Mechanistic exploration of hexokinase 2 and metabolism in diabetic cardiomyopathy
- Authors:
- Bo Li
- Xu Zhao
- Liming Ma
- Xiaoying Wang
- Yan Ding
- Yi Zhang
-
Affiliations: Department of Endocrinology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, Fujian 362000, P.R. China, Emergency and Critical Care Center, Renmin Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China, Hubei Key Laboratory of Embryonic Stem Cell Research, Hubei Provincial Clinical Research Center for Umbilical Cord Blood Hematopoietic Stem Cells, Taihe Hospital, Hubei University of Medicine, Shiyan, Hubei 442000, P.R. China - Published online on: May 26, 2025 https://doi.org/10.3892/mmr.2025.13576
- Article Number: 211
-
Copyright: © Li et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
This article is mentioned in:
Abstract
 |
 |
 |
 |
 |
 |
 |
 |
 |
|
Ogurtsova K, da Rocha Fernandes JD, Huang Y, Linnenkamp U, Guariguata L, Cho NH, Cavan D, Shaw JE and Makaroff LE: IDF diabetes atlas: Global estimates for the prevalence of diabetes for 2015 and 2040. Diabetes Res Clin Pract. 128:40–50. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Peng C and Zhang Y, Lang X and Zhang Y: Role of mitochondrial metabolic disorder and immune infiltration in diabetic cardiomyopathy: New insights from bioinformatics analysis. J Transl Med. 21:662023. View Article : Google Scholar : PubMed/NCBI | |
|
Fuentes-Antrás J, Picatoste B, Ramírez E, Egido J, Tuñón J and Lorenzo Ó: Targeting metabolic disturbance in the diabetic heart. Cardiovasc Diabetol. 14:172015. View Article : Google Scholar : PubMed/NCBI | |
|
Yuan Q, Sun Y, Yang F, Yan D, Shen M, Jin Z, Zhan L, Liu G, Yang L, Zhou Q, et al: CircRNA DICAR as a novel endogenous regulator for diabetic cardiomyopathy and diabetic pyroptosis of cardiomyocytes. Signal Transduct Target Ther. 8:992023. View Article : Google Scholar : PubMed/NCBI | |
|
Tan Y, Zhang Z, Zheng C, Wintergerst KA, Keller BB and Cai L: Mechanisms of diabetic cardiomyopathy and potential therapeutic strategies: Preclinical and clinical evidence. Nat Rev Cardiol. 17:585–607. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Murtaza G, Virk HUH, Khalid M, Lavie CJ, Ventura H, Mukherjee D, Ramu V, Bhogal S, Kumar G, Shanmugasundaram M and Paul TK: Diabetic cardiomyopathy-A comprehensive updated review. Prog Cardiovasc Dis. 62:315–326. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Jia G, Hill MA and Sowers JR: Diabetic cardiomyopathy: An update of mechanisms contributing to this clinical entity. Circ Res. 122:624–638. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Dillmann WH: Diabetic cardiomyopathy. Circ Res. 124:1160–1162. 2019. View Article : Google Scholar : PubMed/NCBI | |
|
Jia G, Whaley-Connell A and Sowers JR: Diabetic cardiomyopathy: A hyperglycaemia- and insulin-resistance-induced heart disease. Diabetologia. 61:21–28. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Adeghate E and Singh J: Structural changes in the myocardium during diabetes-induced cardiomyopathy. Heart Fail Rev. 19:15–23. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Song K, Liang D, Xiao D, Kang A and Ren Y: Role of bariatric surgery in improving diabetic cardiomyopathy: Molecular mechanisms and therapeutic perspectives (Review). Mol Med Rep. 30:1992024. View Article : Google Scholar : PubMed/NCBI | |
|
Jia G, DeMarco VG and Sowers JR: Insulin resistance and hyperinsulinaemia in diabetic cardiomyopathy. Nat Rev Endocrinol. 12:144–153. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Leary S, Anthony R, Gwaltney-Brant S, Cartner S, Dewell R, Webb P, Plummer P, Hoenig DE, Moyer W, Smith SA, et al: AVMA guidelines for the depopulation of animals. 2019. | |
|
Leek JT, Johnson WE, Parker HS, Jaffe AE and Storey JD: The sva package for removing batch effects and other unwanted variation in high-throughput experiments. Bioinformatics. 28:882–883. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Ashburner M, Ball CA, Blake JA, Botstein D, Butler H, Cherry JM, Davis AP, Dolinski K, Dwight SS, Eppig JT, et al: Gene ontology: Tool for the unification of biology. The gene ontology consortium. Nat Genet. 25:25–29. 2000. View Article : Google Scholar : PubMed/NCBI | |
|
Kanehisa M and Goto S: KEGG: Kyoto encyclopedia of genes and genomes. Nucleic Acids Res. 28:27–30. 2000. View Article : Google Scholar : PubMed/NCBI | |
|
Langfelder P and Horvath S: WGCNA: An R package for weighted correlation network analysis. BMC Bioinformatics. 9:5592008. View Article : Google Scholar : PubMed/NCBI | |
|
Gao P, Cao M, Jiang X, Wang X, Zhang G, Tang X, Yang C, Komuro I, Ge J, Li L and Zou Y: Cannabinoid receptor 2-centric molecular feedback loop drives necroptosis in diabetic heart injuries. Circulation. 147:158–174. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Sun HJ, Xiong SP, Wu ZY, Cao L, Zhu MY, Moore PK and Bian JS: Induction of caveolin-3/eNOS complex by nitroxyl (HNO) ameliorates diabetic cardiomyopathy. Redox Biol. 32:1014932020. View Article : Google Scholar : PubMed/NCBI | |
|
Hu L, Wei J, Zhang Y, Wang Z, Tang J, Tang J, Gao Y, Zhang X, Li Y, Liu Y, et al: ANGPTL8 is a negative regulator in pathological cardiac hypertrophy. Cell Death Dis. 13:6212022. View Article : Google Scholar : PubMed/NCBI | |
|
Wu Y, Wang J, Zhao T, Sun M, Xu M, Che S, Pan Z, Wu C and Shen L: Polystyrenenanoplastics lead to ferroptosis in the lungs. J Adv Res. 56:31–41. 2024. View Article : Google Scholar : PubMed/NCBI | |
|
An Z, Hu T, Lv Y, Li P and Liu L: Targeted amino acid and related amines analysis based on iTRAQ®-LC-MS/MS for discovering potential hepatotoxicity biomarkers. J Pharm Biomed Anal. 178:1128122020. View Article : Google Scholar : PubMed/NCBI | |
|
Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Chen W, Gong L, Guo Z, Wang W, Zhang H, Liu X, Yu S, Xiong L and Luo J: A novel integrated method for large-scale detection, identification, and quantification of widely targeted metabolites: Application in the study of rice metabolomics. Mol Plant. 6:1769–1780. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Kaludercic N and Di Lisa F: Mitochondrial ROS formation in the pathogenesis of diabetic cardiomyopathy. Front Cardiovasc Med. 7:122020. View Article : Google Scholar : PubMed/NCBI | |
|
Sitte N, Huber M, Grune T, Ladhoff A, Doecke WD, Von Zglinicki T and Davies KJ: Proteasome inhibition by lipofuscin/ceroid during postmitotic aging of fibroblasts. FASEB J. 14:1490–1498. 2000. View Article : Google Scholar : PubMed/NCBI | |
|
Farhangkhoee H, Khan ZA, Mukherjee S, Cukiernik M, Barbin YP, Karmazyn M and Chakrabarti S: Heme oxygenase in diabetes-induced oxidative stress in the heart. J Mol Cell Cardiol. 35:1439–1448. 2003. View Article : Google Scholar : PubMed/NCBI | |
|
Liu R, Duan T, Yu L, Tang Y, Liu S, Wang C and Fang WJ: Acid sphingomyelinase promotes diabetic cardiomyopathy via NADPH oxidase 4 mediated apoptosis. Cardiovasc Diabetol. 22:252023. View Article : Google Scholar : PubMed/NCBI | |
|
Xiang H, Jin S, Tan F, Xu Y, Lu Y and Wu T: Physiological functions and therapeutic applications of neutral sphingomyelinase and acid sphingomyelinase. Biomed Pharmacother. 139:1116102021. View Article : Google Scholar : PubMed/NCBI | |
|
Imgrund S, Hartmann D, Farwanah H, Eckhardt M, Sandhoff R, Degen J, Gieselmann V, Sandhoff K and Willecke K: Adult ceramide synthase 2 (CERS2)-deficient mice exhibit myelin sheath defects, cerebellar degeneration, and hepatocarcinomas. J Biol Chem. 284:33549–33560. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Cutler RG and Mattson MP: Sphingomyelin and ceramide as regulators of development and lifespan. Mech Ageing Dev. 122:895–908. 2001. View Article : Google Scholar : PubMed/NCBI | |
|
Suzuki R, Murakami C, Dilimulati K, Atsuta-Tsunoda K, Kawai T and Sakane F: Human sphingomyelin synthase 1 generates diacylglycerol in the presence and absence of ceramide via multiple enzymatic activities. FEBS Lett. 597:2672–2686. 2023. View Article : Google Scholar : PubMed/NCBI | |
|
Li X, Wu Y, Zhao J, Wang H, Tan J, Yang M, Li Y, Deng S, Gao S, Li H, et al: Distinct cardiac energy metabolism and oxidative stress adaptations between obese and non-obese type 2 diabetes mellitus. Theranostics. 10:2675–2695. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Da Silva D, Ausina P, Alencar EM, Coelho WS, Zancan P and Sola-Penna M: Metformin reverses hexokinase and phosphofructokinase downregulation and intracellular distribution in the heart of diabetic mice. IUBMB Life. 64:766–774. 2012. View Article : Google Scholar : PubMed/NCBI | |
|
Palsgaard J, Brøns C, Friedrichsen M, Dominguez H, Jensen M, Storgaard H, Spohr C, Torp-Pedersen C, Borup R, De Meyts P and Vaag A: Gene expression in skeletal muscle biopsies from people with type 2 diabetes and relatives: Differential regulation of insulin signaling pathways. PLoS One. 4:e65752009. View Article : Google Scholar : PubMed/NCBI | |
|
Osawa H, Sutherland C, Robey RB, Printz RL and Granner DK: Analysis of the signaling pathway involved in the regulation of hexokinase II gene transcription by insulin. J Biol Chem. 271:16690–16694. 1996. View Article : Google Scholar : PubMed/NCBI | |
|
Ye G, Donthi RV, Metreveli NS and Epstein PN: Overexpression of hexokinase protects hypoxic and diabetic cardiomyocytes by increasing ATP generation. Cardiovasc Toxicol. 5:293–300. 2005. View Article : Google Scholar : PubMed/NCBI | |
|
Wang C, Tanizawa H, Hill C, Havas A, Zhang Q, Liao L, Hao X, Lei X, Wang L, Nie H, et al: METTL3-mediated chromatin contacts promote stress granule phase separation through metabolic reprogramming during senescence. Nat Commun. 15:54102024. View Article : Google Scholar : PubMed/NCBI | |
|
Banani SF, Lee HO, Hyman AA and Rosen MK: Biomolecular condensates: Organizers of cellular biochemistry. Nat Rev Mol Cell Biol. 18:285–298. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Alberti S and Hyman AA: Biomolecular condensates at the nexus of cellular stress, protein aggregation disease and ageing. Nat Rev Mol Cell Biol. 22:196–213. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Zhang H, Ji X, Li P, Liu C, Lou J, Wang Z, Wen W, Xiao Y, Zhang M and Zhu X: Liquid-liquid phase separation in biology: Mechanisms, physiological functions and human diseases. Sci China Life Sci. 63:953–985. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Nott TJ, Craggs TD and Baldwin AJ: Membraneless organelles can melt nucleic acid duplexes and act as biomolecular filters. Nat Chem. 8:569–575. 2016. View Article : Google Scholar : PubMed/NCBI | |
|
Riback JA, Katanski CD, Kear-Scott JL, Pilipenko EV, Rojek AE, Sosnick TR and Drummond DA: Stress-Triggered phase separation is an adaptive, evolutionarily tuned response. Cell. 168:1028–1040.e19. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Mo Y, Feng Y, Huang W, Tan N, Li X, Jie M, Feng T, Jiang H and Jiang L: Liquid-liquid phase separation in cardiovascular diseases. Cells. 11:30402022. View Article : Google Scholar : PubMed/NCBI | |
|
Bayeva M, Sawicki KT and Ardehali H: Taking diabetes to heart-deregulation of myocardial lipid metabolism in diabetic cardiomyopathy. J Am Heart Assoc. 2:e0004332013. View Article : Google Scholar : PubMed/NCBI | |
|
Barbé-Tuana F, Funchal G, Schmitz CRR, Maurmann RM and Bauer ME: The interplay between immunosenescence and age-related diseases. Semin Immunopathol. 42:545–557. 2020. View Article : Google Scholar : PubMed/NCBI | |
|
Henson SM and Aksentijevic D: Senescence and type 2 diabetic cardiomyopathy: How young can you die of old age? Front Pharmacol. 12:7165172021. View Article : Google Scholar : PubMed/NCBI | |
|
Shen CY, Lu CH, Wu CH, Li KJ, Kuo YM, Hsieh SC and Yu CL: The development of maillard reaction, and advanced glycation end product (AGE)-receptor for AGE (RAGE) signaling inhibitors as novel therapeutic strategies for patients with AGE-related diseases. Molecules. 25:55912020. View Article : Google Scholar : PubMed/NCBI | |
|
Bodiga VL, Eda SR and Bodiga S: Advanced glycation end products: Role in pathology of diabetic cardiomyopathy. Heart Fail Rev. 19:49–63. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Nielsen JM, Kristiansen SB, Nørregaard R, Andersen CL, Denner L, Nielsen TT, Flyvbjerg A and Bøtker HE: Blockage of receptor for advanced glycation end products prevents development of cardiac dysfunction in db/db type 2 diabetic mice. Eur J Heart Fail. 11:638–647. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Chong CR, Clarke K and Levelt E: Metabolic remodeling in diabetic cardiomyopathy. Cardiovasc Res. 113:422–430. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Heather LC, Gopal K, Srnic N and Ussher JR: Redefining diabetic cardiomyopathy: Perturbations in substrate metabolism at the heart of its pathology. Diabetes. 73:659–670. 2024. View Article : Google Scholar : PubMed/NCBI | |
|
Loghmani H and Conway EM: Exploring traditional and nontraditional roles for thrombomodulin. Blood. 132:148–158. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Isermann B, Vinnikov IA, Madhusudhan T, Herzog S, Kashif M, Blautzik J, Corat MA, Zeier M, Blessing E, Oh J, et al: Activated protein C protects against diabetic nephropathy by inhibiting endothelial and podocyte apoptosis. Nat Med. 13:1349–1358. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Herzog C, Lorenz A, Gillmann HJ, Chowdhury A, Larmann J, Harendza T, Echtermeyer F, Müller M, Schmitz M, Stypmann J, et al: Thrombomodulin's lectin-like domain reduces myocardial damage by interfering with HMGB1-mediated TLR2 signalling. Cardiovasc Res. 101:400–410. 2014. View Article : Google Scholar : PubMed/NCBI | |
|
Chen S, Khan ZA, Karmazyn M and Chakrabarti S: Role of endothelin-1, sodium hydrogen exchanger-1 and mitogen activated protein kinase (MAPK) activation in glucose-induced cardiomyocyte hypertrophy. Diabetes Metab Res Rev. 23:356–367. 2007. View Article : Google Scholar : PubMed/NCBI | |
|
Wu M, Zhou Y, Pei D and Gao S: Unveiling the role of AGT in lipid metabolism and regulated cell death in colon cancer. Neoplasia. 54:1010092024. View Article : Google Scholar : PubMed/NCBI | |
|
Wu F, Zhang L, Wang L and Zhang D: AGT may serve as a prognostic biomarker and correlated with immune infiltration in gastric cancer. Int J Gen Med. 15:1865–1878. 2022. View Article : Google Scholar : PubMed/NCBI | |
|
Cassis LA, Police SB, Yiannikouris F and Thatcher SE: Local adipose tissue renin-angiotensin system. Curr Hypertens Rep. 10:93–98. 2008. View Article : Google Scholar : PubMed/NCBI | |
|
Wang W, Zhang S, Xu L, Feng Y, Wu X, Zhang M, Yu Z and Zhou X: Involvement of circHIPK3 in the pathogenesis of diabetic cardiomyopathy in mice. Diabetologia. 64:681–692. 2021. View Article : Google Scholar : PubMed/NCBI | |
|
Yurchenco PD: Basement membranes: Cell scaffoldings and signaling platforms. Cold Spring Harb Perspect Biol. 3:a0049112011. View Article : Google Scholar : PubMed/NCBI | |
|
Lu Y, Huo H, Liang F, Xue J, Fang L, Miao Y, Shen L and He B: Role of pericytes in cardiomyopathy-associated myocardial infarction revealed by multiple single-cell sequencing analysis. Biomedicines. 11:28962023. View Article : Google Scholar : PubMed/NCBI | |
|
Fazio A, Evangelisti C, Cappellini A, Mongiorgi S, Koufi FD, Neri I, Marvi MV, Russo M, Ghigo A, Manzoli L, et al: Emerging roles of phospholipase C beta isozymes as potential biomarkers in cardiac disorders. Int J Mol Sci. 24:130962023. View Article : Google Scholar : PubMed/NCBI | |
|
Woodcock EA, Grubb DR, Filtz TM, Marasco S, Luo J, McLeod-Dryden TJ, Kaye DM, Sadoshima J, Du XJ, Wong C, et al: Selective activation of the ‘b’ splice variant of phospholipase Cbeta1 in chronically dilated human and mouse atria. J Mol Cell Cardiol. 47:676–683. 2009. View Article : Google Scholar : PubMed/NCBI | |
|
Bernal-Lopez MR, Llorente-Cortes V, Calleja F, Lopez-Carmona D, Mayas MD, Gomez-Huelgas R, Badimon L and Tinahones FJ: Effect of different degrees of impaired glucose metabolism on the expression of inflammatory markers in monocytes of patients with atherosclerosis. Acta Diabetol. 50:553–562. 2013. View Article : Google Scholar : PubMed/NCBI | |
|
Yue Y, Meng K, Pu Y and Zhang X: Transforming growth factor beta (TGF-β) mediates cardiac fibrosis and induces diabetic cardiomyopathy. Diabetes Res Clin Pract. 133:124–130. 2017. View Article : Google Scholar : PubMed/NCBI | |
|
Tuersuntuoheti M, Zhou L, Li J, Yang S, Zhou S and Gong H: Investigation of crucial genes and mitochondrial function impairment in diabetic cardiomyopathy. Gene. 923:1485632024. View Article : Google Scholar : PubMed/NCBI | |
|
Du X, Li X, Chen L, Zhang M, Lei L, Gao W, Shi Z, Dong Y, Wang Z, Li X and Liu G: Hepatic miR-125b inhibits insulin signaling pathway by targeting PIK3CD. J Cell Physiol. 233:6052–6066. 2018. View Article : Google Scholar : PubMed/NCBI | |
|
Koya D and King GL: Protein kinase C activation and the development of diabetic complications. Diabetes. 47:859–866. 1998. View Article : Google Scholar : PubMed/NCBI |
