Hepatic IDH2 regulates glycolysis and gluconeogenesis

Wang, Huawei; Xiong, Qing; He, Guangzhen; Tang, Jun; Li, Sun; Cheng, Siyuan; Ke, Mengting; Chen, Shangyu; Hu, Yong; Feng, Jieyuan; Song, Lixia; Tong, Beier; Zhang, Zhengwei; Dai, Zhijiang; Yang, Xu

doi:10.1016/j.metabol.2023.155559

Cited by 3 publications

(3 citation statements)

References 19 publications

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“…Interestingly, transcriptional up-regulation of IDH2 expression has been found to be associated with improved mitochondrial function in endothelial progenitor cells in diabetic patients [135]. A recent study observed that elevated levels of IDH2 in the mouse liver under overnutrition contribute to elevated gluconeogenesis and glycogen synthesis [136]. Thus, it can be assumed that deficiency of IDH1 and IDH2 in pancreatic beta cells may be associated with a decrease in the formation of G6PD, which is necessary for the reduction of GSSG to GSH.…”

Section: Discussionmentioning

confidence: 99%

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

Klyosova

Azarova

Буйкин

et al. 2023

IJMS

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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.

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Section: Discussionmentioning

confidence: 99%

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

Klyosova

Azarova

Буйкин

et al. 2023

IJMS

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“…The research by Lee et al, and Wang et al, brings to light the altered expression and activity of IDH1 and IDH2 in diabetic models [ 44 , 52 ]. Elevated levels of IDH1 were noted in diabetic rodents, while increased IDH2 levels were observed in mice on a high-fat diet.…”

Section: Changes In Expression Of Nadph Producing Enzymes In Diabetes...mentioning

confidence: 99%

“…Furthering this, Lee et al, revealed that insulin sensitivity is enhanced in IDH2 knockout mice [ 64 ]. Additionally, IDH2 knockdown also decreased insulin release in INS-1 832/13 cell lines [ 52 ], indicating its dual role in insulin sensitivity and secretion.…”

Section: Role Of Nadph-producing Enzymes In Diabetesmentioning

confidence: 99%

NADPH Dynamics: Linking Insulin Resistance and β-Cells Ferroptosis in Diabetes Mellitus

Moon

2023

IJMS

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This review offers an in-depth exploration of Nicotinamide Adenine Dinucleotide Phosphate (NADPH) in metabolic health. It delves into how NADPH affects insulin secretion, influences insulin resistance, and plays a role in ferroptosis. NADPH, a critical cofactor in cellular antioxidant systems and lipid synthesis, plays a central role in maintaining metabolic homeostasis. In adipocytes and skeletal muscle, NADPH influences the pathophysiology of insulin resistance, a hallmark of metabolic disorders such as type 2 diabetes and obesity. The review explores the mechanisms by which NADPH contributes to or mitigates insulin resistance, including its role in lipid and reactive oxygen species (ROS) metabolism. Parallelly, the paper investigates the dual nature of NADPH in the context of pancreatic β-cell health, particularly in its relation to ferroptosis, an iron-dependent form of programmed cell death. While NADPH’s antioxidative properties are crucial for preventing oxidative damage in β-cells, its involvement in lipid metabolism can potentiate ferroptotic pathways under certain pathological conditions. This complex relationship underscores the delicate balance of NADPH homeostasis in pancreatic health and diabetes pathogenesis. By integrating findings from recent studies, this review aims to illuminate the nuanced roles of NADPH in different tissues and its potential as a therapeutic target. Understanding these dynamics offers vital insights into the development of more effective strategies for managing insulin resistance and preserving pancreatic β-cell function, thereby advancing the treatment of metabolic diseases.

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Integration of proteomics and metabolomics reveals energy and metabolic alterations induced by glucokinase (GCK) partial inactivation in hepatocytes

Xie,

Liu,

Xie

et al. 2024

Cellular Signalling

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Hepatic IDH2 regulates glycolysis and gluconeogenesis

Cited by 3 publications

References 19 publications

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

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

NADPH Dynamics: Linking Insulin Resistance and β-Cells Ferroptosis in Diabetes Mellitus

Integration of proteomics and metabolomics reveals energy and metabolic alterations induced by glucokinase (GCK) partial inactivation in hepatocytes

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