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Methods: The synergistic inhibition of \u03b1-glucosidase and \u03b1-amylase by DNJ-TFs was evaluated using enzyme assays and the Chou\u2013Talalay model. Insulin-resistant (IR) HepG2 cells and high-fat diet (HFD)-induced type 2 diabetes mellitus mice were treated with DNJ, TFs, or DNJ-TFs, determining the efficacy of drug combinations by measuring glycolipids and inflammatory factors. Network pharmacology and molecular docking were used to identify key target genes and signaling pathways, and CETSA experiments were used to verify the binding of drugs to targets. Key genes were further verified by immunofluorescence, Western blot, and Real-time PCR. Results: DNJ-TFs synergistically suppressed \u03b1-glucosidase (CI = 0.85) and \u03b1-amylase (CI = 0.76). In HepG2 cells, DNJ-TFs ameliorated palmitic acid-induced IR by promoting glucose uptake, attenuating lipid accumulation, and regulating glycolipid metabolism. In HFD mice, DNJ-TFs counteracted hyperglycemia, dyslipidemia, systemic inflammation and oxidative stress, elevated HOMA-IR, and hepatic steatosis. Network pharmacology integrated with experimental validation identified PTGS2 and MMP9 as key binding targets of DNJ and TFs. Furthermore, DNJ-TFs could inhibit the increase in liver TNF\u03b1 protein and the decrease in p-AKT, p-GSK\u03b1, p-GSK\u03b2, and GLUT2 protein caused by high fat, both in vivo and in vitro. Conclusions: DNJ and TFs exert synergistic glucose-lowering effects by targeting PTGS2\/MMP9 and regulating the TNF\u03b1\/AKT\/GSK3\/GLUT2 axis, providing a promising natural therapeutic strategy for diabetes management.<\/jats:p>","DOI":"10.3390\/nu18010099","type":"journal-article","created":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T08:47:27Z","timestamp":1766998047000},"page":"99","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["1-Deoxynojirimycin Combined with Theaflavins Targets PTGS2\/MMP9 to Exert a Synergistic Hypoglycemic Effect"],"prefix":"10.3390","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5086-3777","authenticated-orcid":false,"given":"Yuanyuan","family":"Wang","sequence":"first","affiliation":[{"name":"The College of Public Health, Shanghai University of Medicine & Health Sciences, 279 Zhouzhu Road, Pudong New Area, Shanghai 201318, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chenyin","family":"Qu","sequence":"additional","affiliation":[{"name":"The College of Public Health, Shanghai University of Medicine & Health Sciences, 279 Zhouzhu Road, Pudong New Area, Shanghai 201318, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qiannan","family":"Di","sequence":"additional","affiliation":[{"name":"The College of Public Health, Shanghai University of Medicine & Health Sciences, 279 Zhouzhu Road, Pudong New Area, Shanghai 201318, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jingyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"The College of Public Health, Shanghai University of Medicine & Health Sciences, 279 Zhouzhu Road, Pudong New Area, Shanghai 201318, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lixin","family":"Na","sequence":"additional","affiliation":[{"name":"The College of Public Health, Shanghai University of Medicine & Health Sciences, 279 Zhouzhu Road, Pudong New Area, Shanghai 201318, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,12,27]]},"reference":[{"key":"ref_1","unstructured":"Magliano, D.J., and Boyko, E.J. (2021). IDF Diabetes Atlas, International Diabetes Federation. [10th ed.]."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"118898","DOI":"10.1016\/j.jep.2024.118898","article-title":"Network pharmacology analysis revealed the mechanism and active compounds of jiao tai wan in the treatment of type 2 diabetes mellitus via SRC\/PI3K\/AKT signaling","volume":"337","author":"Ye","year":"2025","journal-title":"J. Ethnopharmacol."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"88","DOI":"10.1038\/nrendo.2017.151","article-title":"Global aetiology and epidemiology of type 2 diabetes mellitus and its complications","volume":"14","author":"Zheng","year":"2018","journal-title":"Nat. Rev. Endocrinol."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"S135","DOI":"10.2337\/dc20-S011","article-title":"11. Microvascular Complications and Foot Care: Standards of Medical Care in Diabetes-2020","volume":"43","year":"2020","journal-title":"Diabetes Care"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1007\/s40257-018-0400-7","article-title":"Cutaneous Adverse Effects of Diabetes Mellitus Medications and Medical Devices: A Review","volume":"20","author":"Jedlowski","year":"2019","journal-title":"Am. J. Clin. Dermatol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1882","DOI":"10.1016\/j.crfs.2022.10.006","article-title":"Metabolites of medicine food homology-derived endophytic fungi and their activities","volume":"5","author":"Zhang","year":"2022","journal-title":"Curr. Res. Food Sci."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"155106","DOI":"10.1016\/j.phymed.2023.155106","article-title":"Combinational application of the natural products 1-deoxynojirimycin and morin ameliorates insulin resistance and lipid accumulation in prediabetic mice","volume":"121","author":"Ren","year":"2023","journal-title":"Phytomedicine"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"41","DOI":"10.1080\/13510002.2019.1624085","article-title":"Antioxidant potential of theaflavin ameliorates the activities of key enzymes of glucose metabolism in high fat diet and streptozotocin\u2014Induced diabetic rats","volume":"24","author":"Gothandam","year":"2019","journal-title":"Redox Rep."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Xu, S., Chen, Y., and Gong, Y. (2024). Improvement of Theaflavins on Glucose and Lipid Metabolism in Diabetes Mellitus. Foods, 13.","DOI":"10.3390\/foods13111763"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"2033","DOI":"10.1039\/D1FO03856G","article-title":"Transcriptome analysis provides insight into the anti-diabetic mechanism of theaflavins in high-fat diet and streptozotocin-induced mice","volume":"13","author":"Wang","year":"2022","journal-title":"Food Funct."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1089\/jmf.2023.K.0180","article-title":"The Antiobesity Effects and Potential Mechanisms of Theaflavins","volume":"27","author":"Fang","year":"2024","journal-title":"J. Med. Food"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"S19","DOI":"10.2337\/dc23-S002","article-title":"2. Classification and Diagnosis of Diabetes: Standards of Care in Diabetes-2023","volume":"46","author":"ElSayed","year":"2023","journal-title":"Diabetes Care"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"7573904","DOI":"10.1155\/2017\/7573904","article-title":"Computational Molecular Networks and Network Pharmacology","volume":"2017","author":"Ning","year":"2017","journal-title":"Biomed. Res. Int."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"109798","DOI":"10.1016\/j.biopha.2019.109798","article-title":"Antidiabetic potential of Bauhinia forficata Link leaves: A non-cytotoxic source of lipase and glycoside hydrolases inhibitors and molecules with antioxidant and antiglycation properties","volume":"123","author":"Franco","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"4610","DOI":"10.1021\/jf5008264","article-title":"In vitro inhibitory effect on digestive enzymes and antioxidant potential of commonly consumed fruits","volume":"62","author":"Podsedek","year":"2014","journal-title":"J. Agric. Food Chem."},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1246","DOI":"10.1007\/s10495-017-1394-y","article-title":"Novel combination of salinomycin and resveratrol synergistically enhances the anti-proliferative and pro-apoptotic effects on human breast cancer cells","volume":"22","author":"Dewangan","year":"2017","journal-title":"Apoptosis"},{"key":"ref_17","doi-asserted-by":"crossref","unstructured":"Wang, Y., Zhao, X., Zhang, L., Yang, C., Zhang, K., Gu, Z., Ding, H., Li, S., Qin, J., and Chu, X. (2023). MicroRNA-34a Mediates High-Fat-Induced Hepatic Insulin Resistance by Targeting ENO3. Nutrients, 15.","DOI":"10.3390\/nu15214616"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1007\/s10238-019-00593-4","article-title":"Senescence-associated miR-34a and miR-126 in middle-aged Indians with type 2 diabetes","volume":"20","author":"Banerjee","year":"2020","journal-title":"Clin. Exp. Med."},{"key":"ref_19","first-page":"9050754","article-title":"Evaluation of Decalcification Techniques for Rat Femurs Using HE and Immunohistochemical Staining","volume":"2017","author":"Liu","year":"2017","journal-title":"Biomed. Res. Int."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"D605","DOI":"10.1093\/nar\/gkaa1074","article-title":"The STRING database in 2021: Customizable protein-protein networks, and functional characterization of user-uploaded gene\/measurement sets","volume":"49","author":"Szklarczyk","year":"2021","journal-title":"Nucleic Acids Res."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"11526","DOI":"10.1021\/jf802607x","article-title":"Gossypin up-regulates LDL receptor through activation of ERK pathway: A signaling mechanism for the hypocholesterolemic effect","volume":"56","author":"Lu","year":"2008","journal-title":"J. Agric. Food Chem."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"111738","DOI":"10.1016\/j.fct.2020.111738","article-title":"An overview on the role of bioactive alpha-glucosidase inhibitors in ameliorating diabetic complications","volume":"145","author":"Hossain","year":"2020","journal-title":"Food Chem. Toxicol."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Riyaphan, J., Pham, D.C., Leong, M.K., and Weng, C.F. (2021). In Silico Approaches to Identify Polyphenol Compounds as alpha-Glucosidase and alpha-Amylase Inhibitors against Type-II Diabetes. Biomolecules, 11.","DOI":"10.3390\/biom11121877"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"457","DOI":"10.1126\/science.1103160","article-title":"Endoplasmic reticulum stress links obesity, insulin action, and type 2 diabetes","volume":"306","author":"Ozcan","year":"2004","journal-title":"Science"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1186\/s12944-015-0123-1","article-title":"The role of fatty acids in insulin resistance","volume":"14","author":"Sears","year":"2015","journal-title":"Lipids Health Dis."},{"key":"ref_26","doi-asserted-by":"crossref","unstructured":"Roell, K.R., Reif, D.M., and Motsinger-Reif, A.A. (2017). An Introduction to Terminology and Methodology of Chemical Synergy-Perspectives from Across Disciplines. Front. Pharmacol., 8.","DOI":"10.3389\/fphar.2017.00158"},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"366","DOI":"10.1096\/fj.06-6620com","article-title":"Inhibition of the intestinal glucose transporter GLUT2 by flavonoids","volume":"21","author":"Kwon","year":"2007","journal-title":"FASEB J."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"2180","DOI":"10.2337\/db05-1188","article-title":"Polyphenols stimulate AMP-activated protein kinase, lower lipids, and inhibit accelerated atherosclerosis in diabetic LDL receptor-deficient mice","volume":"55","author":"Zang","year":"2006","journal-title":"Diabetes"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1063","DOI":"10.1096\/fasebj.12.12.1063","article-title":"Cyclooxygenase in biology and disease","volume":"12","author":"Dubois","year":"1998","journal-title":"FASEB J."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1605","DOI":"10.1016\/j.bbamcr.2007.09.001","article-title":"Regulation of cyclooxygenase-2 expression by cyclic AMP","volume":"1773","author":"Klein","year":"2007","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"4157","DOI":"10.7150\/ijbs.86492","article-title":"The PTGS2\/COX2-PGE(2) signaling cascade in inflammation: Pro or anti? A case study with type 1 diabetes mellitus","volume":"19","author":"Lorenzo","year":"2023","journal-title":"Int. J. Biol. Sci."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"9047","DOI":"10.1074\/jbc.275.12.9047","article-title":"The c-Jun NH(2)-terminal kinase promotes insulin resistance during association with insulin receptor substrate-1 and phosphorylation of Ser(307)","volume":"275","author":"Aguirre","year":"2000","journal-title":"J. Biol. Chem."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"30490","DOI":"10.1155\/MI\/2006\/30490","article-title":"Theaflavin ameliorates cerebral ischemia-reperfusion injury in rats through its anti-inflammatory effect and modulation of STAT-1","volume":"2006","author":"Cai","year":"2006","journal-title":"Mediat. Inflamm."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"198","DOI":"10.1002\/mnfr.201000165","article-title":"Effects of the black tea polyphenol theaflavin-2 on apoptotic and inflammatory pathways in vitro and in vivo","volume":"55","author":"Gosslau","year":"2011","journal-title":"Mol. Nutr. Food Res."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1534","DOI":"10.1021\/acs.jnatprod.1c00014","article-title":"Dual-Targeting Antiproliferation Hybrids Derived from 1-Deoxynojirimycin and Kaempferol Induce MCF-7 Cell Apoptosis through the Mitochondria-Mediated Pathway","volume":"84","author":"Zhang","year":"2021","journal-title":"J. Nat. Prod."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"1729","DOI":"10.1161\/01.CIR.0000124718.99562.91","article-title":"Association of type 2 diabetes with cyclooxygenase-mediated inflammation and oxidative stress in an elderly population","volume":"109","author":"Helmersson","year":"2004","journal-title":"Circulation"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"377","DOI":"10.1007\/s00439-003-1000-y","article-title":"Association of a promoter variant in the inducible cyclooxygenase-2 gene (PTGS2) with type 2 diabetes mellitus in Pima Indians","volume":"113","author":"Konheim","year":"2003","journal-title":"Hum. Genet."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1150","DOI":"10.1038\/oby.2008.674","article-title":"It has been re-uploaded","volume":"17","author":"Hsieh","year":"2009","journal-title":"Obesity"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"104","DOI":"10.1016\/j.prostaglandins.2009.04.003","article-title":"Emerging roles of PGE2 receptors in models of neurological disease","volume":"91","author":"Andreasson","year":"2010","journal-title":"Prostaglandins Other Lipid Mediat."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"278","DOI":"10.1124\/pr.117.014647","article-title":"Neuroimmune Axes of the Blood-Brain Barriers and Blood-Brain Interfaces: Bases for Physiological Regulation, Disease States, and Pharmacological Interventions","volume":"70","author":"Erickson","year":"2018","journal-title":"Pharmacol. Rev."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"153","DOI":"10.1172\/JCI59660","article-title":"Obesity is associated with hypothalamic injury in rodents and humans","volume":"122","author":"Thaler","year":"2012","journal-title":"J. Clin. Investig."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"259","DOI":"10.1177\/1753425919887236","article-title":"MMP9 protects against LPS-induced inflammation in osteoblasts","volume":"26","author":"Zhang","year":"2020","journal-title":"Innate Immun."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"222","DOI":"10.3109\/10409238.2013.770819","article-title":"Biochemistry and molecular biology of gelatinase B or matrix metalloproteinase-9 (MMP-9): The next decade","volume":"48","author":"Vandooren","year":"2013","journal-title":"Crit. Rev. Biochem. Mol. Biol."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"30078","DOI":"10.1038\/s41598-025-15556-x","article-title":"Network pharmacology and metabolomics reveal mathurameha, a Thai traditional Anti-Diabetic formula, enhances glucose metabolism through PI3K-AKT\/AMPK\/GLUT4 pathway modulation","volume":"15","author":"Banerjee","year":"2025","journal-title":"Sci. Rep."},{"key":"ref_45","doi-asserted-by":"crossref","unstructured":"Bradley, L.M., Douglass, M.F., Chatterjee, D., Akira, S., and Baaten, B.J. (2012). Matrix metalloprotease 9 mediates neutrophil migration into the airways in response to influenza virus-induced toll-like receptor signaling. PLoS Pathog., 8.","DOI":"10.1371\/journal.ppat.1002641"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"4581","DOI":"10.1074\/jbc.M111.321182","article-title":"Metalloproteinase-mediated Shedding of Integrin beta2 promotes macrophage efflux from inflammatory sites","volume":"287","author":"Gomez","year":"2012","journal-title":"J. Biol. Chem."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"1044","DOI":"10.1074\/mcp.M800449-MCP200","article-title":"MMP-9 sheds the beta2 integrin subunit (CD18) from macrophages","volume":"8","author":"Vaisar","year":"2009","journal-title":"Mol. Cell Proteom."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"11888","DOI":"10.1074\/jbc.M209196200","article-title":"Matrix metalloproteinases are differentially expressed in adipose tissue during obesity and modulate adipocyte differentiation","volume":"278","author":"Chavey","year":"2003","journal-title":"J. Biol. Chem."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"149","DOI":"10.1002\/path.2287","article-title":"TNF-mediated inflammatory disease","volume":"214","author":"Bradley","year":"2008","journal-title":"J. Pathol."},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Xu, Z., Xu, J., Li, S., Cui, H., Zhang, G., Ni, X., and Wang, J. (2022). S-Equol enhances osteoblastic bone formation and prevents bone loss through OPG\/RANKL via the PI3K\/Akt pathway in streptozotocin-induced diabetic rats. Front. Nutr., 9.","DOI":"10.3389\/fnut.2022.986192"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"435","DOI":"10.2147\/DDDT.S330947","article-title":"Network Pharmacology and Molecular Docking Study of the Chinese Miao Medicine Sidaxue in the Treatment of Rheumatoid Arthritis","volume":"16","author":"Wu","year":"2022","journal-title":"Drug Des. Devel Ther."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"3706508","DOI":"10.1155\/2022\/3706508","article-title":"Role of C-Reactive Protein in Diabetic Inflammation","volume":"2022","author":"Stanimirovic","year":"2022","journal-title":"Mediat. Inflamm."},{"key":"ref_53","doi-asserted-by":"crossref","first-page":"45","DOI":"10.1038\/sj.cdd.4401189","article-title":"Tumor necrosis factor signaling","volume":"10","author":"Wajant","year":"2003","journal-title":"Cell Death Differ."},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"389","DOI":"10.1080\/15216540500137669","article-title":"RANKing intracellular signaling in osteoclasts","volume":"57","author":"Feng","year":"2005","journal-title":"IUBMB Life"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"3560819","DOI":"10.1155\/2019\/3560819","article-title":"TNF-alpha Downregulation Modifies Insulin Receptor Substrate 1 (IRS-1) in Metabolic Signaling of Diabetic Insulin-Resistant Hepatocytes","volume":"2019","author":"Alipourfard","year":"2019","journal-title":"Mediat. Inflamm."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"e2401716121","DOI":"10.1073\/pnas.2401716121","article-title":"The serine phosphorylations in the IRS-1 PIR domain abrogate IRS-1 and IR interaction","volume":"121","author":"Woo","year":"2024","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1038\/nrm1837","article-title":"Critical nodes in signalling pathways: Insights into insulin action","volume":"7","author":"Taniguchi","year":"2006","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1016\/j.cmet.2019.03.010","article-title":"Insulin-Driven PI3K-AKT Signaling in the Hepatocyte Is Mediated by Redundant PI3Kalpha and PI3Kbeta Activities and Is Promoted by RAS","volume":"29","author":"Molinaro","year":"2019","journal-title":"Cell Metab."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1728","DOI":"10.1126\/science.292.5522.1728","article-title":"Insulin resistance and a diabetes mellitus-like syndrome in mice lacking the protein kinase Akt2 (PKB beta)","volume":"292","author":"Cho","year":"2001","journal-title":"Science"},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"e300721195147","DOI":"10.2174\/1573399817666210730094225","article-title":"Role of Glycogen Synthase Kinase-3 in the Etiology of Type 2 Diabetes Mellitus: A Review","volume":"18","author":"Bala","year":"2022","journal-title":"Curr. Diabetes Rev."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"9643","DOI":"10.1074\/jbc.R800077200","article-title":"Unique and overlapping functions of GSK-3 isoforms in cell differentiation and proliferation and cardiovascular development","volume":"284","author":"Force","year":"2009","journal-title":"J. Biol. Chem."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"6963","DOI":"10.1007\/s11033-023-08535-w","article-title":"The role of GLUT2 in glucose metabolism in multiple organs and tissues","volume":"50","author":"Sun","year":"2023","journal-title":"Mol. Biol. Rep."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1007\/s12020-016-1031-5","article-title":"20-HETE attenuates the response of glucose-stimulated insulin secretion through the AKT\/GSK-3beta\/Glut2 pathway","volume":"54","author":"Zhang","year":"2016","journal-title":"Endocrine"},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"4506","DOI":"10.3892\/mmr.2016.5081","article-title":"3-Deoxyglucosone induces insulin resistance by impairing insulin signaling in HepG2 cells","volume":"13","author":"Liang","year":"2016","journal-title":"Mol. Med. Rep."},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"383","DOI":"10.1038\/nrm3351","article-title":"Regulation of glucose transport by insulin: Traffic control of GLUT4","volume":"13","author":"Leto","year":"2012","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"ref_66","doi-asserted-by":"crossref","unstructured":"Wang, K., Chen, D., Yu, B., He, J., Mao, X., Huang, Z., Yan, H., Wu, A., Luo, Y., and Zheng, P. (2022). Eugenol alleviates transmissible gastroenteritis virus-induced intestinal epithelial injury by regulating NF-kappaB signaling pathway. Front. Immunol., 13.","DOI":"10.3389\/fimmu.2022.921613"},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1016\/j.pharmthera.2014.11.016","article-title":"Glycogen synthase kinase-3 (GSK3): Regulation, actions, and diseases","volume":"148","author":"Beurel","year":"2015","journal-title":"Pharmacol. Ther."},{"key":"ref_68","doi-asserted-by":"crossref","unstructured":"Llorens-Martin, M., Jurado, J., Hernandez, F., and Avila, J. (2014). GSK-3beta, a pivotal kinase in Alzheimer disease. Front. Mol. Neurosci., 7.","DOI":"10.3389\/fnmol.2014.00046"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"1455","DOI":"10.2337\/db11-0390","article-title":"Inhibition of hypothalamic inflammation reverses diet-induced insulin resistance in the liver","volume":"61","author":"Milanski","year":"2012","journal-title":"Diabetes"},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1069","DOI":"10.4103\/NRR.NRR-D-23-01770","article-title":"Role of metabolic dysfunction and inflammation along the liver-brain axis in animal models with obesity-induced neurodegeneration","volume":"20","author":"Asimakidou","year":"2025","journal-title":"Neural Regen. Res."}],"container-title":["Nutrients"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/1\/99\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,12,29]],"date-time":"2025-12-29T08:54:32Z","timestamp":1766998472000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2072-6643\/18\/1\/99"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,12,27]]},"references-count":70,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2026,1]]}},"alternative-id":["nu18010099"],"URL":"https:\/\/doi.org\/10.3390\/nu18010099","relation":{},"ISSN":["2072-6643"],"issn-type":[{"value":"2072-6643","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,12,27]]}}}