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1.
Diabetes ; 70(8): 1885-1897, 2021 08.
Article in English | MEDLINE | ID: mdl-34035041

ABSTRACT

Type 1 diabetes (T1D) has a multifactorial autoimmune etiology, involving environmental prompts and polygenic predisposition. We hypothesized that pancreata from individuals with and at risk for T1D would exhibit dysregulated expression of genes associated with monogenic forms of diabetes caused by nonredundant single-gene mutations. Using a "monogenetic transcriptomic strategy," we measured the expression of these genes in human T1D, autoantibody-positive (autoantibody+), and control pancreas tissues with real-time quantitative PCR in accordance with the Minimum Information for Publication of Quantitative Real-Time PCR Experiments (MIQE) guidelines. Gene and protein expression was visualized in situ with use of immunofluorescence, RNAscope, and confocal microscopy. Two dozen monogenic diabetes genes showed altered expression in human pancreata from individuals with T1D versus unaffected control subjects. Six of these genes also saw dysregulation in pancreata from autoantibody+ individuals at increased risk for T1D. 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 T1D 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 T1D disease process and likely contribute to the disorder's pathogenesis.


Subject(s)
Diabetes Mellitus, Type 1/genetics , Gene Expression Regulation , Pancreas/metabolism , Transcriptome , Autoantibodies , Humans , Mutation , Retrospective Studies
2.
Pediatr Diabetes ; 15(1): 1-9, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24325575

ABSTRACT

nPOD actively promotes a multidisciplinary and unbiased approach toward a better understanding of T1D and identify novel therapeutic targets, through its focus on the study of human samples. Unique to this effort is the coordination of collaborative efforts and real-time data sharing. Studies supported by nPOD are providing direct evidence that human T1D isa complex and heterogeneous disease, in which a multitude of pathogenic factors may be operational and may contribute to the onset of the disease. Importantly, the concept that beta cell destruction is almost completed and that the autoimmune process is almost extinguished soon after diagnosis is being challenged. nPOD investigators are exploring the hypothesis that beta cell dysfunction may also be a significant cause of hyperglycemia, at least around the time of diagnosis, and are uncovering novel molecules and pathways that are linked to the pathogenesis and etiology of human T1D. The validation of therapeutic targets is also a key component of this effort, with recent and future findings providing new strategic direction for clinical trials.


Subject(s)
Diabetes Mellitus, Type 1/physiopathology , Tissue Donors , Adult , Aged , Autoantibodies/physiology , Cooperative Behavior , Diabetes Mellitus, Type 1/virology , Female , Humans , Insulin-Secreting Cells/immunology , Insulin-Secreting Cells/physiology , Male , Middle Aged , Pancreas/immunology , Pancreas/pathology , Pancreas Transplantation , Regeneration , Tissue Banks , Young Adult
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