O-GlcNAc糖基化在糖尿病及其并发症中的研究进展
Research Progress on O-GlcNAc Glycosylation in Diabetes Mellitus and Its Complications
DOI: 10.12677/pi.2026.153028, PDF,   
作者: 程 露, 吴斐华*：中国药科大学中药学院，江苏 南京
关键词: O-GlcNAc糖基化；糖尿病；糖尿病并发症；O-GlcNAc Glycosylation； Diabetes Mellitus； Diabetic Complications
摘要: O-连接β-N-乙酰葡糖胺(O-Linked β-N-Acetylglucosamine, O-GlcNAc)糖基化是一种动态可逆的蛋白质翻译后修饰，可发生于细胞内数千种蛋白的丝氨酸或苏氨酸残基上，通过调控转录、表观遗传和信号传导在各种细胞过程中起重要作用。糖尿病是一种慢性代谢疾病，长期高血糖可累及多种组织器官，导致一系列并发症。近年来，越来越多的证据表明，O-GlcNAc糖基化修饰广泛参与糖尿病及其并发症的发生与发展。文章梳理了O-GlcNAc糖基化修饰调控机制和生理作用，重点探讨了O-GlcNAc糖基化修饰在糖尿病及其并发症中的作用机制。
Abstract: O-linked β-N-acetylglucosamine (O-GlcNAc) glycosylation is a dynamically reversible protein post-translational modification that is present on serine or threonine residues of thousands of proteins in cells and plays an important role in various cellular processes by regulating transcription, epigenetics, and signaling. Diabetes is a chronic metabolic disease, and long-term hyperglycemia can affect a variety of tissues and organs, leading to a series of complications. In recent years, accumulating evidence has indicated that O-GlcNAc glycosylation is extensively involved in the occurrence and development of diabetes and its complications. This article reviews the regulatory mechanisms and physiological functions of O-GlcNAc glycosylation, with a focus on its mechanistic roles in diabetes and its complications.
文章引用：程露, 吴斐华. O-GlcNAc糖基化在糖尿病及其并发症中的研究进展[J]. 药物资讯, 2026, 15(3): 251-261. https://doi.org/10.12677/pi.2026.153028

参考文献

[1] Abel, E.D., Gloyn, A.L., Evans-Molina, C., Joseph, J.J., Misra, S., Pajvani, U.B., et al. (2024) Diabetes Mellitus—Progress and Opportunities in the Evolving Epidemic. Cell, 187, 3789-3820. [Google Scholar] [CrossRef] [PubMed]
[2] Luk, A., Wild, S.H., Jones, S., Anjana, R.M., Hivert, M., McCaffrey, J., et al. (2025) Early-Onset Type 2 Diabetes: The Next Major Diabetes Transition. The Lancet, 405, 2313-2326. [Google Scholar] [CrossRef] [PubMed]
[3] Ong, K.L., Stafford, L.K., McLaughlin, S.A., Boyko, E.J., Vollset, S.E., Smith, A.E., et al. (2023) Global, Regional, and National Burden of Diabetes from 1990 to 2021, with Projections of Prevalence to 2050: A Systematic Analysis for the Global Burden of Disease Study 2021. The Lancet, 402, 203-234. [Google Scholar] [CrossRef] [PubMed]
[4] Xie, Z., Xie, T., Liu, J., Zhang, Q. and Xiao, X. (2023) Emerging Role of Protein O-GlcNAcylation in Liver Metabolism: Implications for Diabetes and NAFLD. International Journal of Molecular Sciences, 24, Article 2142. [Google Scholar] [CrossRef] [PubMed]
[5] Lee, C., Kim, S.M., Kim, D.Y. and Han, I.O. (2025) O-GlcNAc Cycling in Neuroinflammation: From Molecular Mechanisms and Therapeutic Perspectives. Neurobiology of Disease, 217, Article 107160. [Google Scholar] [CrossRef] 
[6] Hardivillé, S. and Hart, G.W. (2014) Nutrient Regulation of Signaling, Transcription, and Cell Physiology by O-GlcNAcylation. Cell Metabolism, 20, 208-213. [Google Scholar] [CrossRef] [PubMed]
[7] Hong, Z.Z., Lowe, J. and Jiang, J. (2025) Dissecting the Mechanisms Underlying Substrate Recognition and Functional Regulation of O-GlcNAc Cycling Enzymes. ACS Chemical Biology, 20, 2534-2546. [Google Scholar] [CrossRef] 
[8] Lazarus, M.B., Nam, Y., Jiang, J., Sliz, P. and Walker, S. (2011) Structure of Human O-GlcNAc Transferase and Its Complex with a Peptide Substrate. Nature, 469, 564-567. [Google Scholar] [CrossRef] [PubMed]
[9] Griffin, M.E., Thompson, J.W., Xiao, Y., Sweredoski, M.J., Jensen, E.H., Aksenfeld, R.B., et al. (2026) Functional Analysis of O-GlcNAcylation by Networking of OGT Interactors and Substrates. Nature Chemical Biology, 2026, 1-12. [Google Scholar] [CrossRef] 
[10] Nyenhuis, S.B., Steenackers, A., Mukherjee, M.M., Hinshaw, J.E. and Hanover, J.A. (2025) Human O-GlcNAcase Catalytic-Stalk Dimer Anchors Flexible Histone Binding Domains. Communications Chemistry, 9, Article No. 8. [Google Scholar] [CrossRef] 
[11] Lu, P., Liu, Y., He, M., Cao, T., Yang, M., Qi, S., et al. (2023) Cryo-EM Structure of Human O-GlcNAcylation Enzyme Pair OGT-OGA Complex. Nature Communications, 14, Article No. 6952. [Google Scholar] [CrossRef] [PubMed]
[12] Wulff-Fuentes, E., Berendt, R.R., Massman, L., Danner, L., Malard, F., Vora, J., et al. (2021) The Human O-GlcNAcome Database and Meta-Analysis. Scientific Data, 8, Article No. 25. [Google Scholar] [CrossRef] [PubMed]
[13] Ma, J., Hou, C. and Wu, C. (2022) Demystifying the O-GlcNAc Code: A Systems View. Chemical Reviews, 122, 15822-15864. [Google Scholar] [CrossRef] [PubMed]
[14] Mody, A.C., Ramirez, D.H. and Woo, C.M. (2025) Targeted Protein O-GlcNAc Reveals Transcriptional Functions for O-GlcNAc. Cell Chemical Biology, 32, 1486-1502.e7. [Google Scholar] [CrossRef] 
[15] Lewis, B.A., Burlingame, A.L. and Myers, S.A. (2016) Human RNA Polymerase II Promoter Recruitment in Vitro Is Regulated by O-Linked N-Acetylglucosaminyltransferase (OGT). Journal of Biological Chemistry, 291, 14056-14061. [Google Scholar] [CrossRef] [PubMed]
[16] Sakabe, K., Wang, Z. and Hart, G.W. (2010) β-N-Acetylglucosamine (O-GlcNAc) Is Part of the Histone Code. Proceedings of the National Academy of Sciences, 107, 19915-19920. [Google Scholar] [CrossRef] [PubMed]
[17] Wu, D., Cai, Y. and Jin, J. (2017) Potential Coordination Role between O-GlcNAcylation and Epigenetics. Protein & Cell, 8, 713-723. [Google Scholar] [CrossRef] [PubMed]
[18] Zhang, S., Roche, K., Nasheuer, H. and Lowndes, N.F. (2011) Modification of Histones by Sugar β-N-Acetylglucosamine (GlcNAc) Occurs on Multiple Residues, Including Histone H3 Serine 10, and Is Cell Cycle-Regulated. Journal of Biological Chemistry, 286, 37483-37495. [Google Scholar] [CrossRef] [PubMed]
[19] Shi, F., Kim, H., Lu, W., He, Q., Liu, D., Goodell, M.A., et al. (2013) Ten-Eleven Translocation 1 (Tet1) Is Regulated by O-Linked N-Acetylglucosamine Transferase (OGT) for Target Gene Repression in Mouse Embryonic Stem Cells. Journal of Biological Chemistry, 288, 20776-20784. [Google Scholar] [CrossRef] [PubMed]
[20] Yang, X. and Qian, K. (2017) Protein O-GlcNAcylation: Emerging Mechanisms and Functions. Nature Reviews Molecular Cell Biology, 18, 452-465. [Google Scholar] [CrossRef] [PubMed]
[21] Leney, A.C., El Atmioui, D., Wu, W., Ovaa, H. and Heck, A.J.R. (2017) Elucidating Crosstalk Mechanisms between Phosphorylation and O-GlcNAcylation. Proceedings of the National Academy of Sciences, 114, E7255-E7261. [Google Scholar] [CrossRef] [PubMed]
[22] Wong, A., Pritchard, S., Moore, M., Akhaphong, B., Avula, N., Beetch, M., et al. (2023) Overexpression of Pdx1, Reduction of P53, or Deletion of CHOP Attenuates Pancreas Hypoplasia in Mice with Pancreas-Specific O-GlcNAc Transferase Deletion. Journal of Biological Chemistry, 299, Article 102878. [Google Scholar] [CrossRef] [PubMed]
[23] Lockridge, A., Jo, S., Gustafson, E., Damberg, N., Mohan, R., Olson, M., et al. (2020) Islet O-GlcNAcylation Is Required for Lipid Potentiation of Insulin Secretion through Serca2. Cell Reports, 31, Article 107609. [Google Scholar] [CrossRef] [PubMed]
[24] Kang, E., Han, D., Park, J., Kwak, T.K., Oh, M., Lee, S., et al. (2008) O-GlcNAc Modulation at Akt1 Ser473 Correlates with Apoptosis of Murine Pancreatic Β Cells. Experimental Cell Research, 314, 2238-2248. [Google Scholar] [CrossRef] [PubMed]
[25] Filhoulaud, G., Benhamed, F., Pagesy, P., Bonner, C., Fardini, Y., Ilias, A., et al. (2019) O-GlcNAcylation Links TxNIP to Inflammasome Activation in Pancreatic Β Cells. Frontiers in Endocrinology, 10, Article 291. [Google Scholar] [CrossRef] [PubMed]
[26] Jo, S., Esch, N., Nguyen, A., Wong, A., Mohan, R., Kim, C., et al. (2024) Loss of O-GlcNAcylation Modulates mTORC1 and Autophagy in β Cells, Driving Diabetes 2 Progression. JCI Insight, 9, e183033. [Google Scholar] [CrossRef] [PubMed]
[27] Mohan, R., Jo, S., Lockridge, A., Ferrington, D.A., Murray, K., Eschenlauer, A., et al. (2021) OGT Regulates Mitochondrial Biogenesis and Function via Diabetes Susceptibility Gene Pdx1. Diabetes, 70, 2608-2625. [Google Scholar] [CrossRef] [PubMed]
[28] Robles-Flores, M., Meléndez, L., García, W., Mendoza-Hernández, G., Lam, T.T., Castañeda-Patlán, C., et al. (2008) Posttranslational Modifications on Protein Kinase C Isozymes. Effects of Epinephrine and Phorbol Esters. Biochimica et Biophysica Acta—Molecular Cell Research, 1783, 695-712. [Google Scholar] [CrossRef] [PubMed]
[29] Yang, X., Ongusaha, P.P., Miles, P.D., Havstad, J.C., Zhang, F., So, W.V., et al. (2008) Phosphoinositide Signalling Links O-GlcNAc Transferase to Insulin Resistance. Nature, 451, 964-969. [Google Scholar] [CrossRef] [PubMed]
[30] Banerjee, P.S., Lagerlöf, O. and Hart, G.W. (2016) Roles of O-GlcNAc in Chronic Diseases of Aging. Molecular Aspects of Medicine, 51, 1-15. [Google Scholar] [CrossRef] [PubMed]
[31] Nabeebaccus, A.A., Zoccarato, A., Hafstad, A.D., Santos, C.X.C., Aasum, E., Brewer, A.C., et al. (2017) Nox4 Reprograms Cardiac Substrate Metabolism via Protein O-GlcNAcylation to Enhance Stress Adaptation. JCI Insight, 2, e96184. [Google Scholar] [CrossRef] [PubMed]
[32] Hu, Y., Belke, D., Suarez, J., Swanson, E., Clark, R., Hoshijima, M., et al. (2005) Adenovirus-Mediated Overexpression of O-GlcNAcase Improves Contractile Function in the Diabetic Heart. Circulation Research, 96, 1006-1013. [Google Scholar] [CrossRef] [PubMed]
[33] Clark, R.J., McDonough, P.M., Swanson, E., Trost, S.U., Suzuki, M., Fukuda, M., et al. (2003) Diabetes and the Accompanying Hyperglycemia Impairs Cardiomyocyte Calcium Cycling through Increased Nuclear O-GlcNAcylation. Journal of Biological Chemistry, 278, 44230-44237. [Google Scholar] [CrossRef] [PubMed]
[34] Aguilar, H., Fricovsky, E., Ihm, S., Schimke, M., Maya-Ramos, L., Aroonsakool, N., et al. (2014) Role for High-Glucose-Induced Protein O-GlcNAcylation in Stimulating Cardiac Fibroblast Collagen Synthesis. American Journal of Physiology-Cell Physiology, 306, C794-C804. [Google Scholar] [CrossRef] [PubMed]
[35] Chatham, J.C. and Wende, A.R. (2024) The Role of Protein O-GlcNAcylation in Diabetic Cardiomyopathy. Biochemical Society Transactions, 52, 2343-2358. [Google Scholar] [CrossRef] [PubMed]
[36] Ding, M., Shi, R., Du, Y., Chang, P., Gao, T., De, D., et al. (2025) O-GlcNAcylation-Mediated Endothelial Metabolic Memory Contributes to Cardiac Damage via Small Extracellular Vesicles. Cell Metabolism, 37, 1344-1363.e6. [Google Scholar] [CrossRef] [PubMed]
[37] Si, R., Zhang, Q., Tsuji-Hosokawa, A., Watanabe, M., Willson, C., Lai, N., et al. (2020) Overexpression of P53 Due to Excess Protein O-GlcNAcylation Is Associated with Coronary Microvascular Disease in Type 2 Diabetes. Cardiovascular Research, 116, 1186-1198. [Google Scholar] [CrossRef] [PubMed]
[38] Makino, A., Dai, A., Han, Y., Youssef, K.D., Wang, W., Donthamsetty, R., et al. (2015) O-Glcnacase Overexpression Reverses Coronary Endothelial Cell Dysfunction in Type 1 Diabetic Mice. American Journal of Physiology-Cell Physiology, 309, C593-C599. [Google Scholar] [CrossRef] [PubMed]
[39] Lo, W.Y., Yang, W.K., Peng, C.T., Pai, W.Y. and Wang, H.J. (2018) MicroRNA-200a/200b Modulate High Glucose-Induced Endothelial Inflammation by Targeting O-Linked N-Acetylglucosamine Transferase Expression. Frontiers in Physiology, 9, Article 355. [Google Scholar] [CrossRef] [PubMed]
[40] Chikanishi, T., Fujiki, R., Hashiba, W., Sekine, H., Yokoyama, A. and Kato, S. (2010) Glucose-Induced Expression of MIP-1 Genes Requires O-GlcNAc Transferase in Monocytes. Biochemical and Biophysical Research Communications, 394, 865-870. [Google Scholar] [CrossRef] [PubMed]
[41] Wen, L., Dai, R., Yu, S. and Yu, H. (2026) OGT-Mediated O-GlcNAcylation of MAGI1 Exacerbates High Glucose-Triggered Inflammation and Dedifferentiation of Vascular Smooth Muscle Cells by Activating the PI3K/AKT Pathway. Hereditas, 163, Article 22. [Google Scholar] [CrossRef] 
[42] Byon, C.H. and Kim, S.W. (2020) Regulatory Effects of O-GlcNAcylation in Vascular Smooth Muscle Cells on Diabetic Vasculopathy. Journal of Lipid and Atherosclerosis, 9, 243-254. [Google Scholar] [CrossRef] [PubMed]
[43] Koyama, T. and Kamemura, K. (2015) Global Increase in O-Linked N-Acetylglucosamine Modification Promotes Osteoblast Differentiation. Experimental Cell Research, 338, 194-202. [Google Scholar] [CrossRef] [PubMed]
[44] Vigetti, D., Deleonibus, S., Moretto, P., Karousou, E., Viola, M., Bartolini, B., et al. (2012) Role of UDP-N-Acetylglucosamine (GlcNAc) and O-GlcNAcylation of Hyaluronan Synthase 2 in the Control of Chondroitin Sulfate and Hyaluronan Synthesis. Journal of Biological Chemistry, 287, 35544-35555. [Google Scholar] [CrossRef] [PubMed]
[45] Weigert, C., Brodbeck, K., Sawadogo, M., Häring, H.U. and Schleicher, E.D. (2004) Upstream Stimulatory Factor (USF) Proteins Induce Human TGF-β1 Gene Activation via the Glucose-Response Element-1013/-1002 in Mesangial Cells: Up-Regulation of USF Activity by the Hexosamine Biosynthetic Pathway. Journal of Biological Chemistry, 279, 15908-15915. [Google Scholar] [CrossRef] [PubMed]
[46] Qi, B., Chen, Y., Chai, S., Lu, X. and Kang, L. (2025) O-Linked β-N-Acetylglucosamine (O-GlcNAc) Modification: Emerging Pathogenesis and a Therapeutic Target of Diabetic Nephropathy. Diabetic Medicine, 42, e15436. [Google Scholar] [CrossRef] [PubMed]
[47] Gellai, R., Hodrea, J., Lenart, L., Hosszu, A., Koszegi, S., Balogh, D., et al. (2016) Role of O-Linkedn-Acetylglucosamine Modification in Diabetic Nephropathy. American Journal of Physiology-Renal Physiology, 311, F1172-F1181. [Google Scholar] [CrossRef] [PubMed]
[48] Park, M., Kim, D., Lim, S., Choi, J., Han, H., Yoon, K., et al. (2014) High Glucose-Induced O-GlcNAcylated Carbohydrate Response Element-Binding Protein (ChREBP) Mediates Mesangial Cell Lipogenesis and Fibrosis: The Possible Role in the Development of Diabetic Nephropathy. Journal of Biological Chemistry, 289, 13519-13530. [Google Scholar] [CrossRef] [PubMed]
[49] Goldberg, H.J., Whiteside, C.I., Hart, G.W. and Fantus, I.G. (2006) Posttranslational, Reversible O-Glycosylation Is Stimulated by High Glucose and Mediates Plasminogen Activator Inhibitor-1 Gene Expression and Sp1 Transcriptional Activity in Glomerular Mesangial Cells. Endocrinology, 147, 222-231. [Google Scholar] [CrossRef] [PubMed]
[50] Chen, W., Liu, J., Zou, Y., Lu, F., Zhang, J., Hu, Y., et al. (2025) O-GlcNAcylation Stabilizes NEK7 to Drive Podocyte Pyroptosis in Diabetic Kidney Disease. Diabetes, 74, 2279-2290. [Google Scholar] [CrossRef] 
[51] Park, S.Y., Kim, H.S., Kim, N.H., Ji, S., Cha, S.Y., Kang, J.G., et al. (2010) Snail1 Is Stabilized by O-GlcNAc Modification in Hyperglycaemic Condition. The EMBO Journal, 29, 3787-3796. [Google Scholar] [CrossRef] [PubMed]
[52] Lin, S., Wang, Q., Huang, X., Feng, J., Wang, Y., Shao, T., et al. (2023) Wounds under Diabetic Milieu: The Role of Immune Cellar Components and Signaling Pathways. Biomedicine & Pharmacotherapy, 157, Article 114052. [Google Scholar] [CrossRef] [PubMed]
[53] Machacek, M., Saunders, H., Zhang, Z., Tan, E.P., Li, J., Li, T., et al. (2019) Elevated O-GlcNAcylation Enhances Pro-Inflammatory Th17 Function by Altering the Intracellular Lipid Microenvironment. Journal of Biological Chemistry, 294, 8973-8990. [Google Scholar] [CrossRef] [PubMed]
[54] Zibrova, D., Vandermoere, F., Göransson, O., Peggie, M., Mariño, K.V., Knierim, A., et al. (2017) GFAT1 Phosphorylation by AMPK Promotes VEGF-Induced Angiogenesis. Biochemical Journal, 474, 983-1001. [Google Scholar] [CrossRef] [PubMed]
[55] Qi, B., Chai, S., Chen, Y., Zhou, G., Li, P., Li, X., et al. (2025) O-Linked β-N-Acetylglucosamine Modification in Diabetic Foot Ulcer Pathogenesis. Burns & Trauma, 13, tkaf044. [Google Scholar] [CrossRef] 
[56] Zhang, J., Yang, P., Liu, D., Gao, M., Wang, J., Yu, T., et al. (2021) Inhibiting Hyper-O-GlcNAcylation of C-Myc Accelerate Diabetic Wound Healing by Alleviating Keratinocyte Dysfunction. Burns & Trauma, 9, tkab031. [Google Scholar] [CrossRef] [PubMed]
[57] Yuzwa, S.A., Macauley, M.S., Heinonen, J.E., Shan, X., Dennis, R.J., He, Y., et al. (2008) A Potent Mechanism-Inspired O-GlcNAcase Inhibitor That Blocks Phosphorylation of Tau in Vivo. Nature Chemical Biology, 4, 483-490. [Google Scholar] [CrossRef] [PubMed]
[58] Yan, X., Zheng, J., Ren, W., Li, S., Yang, S., Zhi, K., et al. (2024) O-GlcNAcylation: Roles and Potential Therapeutic Target for Bone Pathophysiology. Cell Communication and Signaling, 22, Article No. 279. [Google Scholar] [CrossRef] [PubMed]
[59] Ortiz-Meoz, R.F., Jiang, J., Lazarus, M.B., Orman, M., Janetzko, J., Fan, C., et al. (2015) A Small Molecule That Inhibits OGT Activity in Cells. ACS Chemical Biology, 10, 1392-1397. [Google Scholar] [CrossRef] [PubMed]
[60] Ma, B., Khan, K.S., Xu, T., et al. (2024) Targeted Protein O-GlcNAcylation Using Bifunctional Small Molecules. Journal of the American Chemical Society, 146, 9779-9789. [Google Scholar] [CrossRef] [PubMed]