Differentially Expressed Genes Regulating Glutathione Metabolism, Protein-Folding, and Unfolded Protein Response in Pancreatic β-Cells in Type 2 Diabetes Mellitus

Elena Klyosova; Iuliia Azarova; Stepan Buikin; Alexey Polonikov

doi:10.3390/ijms241512059

Differentially Expressed Genes Regulating Glutathione Metabolism, Protein-Folding, and Unfolded Protein Response in Pancreatic β-Cells in Type 2 Diabetes Mellitus

Int J Mol Sci. 2023 Jul 27;24(15):12059. doi: 10.3390/ijms241512059.

Authors

Elena Klyosova^{1

2}, Iuliia Azarova^{1

3}, Stepan Buikin^{4

5}, Alexey Polonikov^{2

6}

Affiliations

¹ Laboratory of Biochemical Genetics and Metabolomics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya Street, 305041 Kursk, Russia.
² Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia.
³ Department of Biological Chemistry, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia.
⁴ Centre of Omics Technology, I.M. Sechenov First Moscow State Medical University, 8-2 Trubetskaya Street, 119991 Moscow, Russia.
⁵ Department of Internal Diseases, Yaroslav the Wise Novgorod State University, 41 Bolshaya St. Petersburg Street, 173003 Veliky Novgorod, Russia.
⁶ Laboratory of Statistical Genetics and Bioinformatics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya Street, 305041 Kursk, Russia.

Abstract

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 limma and GREIN software, respectively. Diabetic β-cells showed dataset-specific patterns of DEGs (FDR ≤ 0.05) implicated in the regulation of glutathione metabolism (ANPEP, PGD, IDH2, and CTH), protein-folding (HSP90AB1, HSP90AA1, HSPA1B, HSPA8, BAG3, NDC1, NUP160, RLN1, and RPS19BP1), and unfolded protein response (CREB3L4, ERP27, and BID). The GCLC 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 (p ≤ 0.05). Regression analysis established that genes involved in the de novo synthesis of glutathione, GCLC, GCLM, and GSS 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.

Keywords: apoptosis; differentially expressed genes (DEGs); gene expression; glutathione metabolism; proinsulin misfolding; protein folding; redox homeostasis; type 2 diabetes; unfolded protein response; β-cells.

Grants and funding

22-25-00585/Russian Science Foundation