Abstract
Type 1 diabetes (T1D) arises from autoimmune-mediated destruction of insulin-producing β-cells leading to impaired insulin secretion and hyperglycemia. T1D is accompanied by DNA damage, oxidative stress, and inflammation, although there is still scarce information about the oxidative stress response and DNA repair in T1D pathogenesis. We used the microarray method to assess mRNA expression profiles in peripheral blood mononuclear cells (PBMCs) of 19 T1D patients compared to 11 controls and identify mRNA targets of microRNAs that were previously reported for T1D patients. We found 277 differentially expressed genes (220 upregulated and 57 downregulated) in T1D patients compared to controls. Analysis by gene sets (GSA and GSEA) showed an upregulation of processes linked to ROS generation, oxidative stress, inflammation, cell death, ER stress, and DNA repair in T1D patients. Besides, genes related to oxidative stress responses and DNA repair (PTGS2, ATF3, FOSB, DUSP1, and TNFAIP3) were found to be targets of four microRNAs (hsa-miR-101, hsa-miR148a, hsa-miR-27b, and hsa-miR-424). The expression levels of these mRNAs and microRNAs were confirmed by qRT-PCR. Therefore, the present study on differential expression profiles indicates relevant biological functions related to oxidative stress response, DNA repair, inflammation, and apoptosis in PBMCs of T1D patients relative to controls. We also report new insights regarding microRNA-mRNA interactions, which may play important roles in the T1D pathogenesis.
Highlights
Type 1 diabetes (T1D) or insulin-dependent diabetes mellitus (IDDM) is a polygenic disorder possibly triggered by environmental factors that results from a T cell-mediated autoimmune attack against the insulin-producing β-cells localized in the pancreatic islets of Langerhans [1]
After normalization and adjustment of data, the analysis performed by rank products revealed 277 differentially expressed genes (DEGs) in peripheral blood mononuclear cells (PBMCs) of patients with T1D compared to controls (220 upregulated and 57 downregulated) (Table S1)
Pathways associated with endoplasmic reticulum stress and unfolded protein response, reactive nitrogen species, and DNA repair were found statistically enriched for T1D patients (Figures 1(a) and 1(b))
Summary
Type 1 diabetes (T1D) or insulin-dependent diabetes mellitus (IDDM) is a polygenic disorder possibly triggered by environmental factors that results from a T cell-mediated autoimmune attack against the insulin-producing β-cells localized in the pancreatic islets of Langerhans [1]. The typical pathological lesion is a destructive immune cell infiltrate (insulitis), affecting insulin-producing β-cells at several levels and impairing insulin synthesis as a consequence [2]. During this process, islet-infiltrating mononuclear cells release proinflammatory cytokines and specific biochemical markers in the serum of patients, which have been exploited as potential markers for the pathogenesis of T1D. There is evidence that oxidative stress can increase the release of proinflammatory cytokines, subsequently leading to inflammation and β-cell destruction, contributing to T1D progression [7]. There is still scarce information about molecular signaling pathways and genes implicated in biological processes related to oxidative stress responses and DNA repair in T1D
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