Type 2 diabetes has been associated with a regulatory gene network and functional problems in the pancreatic beta cells that produce insulin, according to a comprehensive study that combines multiple analytic methodologies. The study establishes the groundwork for finding more type 2 diabetes early disease-driving events and offers a model for identifying regulatory networks that drive other diseases. It was published Nov. 8 in the journal Nature.
According to the Centers for Disease Control and Prevention, type 2 diabetes affects around 35 million individuals in the US and increases mortality as well as the risk of major health problems like blindness, renal failure, heart disease, and stroke.
Hundreds of sites in the genome have been associated by genome-wide association studies (GWAS) to an elevated risk of type 2 diabetes; however, 90% of these sites are found in non-coding DNA regions rather than protein-coding DNA.
“There is a lack of understanding regarding the relationship between molecular changes in gene expression, tissue architecture, and cellular physiology in type 2 diabetes and this genetic variation at the population level,” stated Marcela Brissova, Ph.D., lead co-corresponding author of the new study and research professor of medicine at Vanderbilt University Medical Center. The paper’s co-first authors are Jack Walker, MD, Ph.D., a graduate of Vanderbilt’s Medical Scientist Training Program, and Diane Saunders, Ph.D., a research assistant professor of medicine at VUMC.
Human islets, which are tiny organs that contain beta cells and several other cell types, are different from rat islets in several respects, even though pathways that lead to type 2 diabetes have been investigated in rodent models.
“Our focus was on defining the mechanisms that lead to and maintain islet dysfunction in primary human islets,” stated Alvin C. Powers, MD, co-corresponding author of the study, director of the Vanderbilt Diabetes Research and Training Center, and Joe C. Davis Professor of Biomedical Science.
The utilization of the Vanderbilt Pancreas Biorepository, which has been compiled over the previous ten years, and the examination of pancreatic tissue and isolated islets from the same are crucial components of the team’s methodology.
The Vanderbilt team studied pancreas and islets from donors with early-stage type 2 diabetes and controls using an integrated, multimodal approach. They employed multiplex imaging to evaluate islet cellular architecture, extensive transcriptional (gene expression) study using RNA-sequencing, and ex vivo (in a mouse model) examination of islet function.
“The relative contributions of impaired beta cell function and reduced beta cell mass have long been debated in type 2 diabetes,” Saunders stated. “Our data indicate that beta cell loss is not a major component in disease pathogenesis in early-stage type 2 diabetes.”
The interdisciplinary team linked population-scale genetics to laboratory results from single cells by collaborating with co-corresponding author Stephen Parker, Ph.D., and his colleagues in the University of Michigan’s Department of Computational Medicine & Bioinformatics. They also incorporated the knowledge of Jennifer Below, Ph.D., and Hung-Hsin Chen, Ph.D., in the Division of Genetic Medicine at VUMC.
In order to find gene “modules” that connected donor characteristics, GWAS variations, and beta cell transcriptional profiles with beta cell functional parameters, the researchers also conducted network analysis.
The transcription factor RFX6, a highly linked hub factor, was discovered to be diminished in type 2 diabetic patients’ beta cells.
In another research on RFX6 and its regulatory network, the scientists demonstrated that RFX6 disruption in beta cells resulted in decreased insulin secretion and changed chromatin architecture at locations enriched for type 2 diabetes GWAS signals using an in vitro human pseudoislet model. By utilizing genotype and phenotype data from the UK Biobank spanning almost 500,000 individuals with European heritage, they discovered a causal relationship between type 2 diabetes and the anticipated reduction in RFX6 islet expression.
“Our integrated, multimodal studies identify beta cell dysfunction arising within the beta cell—including from an RFX6-mediated network—as a key event in early-stage type 2 diabetes pathogenesis,” Brissova stated.”Precisely what underlies the initial RFX6 dysregulation and whether it can be targeted to prevent or reverse early-stage molecular and functional defects in the beta cell will be important areas of further investigation.”
Provided by Vanderbilt University Medical Center