EIF2AK2 regulates the apoptotic genes in pancreatic beta cell damage associated with diabetes mellitus
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ABSTRACT:
ORGANISM(S): Rattus norvegicus
PROVIDER: GSE252033 | GEO | 2025/12/31
REPOSITORIES: GEO
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Project description:EIF2AK2 regulates the apoptotic genes in pancreatic beta cell damage associated with diabetes mellitus
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Project description:Transient Pax8 expression was reported in mouse islets during gestation, whereas a genome-wide linkage and admixture mapping study highlighted PAX8 as a candidate gene for diabetes mellitus (DM). We sought the significance of PAX8 expression in mouse and human islet biology. PAX8 was induced in gestating mouse islets and in human islets treated with recombinant prolactin. Global gene expression profiling of human and mouse islets overexpressing the corresponding species-specific PAX8 revealed the modulation of distinct genetic pathways that converge on cell survival. Accordingly, apoptosis was reduced in PAX8-overexpressing islets. These findings support that PAX8 could be a candidate gene for the study of gestational DM (GDM). PAX8 was genotyped in patients with GDM and gestational thyroid dysfunction (GTD), a pathology commonly found in patients with mutations on PAX8 A novel missense PAX8 mutation (p.T356M, c.1067C>T) was identified in a female diagnosed with GDM and GTD as well as in her father with type 2 DM but was absent in control patients. The p.T356M variant did not alter protein stability or cellular localization, whereas its transactivation activity was hindered. In parallel, a retrospective clinical analysis uncovered that a pregnant female harboring a second PAX8 mutation (p.P25R, c.74C>G) previously reported to cause congenital hypothyroidism also developed GDM. These data indicate that increased expression of PAX8 affects islet viability and that PAX8 could be considered as a candidate gene for the study of GDM.
2019-12-31 | GSE94846 | GEO
Project description:Diabetes mellitus (DM) after transplantation remains a crucial clinical problem in kidney transplantation. To obtain insights into molecular mechanisms underlying the development of post-transplant diabetes mellitus (PTDM) and its early impact on glomerular structures, here we comparatively analyze the proteome of histologically normal appearing glomeruli from patients with PTDM from normoglycemic (NG) transplant recipients, and from recipients with pre-existing type 2 DM (PTDM)
2023-10-24 | PXD042188 | Pride
Project description:Diabetes mellitus (DM) is a leading cause of chronic kidney disease and the pathobiology of diabetic nephropathy is widely studied. Less, however, is known about urinary bladder disease in DM despite dysfunctional voiding being a common clinical problem. We hypothesised that diabetic cystopathy would have a characteristic molecular signature, due to the adaptive response to increased urine load combined with the metabolic impacts of DM. To distinguish the consequences of DM from polyuria we compared bladders of untreated control, diabetic (streptozotocin-induced) and sucrose-treated male Wistar rats after 16 weeks using gene array
2021-07-17 | E-MTAB-9255 | biostudies-arrayexpress
Project description:Pancreatic tumors with small size can cause type3C Diabetes Mellitus (PCA-DM) but the mechanism is unknown. In this study we aimed at revealing the mRNA and long noncoding RNA (LncRNA) expression patterns of pancreatic tumors that triggered PCA-DM. Four pancreatic tumors from patients with PCA-DM (A1-A4), four pancreatic tumors from patients without PCA-DM (B1-B4), and four pancreatic tissues from patients with pancreatitis were individually profiled with Agilent microarrays(Arraystar Human LncRNA Array v3.0).
2014-09-06 | GSE61166 | GEO
Project description:Introduction. Epigenetic modifications have been implicated to mediate several complications of diabetes mellitus (DM), especially nephropathy and retinopathy. Our aims were to ascertain if epigenetic alterations in whole blood discriminate among DM patients with normal, delayed and rapid gastric emptying (GE). Methods. Using ChIP-seq (Chromatin immunoprecipitation combined with next generation sequencing) assays, we compared the genome-wide enrichment of three histone modifications (ie, H3K4me3, H3K9ac and H3K27ac) in buffy coats from 20 DM patients with normal (n=6), delayed (n=8), or rapid (n=6) GE. Results. Between DM patients with delayed versus normal GE, there were 108 and 54 genes that were differentially-bound (FDR < 0.05) with H3K27ac and H3K9ac; 100 genes were differentially bound with H3K9ac in patients with rapid versus normal GE. The differentially bound genes with H3K27ac were functionally linked to the type 2 immune response, particularly Th2 cell activation and function (eg, CCR3, CRLF2, CXCR4, IL5RA, and IL1RL1) and glucose homeostasis (FBP-1, PDE4A, CMKLR1). For H3K9ac, the differentially occupied genes were related to T cell development and function (eg, ICOS and CCR3) and innate immunity (RELB, CD300LB, CLEC2D). Compared to normal, rapid GE had differential H3K9ac peaks at the promoter site of diverse immunity-related genes (eg, TNFRSF25 and CXCR4) and genes related to insulin resistance and glucose metabolism. The motif analysis disclosed enrichment of binding sites for several transcription factors relevant to the pathogenesis and complications of DM. Conclusions. GE disturbances in DM are associated with epigenetic alterations that may serve as biomarkers and provide clues to the pathogenesis
2021-12-26 | GSE142178 | GEO
Project description:Pancreatic tumors with small size can cause type3C Diabetes Mellitus (PCA-DM) but the mechanism is unknown. In this study we aimed at revealing the mRNA and long noncoding RNA (LncRNA) expression patterns of pancreatic tumors that triggered PCA-DM. Four pancreatic tumors from patients with PCA-DM (A1-A4), four pancreatic tumors from patients without PCA-DM (B1-B4), and four pancreatic tissues from patients with pancreatitis were individually profiled with Agilent microarrays(Arraystar Human LncRNA Array v3.0). Pancreatic tumors with PCA-DM or without PCA-DM, and pancreatic tissues of pancreatitis were individually profiled.
2014-09-06 | E-GEOD-61166 | biostudies-arrayexpress
Project description:In traditional Chinese medicine (TCM), blood stasis syndrome (BSS) is mainly manifested by the increase of blood viscosity, platelet adhesion rate and aggregation, and the change of microcirculation, resulting in vascular endothelial injury. It is an important factor in the development of diabetes mellitus (DM). The aim of this study was to screen out the potential candidate microRNAs (miRNAs) in DM patients with BSS by high-throughput sequencing (HTS) and bioinformatics analysis. CRL-1730 human umbilical vein endothelial cells (HUVECs) were incubated with 10% human serum to establish models of DM with BSS, DM without BSS (NBS) and normal control (NC). Total RNA of each sample was extracted and sequenced by the Hiseq2000 platform. Differentially expressed miRNAs (DE-miRNAs) and mRNAs (DE-mRNAs) were screened between samples. Target genes of miRNAs were predicted by softwares. Gene Ontology (GO) and pathway enrichment analysis of the target genes were conducted. According to the significantly enriched GO annotations and pathways (P value ≤0.001), we selected the key miRNAs of DM with BSS.
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Project description:Checkpoint inhibitors (CPIs) targeting PD-1/PD-L1 and CTLA-4 have revolutionized cancer treatment but can trigger autoimmune complications including CPI-induced diabetes (CPI-DM), which occurs preferentially with PD-1 blockade. We found evidence of pancreatic inflammation in patients with CPI-DM with shrinkage of pancreases, increased pancreatic enzymes, and in a case from a patient who died with CPI-DM, peri-islet lymphocytic infiltration. In the NOD mouse model, anti-PD-L1 but not anti-CTLA-4 induces DM rapidly. RNA sequencing revealed that cytolytic IFNγ+ CD8+ T cells infiltrated islets with anti-PD-L1. Changes in β cells were predominantly driven by IFNγ and TNFα and included induction of a novel β cell population with transcriptional changes suggesting dedifferentiation. IFNγ increased checkpoint ligand expression and activated apoptosis pathways in human β cells in vitro. Treatment with anti-IFNγ and anti-TNFα prevented CPI-DM in anti-PD-L1 treated NOD mice. CPIs targeting the PD-1/PD-L1 pathway result in transcriptional changes in β cells and immune infiltrates that may lead to the development of diabetes. Inhibition of inflammatory cytokines can prevent CPI-DM, suggesting a strategy for clinical application to prevent this complication.
2022-10-27 | GSE209587 | GEO
Project description:Checkpoint inhibitors (CPIs) targeting PD-1/PD-L1 and CTLA-4 have revolutionized cancer treatment but can trigger autoimmune complications including CPI-induced diabetes (CPI-DM), which occurs preferentially with PD-1 blockade. We found evidence of pancreatic inflammation in patients with CPI-DM with shrinkage of pancreases, increased pancreatic enzymes, and in a case from a patient who died with CPI-DM, peri-islet lymphocytic infiltration. In the NOD mouse model, anti-PD-L1 but not anti-CTLA-4 induces DM rapidly. RNA sequencing revealed that cytolytic IFNγ+ CD8+ T cells infiltrated islets with anti-PD-L1. Changes in β cells were predominantly driven by IFNγ and TNFα and included induction of a novel β cell population with transcriptional changes suggesting dedifferentiation. IFNγ increased checkpoint ligand expression and activated apoptosis pathways in human β cells in vitro. Treatment with anti-IFNγ and anti-TNFα prevented CPI-DM in anti-PD-L1 treated NOD mice. CPIs targeting the PD-1/PD-L1 pathway result in transcriptional changes in β cells and immune infiltrates that may lead to the development of diabetes. Inhibition of inflammatory cytokines can prevent CPI-DM, suggesting a strategy for clinical application to prevent this complication.
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