysfunction and suggest actionable pathways for pharmacological intervention.