Klyosova Elena, Azarova Iuliia, Buikin Stepan, Polonikov Alexey
Laboratory of Biochemical Genetics and Metabolomics, Research Institute for Genetic and Molecular Epidemiology, Kursk State Medical University, 18 Yamskaya Street, 305041 Kursk, Russia.
Department of Biology, Medical Genetics and Ecology, Kursk State Medical University, 3 Karl Marx Street, 305041 Kursk, Russia.
Int J Mol Sci. 2023 Jul 27;24(15):12059. doi: 10.3390/ijms241512059.
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 and GREIN software, respectively. Diabetic β-cells showed dataset-specific patterns of DEGs (FDR ≤ 0.05) implicated in the regulation of glutathione metabolism ( and ), protein-folding (, and ), and unfolded protein response (, and ). The 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 ( ≤ 0.05). Regression analysis established that genes involved in the de novo synthesis of glutathione, , , and 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.
内质网（ER）中氧化还原稳态受损可能导致胰岛素原错误折叠，从而激活未折叠蛋白反应（UPR）和凋亡途径，最终导致胰腺β细胞丢失和2型糖尿病（T2D）。本研究旨在鉴定编码谷胱甘肽代谢酶的差异表达基因（DEGs）及其对T2D患者β细胞中调节蛋白质折叠和UPR的基因表达水平的影响。分别使用 和GREIN软件分析了糖尿病患者和非糖尿病患者β细胞的GEO转录组数据集GSE20966和GSE81608中的142个感兴趣的基因。糖尿病β细胞显示出与数据集相关的DEGs模式（FDR≤0.05），这些DEGs与谷胱甘肽代谢（ 和 ）、蛋白质折叠（ 、 和 ）以及未折叠蛋白反应（ 、 和 ）的调节有关。编码谷氨酸-半胱氨酸连接酶催化亚基的 基因是谷胱甘肽生物合成的第一个限速酶，在两个数据集中的糖尿病β细胞中均中度下调（ ≤0.05）。回归分析表明，参与谷胱甘肽从头合成的基因 、 、 和 影响编码分子伴侣的基因以及参与UPR途径的基因的表达水平。本研究首次表明，糖尿病β细胞在调节谷胱甘肽代谢、蛋白质折叠和UPR的基因表达方面存在改变，并为2型糖尿病内质网应激背后氧化还原稳态受损与异常蛋白质折叠之间的分子串扰提供了证据。
