RFX6-mediated dysregulation defines human β cell dysfunction in early type 2 diabetes

A hallmark of type 2 diabetes (T2D) is dysfunction of insulin-producing β cells in islets of Langerhans. T2D genome-wide association studies (GWAS) have identified hundreds of signals but translating these into biological mechanisms is challenging. To identify early disease-driving events, we performed integrated studies of short-duration T2D and control donors including pancreatic tissue single cell spatial proteomics and islet physiology and transcriptomics. We show that T2D is associated with β cell dysfunction, but not β cell loss, and define cellular neighborhood organizational changes in intraislet capillaries and T cells. We found that a transcription factor RFX6 gene regulatory network is associated with insulin secretion defects and T2D GWAS variants, and further validated the RFX6 role in β cells through direct perturbation in human pseudoislets with physiological and single nuclei multiome readouts. Thus, β cell-intrinsic defects, including RFX6-mediated β cell chromatin, transcriptome, and insulin secretion dysregulation, define early-stage T2D signatures.