Study links gene network and pancreatic beta cell defects to Type 2 diabetes

A comprehensive study that integrates multiple analytic approaches has linked a regulatory gene network and functional defects in insulin-producing pancreatic beta cells to Type 2 diabetes. The study, lays the foundation for identifying additional early disease-driving events for Type 2 diabetes, and it also provides a template for identifying regulatory networks that drive other diseases.

The Vanderbilt team used an integrated, multimodal approach to study pancreas and islets from donors with early-stage Type 2 diabetes and controls. They analyzed islet function ex vivo and in vivo (in a mouse model), performed comprehensive transcriptional (gene expression) analysis using RNA-sequencing, and assessed islet cellular architecture using multiplex imaging.

The team found that the transcription factor RFX6 is a highly connected hub factor and is reduced in beta cells from individuals with Type 2 diabetes. In further studies of RFX6 and its regulatory network, the researchers used an in vitro human pseudoislet model to show that disruption of RFX6 in beta cells led to reduced insulin secretion and altered chromatin architecture at regions enriched for Type 2 diabetes GWAS signals. Using phenotype and genotype data from the UK Biobank across nearly one-half million people of European ancestry, they found that predicted decreased islet expression of RFX6 was causally associated with Type 2 diabetes.

Reference: VANDERBILT UNIVERSITY MEDICAL CENTER

JOURNAL: Nature