RFX6 is a transcription factor essential for pancreatic endocrine development and glucose homeostasis. As a master hub gene, RFX6 directs differentiation of four of five islet cell types—alpha, beta, delta, and epsilon cells—by acting downstream of NEUROG3 and forming heterodimers with RFX3 to bind X-box promoter elements and activate target genes 1. In beta cells specifically, RFX6 regulates genes controlling insulin secretion and L-type calcium channel expression, promoting glucose-stimulated insulin secretion 2. In alpha cells, RFX6 maintains expression of genes governing nutrient sensing, hormone processing, and glucagon secretion 3. RFX6 dysfunction underlies multiple diabetes forms: homozygous loss-of-function mutations cause neonatal diabetes with pancreatic hypoplasia through increased endocrine cell apoptosis and downregulation of endocrine differentiation genes 4; heterozygous mutations predispose to maturity-onset diabetes of the young (MODY) 5 and type 2 diabetes through RFX6 haploinsufficiency impairing beta cell maturation and insulin secretion without affecting beta cell number 6. Population-scale genetic analyses demonstrate that genetically predicted reduced RFX6 expression causally increases type 2 diabetes risk through altered beta cell chr6 architecture at diabetes-associated loci 7. Beyond endocrine function, RFX6 regulates intestinal patterning upstream of PDX1 8.