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 <i>in situ</i> 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 eIF2a-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.