The RFX6 mechanism spine: A unified model linking transcriptional coordination to endocrine resilience and diabetes...

Glucose homeostasis requires coordinated insulin, glucagon, and incretin secretion across pancreatic and gastrointestinal endocrine systems. Despite heterogeneous genetic and environmental triggers, diabetes converges on β-cell dysfunction and disrupted inter-endocrine coordination. Regulatory Factor X6 (RFX6) is essential for endocrine development and remains expressed in adult islets and enteroendocrine cells; however, its functions have largely been studied in isolated contexts. Here, we integrate developmental, epigenomic, physiological, and genetic evidence into a hypothesis-generating framework in which RFX6 functions as a dosage-sensitive endocrine regulator. RFX6-associated programs are linked to glucose sensing, membrane excitability, insulin secretion, redox stability, and gut-islet signaling. Available genetic and functional evidence supports a model in which graded reduction in RFX6 activity correlates with a spectrum of phenotypes: biallelic loss-of-function variants cause syndromic neonatal diabetes (Mitchell-Riley syndrome), heterozygous variants are associated to impaired insulin secretion in RFX6-MODY, and common regulatory variants near the RFX6 locus contribute to susceptibility to polygenic type 2 diabetes. We propose a five-tier "Mechanism Spine" linking chromatin regulation to endocrine physiology and clinical phenotype while emphasizing that its translational implications remain preliminary.