Monogenic Diabetes and Integrated Stress Response Genes Display Altered Gene Expression in Type 1 Diabetes

Abstract

Type 1 diabetes has a multifactorial autoimmune etiology, involving environmental prompts and polygenic predisposition. We hypothesized that pancreata from individuals with and at risk for type 1 diabetes would exhibit dysregulated expression of genes associated with monogenic forms of diabetes caused by non-redundant single-gene mutations. Employing a "monogenetic transcriptomic strategy," we measured the expression of these genes in human type 1 diabetes, autoantibody positive (autoantibody+), and control pancreas tissues using RTqPCR in accordance with the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines. Gene and protein expression were visualized in situ using immunofluorescence, RNAScope, and confocal microscopy. Two-dozen monogenic diabetes genes showed altered expression in human pancreata from individuals with type 1 diabetes versus unaffected controls. Six of these genes also saw dysregulation in pancreata from autoantibody+ persons at increased-risk for type 1 diabetes. As a subset of these genes are related to cellular stress responses, we measured integrated stress response (ISR) genes and identified 20 with altered expression in type 1 diabetes pancreata, including three of the four eIF2α-dependent kinases. Equally intriguing, we observed significant repression of the three arms of the ISR in autoantibody+ pancreata. Collectively, these efforts suggest monogenic diabetes and ISR genes are dysregulated early in the type 1 diabetes disease process and likely contribute to the disorder's pathogenesis.