Differentially Expressed Genes Regulating Glutathione Metabolism, Protein-Folding, and Unfolded Protein Response in Pancreatic β-Cells in Type 2 Diabetes Mellitus
Impaired redox homeostasis in the endoplasmic reticulum (ER) may contribute to proinsulin misfolding and thus to activate the unfolded protein response (UPR) and apoptotic pathways, culminating in pancreatic β-cell loss and type 2 diabetes (T2D). The present study was designed to identify differenti...
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MDPI AG
2023-07-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/24/15/12059 |
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| author | Elena Klyosova Iuliia Azarova Stepan Buikin Alexey Polonikov |
| author_facet | Elena Klyosova Iuliia Azarova Stepan Buikin Alexey Polonikov |
| author_sort | Elena Klyosova |
| collection | DOAJ |
| description | Impaired redox homeostasis in the endoplasmic reticulum (ER) may contribute to proinsulin misfolding and thus to activate the unfolded protein response (UPR) and apoptotic pathways, culminating in pancreatic β-cell loss and type 2 diabetes (T2D). The present study was designed to identify differentially expressed genes (DEGs) encoding enzymes for glutathione metabolism and their impact on the expression levels of genes regulating protein folding and UPR in β-cells of T2D patients. The GEO transcriptome datasets of β-cells of diabetics and non-diabetics, GSE20966 and GSE81608, were analyzed for 142 genes of interest using <i>limma</i> and GREIN software, respectively. Diabetic β-cells showed dataset-specific patterns of DEGs (FDR ≤ 0.05) implicated in the regulation of glutathione metabolism (<i>ANPEP, PGD, IDH2,</i> and <i>CTH</i>), protein-folding (<i>HSP90AB1, HSP90AA1, HSPA1B, HSPA8, BAG3, NDC1, NUP160, RLN1</i>, and <i>RPS19BP1</i>), and unfolded protein response (<i>CREB3L4, ERP27</i>, and <i>BID</i>). The <i>GCLC</i> gene, encoding the catalytic subunit of glutamate–cysteine ligase, the first rate-limiting enzyme of glutathione biosynthesis, was moderately down-regulated in diabetic β-cells from both datasets (<i>p</i> ≤ 0.05). Regression analysis established that genes involved in the de novo synthesis of glutathione, <i>GCLC</i>, <i>GCLM</i>, and <i>GSS</i> affect the expression levels of genes encoding molecular chaperones and those involved in the UPR pathway. This study showed for the first time that diabetic β-cells exhibit alterations in the expression of genes regulating glutathione metabolism, protein-folding, and UPR and provided evidence for the molecular crosstalk between impaired redox homeostasis and abnormal protein folding, underlying ER stress in type 2 diabetes. |
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| language | English |
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| publishDate | 2023-07-01 |
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| spelling | doaj.art-859fd1136dfc4d0c8b5fe171a6eea83d2023-11-18T22:59:48ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672023-07-0124151205910.3390/ijms241512059Differentially Expressed Genes Regulating Glutathione Metabolism, Protein-Folding, and Unfolded Protein Response in Pancreatic β-Cells in Type 2 Diabetes MellitusElena Klyosova0Iuliia Azarova1Stepan Buikin2Alexey Polonikov3Laboratory of Biochemical Genetics and Metabolomics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya Street, 305041 Kursk, RussiaLaboratory of Biochemical Genetics and Metabolomics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya Street, 305041 Kursk, RussiaCentre of Omics Technology, I.M. Sechenov First Moscow State Medical University, 8-2 Trubetskaya Street, 119991 Moscow, RussiaDepartment of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, RussiaImpaired redox homeostasis in the endoplasmic reticulum (ER) may contribute to proinsulin misfolding and thus to activate the unfolded protein response (UPR) and apoptotic pathways, culminating in pancreatic β-cell loss and type 2 diabetes (T2D). The present study was designed to identify differentially expressed genes (DEGs) encoding enzymes for glutathione metabolism and their impact on the expression levels of genes regulating protein folding and UPR in β-cells of T2D patients. The GEO transcriptome datasets of β-cells of diabetics and non-diabetics, GSE20966 and GSE81608, were analyzed for 142 genes of interest using <i>limma</i> and GREIN software, respectively. Diabetic β-cells showed dataset-specific patterns of DEGs (FDR ≤ 0.05) implicated in the regulation of glutathione metabolism (<i>ANPEP, PGD, IDH2,</i> and <i>CTH</i>), protein-folding (<i>HSP90AB1, HSP90AA1, HSPA1B, HSPA8, BAG3, NDC1, NUP160, RLN1</i>, and <i>RPS19BP1</i>), and unfolded protein response (<i>CREB3L4, ERP27</i>, and <i>BID</i>). The <i>GCLC</i> gene, encoding the catalytic subunit of glutamate–cysteine ligase, the first rate-limiting enzyme of glutathione biosynthesis, was moderately down-regulated in diabetic β-cells from both datasets (<i>p</i> ≤ 0.05). Regression analysis established that genes involved in the de novo synthesis of glutathione, <i>GCLC</i>, <i>GCLM</i>, and <i>GSS</i> affect the expression levels of genes encoding molecular chaperones and those involved in the UPR pathway. This study showed for the first time that diabetic β-cells exhibit alterations in the expression of genes regulating glutathione metabolism, protein-folding, and UPR and provided evidence for the molecular crosstalk between impaired redox homeostasis and abnormal protein folding, underlying ER stress in type 2 diabetes.https://www.mdpi.com/1422-0067/24/15/12059type 2 diabetesredox homeostasisglutathione metabolismβ-cellsapoptosisprotein folding |
| spellingShingle | Elena Klyosova Iuliia Azarova Stepan Buikin Alexey Polonikov Differentially Expressed Genes Regulating Glutathione Metabolism, Protein-Folding, and Unfolded Protein Response in Pancreatic β-Cells in Type 2 Diabetes Mellitus International Journal of Molecular Sciences type 2 diabetes redox homeostasis glutathione metabolism β-cells apoptosis protein folding |
| title | Differentially Expressed Genes Regulating Glutathione Metabolism, Protein-Folding, and Unfolded Protein Response in Pancreatic β-Cells in Type 2 Diabetes Mellitus |
| title_full | Differentially Expressed Genes Regulating Glutathione Metabolism, Protein-Folding, and Unfolded Protein Response in Pancreatic β-Cells in Type 2 Diabetes Mellitus |
| title_fullStr | Differentially Expressed Genes Regulating Glutathione Metabolism, Protein-Folding, and Unfolded Protein Response in Pancreatic β-Cells in Type 2 Diabetes Mellitus |
| title_full_unstemmed | Differentially Expressed Genes Regulating Glutathione Metabolism, Protein-Folding, and Unfolded Protein Response in Pancreatic β-Cells in Type 2 Diabetes Mellitus |
| title_short | Differentially Expressed Genes Regulating Glutathione Metabolism, Protein-Folding, and Unfolded Protein Response in Pancreatic β-Cells in Type 2 Diabetes Mellitus |
| title_sort | differentially expressed genes regulating glutathione metabolism protein folding and unfolded protein response in pancreatic β cells in type 2 diabetes mellitus |
| topic | type 2 diabetes redox homeostasis glutathione metabolism β-cells apoptosis protein folding |
| url | https://www.mdpi.com/1422-0067/24/15/12059 |
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