Dissecting the Heterogeneity of Human Islet Stress Responses in Type 2 Diabetes
Abstract
The overall objective of this project is to dissect the genetic regulation of islet stress responses and to determine how genetic variants, including those associated with type 2 diabetes (T2D SNPs), modulate these responses to contribute to islet dysfunction and T2D pathogenesis. This project will address significant gaps in our knowledge of the genetic and cellular heterogeneity of T2D by 1) defining the precise transcriptomic and epigenomic alterations in islets associated with diabetogenic oxidative/metabolic and inflammatory stressors; 2) determining how each islet cell type responds to each stressor; 3) identifying individual genetic variants, particularly T2D SNPs, that modulate these responses to increase or decrease diabetes susceptibility; and 4) testing whether the genes and pathways induced by these stressors are compensatory/protective or pathogenic. In the first year of this project, we have completed longitudinal profiling of islets from six individuals and identified 1,382 islet genes that are consistently induced (n=967) or repressed (n=415) by oxidative and/or inflammatory cytokine stresses. This gene set included two genes, C2CD4A and C2CD4B, which we have recently identified as putative T2D GWAS effector genes, as well as 142 additional putative T2D GWAS effector genes based on reported positional candidate scores. Preliminary single cell transcriptome analyses have revealed provocative differences in both the dynamics and features of transcriptional stress responses in islet insulin-secreting beta vs. glucagon-secreting alpha cells.
Document Details
- Document Type
- Technical Report
- Publication Date
- Sep 01, 2019
- Accession Number
- AD1086482
Entities
People
- Duygu Ucar
Organizations
- Jackson Laboratory