{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T11:57:58Z","timestamp":1785412678573,"version":"3.56.0"},"reference-count":70,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T00:00:00Z","timestamp":1784592000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Health Science and Technology Capability Enhancement Project of Jilin Province","award":["2023JC053"],"award-info":[{"award-number":["2023JC053"]}]},{"DOI":"10.13039\/100007847","name":"Natural Science Foundation of Jilin Province","doi-asserted-by":"publisher","award":["YDZJ202401124ZYTS"],"award-info":[{"award-number":["YDZJ202401124ZYTS"]}],"id":[{"id":"10.13039\/100007847","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Doctoral Research Initiation Funding, Jilin Medical University","award":["JYBS2023003LK"],"award-info":[{"award-number":["JYBS2023003LK"]}]},{"award":["JYBS2023003LK"],"award-info":[{"award-number":["JYBS2023003LK"]}],"id":[{"id":"https:\/\/ror.org\/03mzw7781","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Metabolites"],"abstract":"<jats:p>Obesity and type 2 diabetes mellitus (T2DM) represent pandemic metabolic illnesses hallmarked by defective pancreatic \u03b2-cell function and blunted insulin release. As a conserved small GTPase (guanosine triphosphatase), ADP-ribosylation factor 6 (ARF6) governs fundamental cellular events encompassing vesicle trafficking, cytoskeleton remodeling and lipid metabolic turnover. Emerging data confirm that ARF6 acts as a master rheostat of glucose-stimulated insulin secretion (GSIS) in \u03b2-cells through downstream cell division control protein 42\/Ras-related C3 botulinum toxin substrate 1 (Cdc42\/Rac1) cascades. Pathogenic ARF6 hyperactivation triggers a cascade of \u03b2-cell lesions: mitochondrial impairment, autophagic suppression and exacerbated inflammatory signaling, accelerating the progression of obesity and T2DM. First-line therapeutics ranging from GLP-1 (Glucagon-like peptide-1) receptor agonists and metformin to SGLT2 (Sodium-Glucose Cotransporter 2) inhibitors partially restore metabolic homeostasis by rectifying aberrant ARF6-dependent signaling axes. This review comprehensively delineates ARF6\u2019s canonical cellular roles, mechanistic bridges connecting ARF6 to \u03b2-cell failure and metabolic deterioration, and functional crosstalk between ARF6 and established anti-metabolic pharmacotherapies. We further address unresolved research gaps and prospective translational avenues, offering actionable perspectives to advance ARF6 as a tractable therapeutic target for obesity and T2DM management.<\/jats:p>","DOI":"10.3390\/metabo16070508","type":"journal-article","created":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T10:35:52Z","timestamp":1784630152000},"page":"508","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["The Potential Target Value of ADP-Ribosylation Factor 6 in Insulin Secretion Regulation and the Treatment of Metabolic Disorders"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0009-0008-2786-5350","authenticated-orcid":false,"given":"Yangyang","family":"Wang","sequence":"first","affiliation":[{"name":"Jilin Collaborative Innovation Center for Antibody Engineering, Jilin Medical University, Jilin 132013, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1895\/wormbook.1.67.2","article-title":"Small GTPases","volume":"2018","author":"Reiner","year":"2018","journal-title":"WormBook"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Fujibayashi, K., and Mima, J. (2021). The Small GTPase Arf6 Functions as a Membrane Tether in a Chemically-Defined Reconstitution System. Front. Cell Dev. Biol., 9.","DOI":"10.3389\/fcell.2021.628910"},{"key":"ref_3","doi-asserted-by":"crossref","unstructured":"M\u00f8ller, L.L.V., Klip, A., and Sylow, L. (2019). Rho GTPases-Emerging Regulators of Glucose Homeostasis and Metabolic Health. Cells, 8.","DOI":"10.20944\/preprints201904.0155.v1"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Veluthakal, R., and Thurmond, D.C. (2021). Emerging Roles of Small GTPases in Islet \u03b2-Cell Function. Cells, 10.","DOI":"10.3390\/cells10061503"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1016","DOI":"10.1016\/j.bcp.2011.01.006","article-title":"Arf nucleotide binding site opener [ARNO] promotes sequential activation of Arf6, Cdc42 and Rac1 and insulin secretion in INS 832\/13 \u03b2-cells and rat islets","volume":"81","author":"Jayaram","year":"2011","journal-title":"Biochem. Pharmacol."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"533","DOI":"10.1159\/000354457","article-title":"Nm23-H1 regulates glucose-stimulated insulin secretion in pancreatic \u03b2-cells via Arf6-Rac1 signaling axis","volume":"32","author":"Veluthakal","year":"2013","journal-title":"Cell. Physiol. Biochem."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1089\/dia.2014.0214","article-title":"Relationship between \u03b2-cell function, metabolic control, and microvascular complications in type 2 diabetes mellitus","volume":"17","author":"Zhao","year":"2015","journal-title":"Diabetes Technol. Ther."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"9384","DOI":"10.1038\/s41598-022-13084-6","article-title":"Differences in complication patterns in subgroups of type 2 diabetes according to insulin resistance and beta-cell function","volume":"12","author":"Cho","year":"2022","journal-title":"Sci. Rep."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"890","DOI":"10.4161\/cc.28189","article-title":"Mitochondrial alteration in type 2 diabetes and obesity: An epigenetic link","volume":"13","author":"Cheng","year":"2014","journal-title":"Cell Cycle"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Armandi, A., Rosso, C., Caviglia, G.P., and Bugianesi, E. (2021). Insulin Resistance across the Spectrum of Nonalcoholic Fatty Liver Disease. Metabolites, 11.","DOI":"10.3390\/metabo11030155"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"505","DOI":"10.1016\/j.pcd.2019.03.009","article-title":"Association of non-alcoholic fatty liver disease with microvascular complications of type 2 diabetes","volume":"13","author":"Afarideh","year":"2019","journal-title":"Prim. Care Diabetes"},{"key":"ref_12","first-page":"105","article-title":"Non-alcoholic fatty liver disease in type 2 diabetes\u2014A specific entity?","volume":"41","author":"Kahl","year":"2021","journal-title":"Liver Int. Off. J. Int. Assoc. Study Liver"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"e13519","DOI":"10.1111\/eci.13519","article-title":"Nonalcoholic fatty liver disease or metabolic dysfunction-associated fatty liver disease diagnoses and cardiovascular diseases: From epidemiology to drug approaches","volume":"51","author":"Dongiovanni","year":"2021","journal-title":"Eur. J. Clin. Investig."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1038\/s41575-019-0212-0","article-title":"Genetic contributions to NAFLD: Leveraging shared genetics to uncover systems biology","volume":"17","author":"Eslam","year":"2020","journal-title":"Nat. Rev. Gastroenterol. Hepatol."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Yeh, K.H., Hsu, L.A., Teng, M.S., Wu, S., Chou, H.H., and Ko, Y.L. (2022). Pleiotropic Effects of Common and Rare GCKR Exonic Mutations on Cardiometabolic Traits. Genes, 13.","DOI":"10.3390\/genes13030491"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"6661858","DOI":"10.1155\/2023\/6661858","article-title":"Prevalence of GCKR rs1260326 Variant in Subjects with Obesity Associated NAFLD and T2DM: A Case-Control Study in South Punjab, Pakistan","volume":"2023","author":"Nisar","year":"2023","journal-title":"J. Obes."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1206","DOI":"10.1089\/ars.2022.0101","article-title":"Diabetic Ferroptosis and Pancreatic Cancer: Foe or Friend?","volume":"37","author":"Li","year":"2022","journal-title":"Antioxid. Redox Signal."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"313","DOI":"10.2337\/db19-0327","article-title":"A Novel Model of Diabetic Complications: Adipocyte Mitochondrial Dysfunction Triggers Massive \u03b2-Cell Hyperplasia","volume":"69","author":"Kusminski","year":"2020","journal-title":"Diabetes"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1186\/s12929-017-0375-3","article-title":"Role of mitochondrial dysfunction and dysregulation of Ca2+ homeostasis in the pathophysiology of insulin resistance and type 2 diabetes","volume":"24","author":"Wang","year":"2017","journal-title":"J. Biomed. Sci."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"1101","DOI":"10.1161\/ATVBAHA.123.319375","article-title":"Endothelial-Specific Reduction in Arf6 Impairs Insulin-Stimulated Vasodilation and Skeletal Muscle Blood Flow Resulting in Systemic Insulin Resistance in Mice","volume":"44","author":"Islam","year":"2024","journal-title":"Arterioscler. Thromb. Vasc. Biol."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Ye, H., Wang, R., Wei, J., Wang, Y., Zhang, X., and Wang, L. (2022). Bioinformatics Analysis Identifies Potential Ferroptosis Key Gene in Type 2 Diabetic Islet Dysfunction. Front. Endocrinol., 13.","DOI":"10.3389\/fendo.2022.904312"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Van Acker, T., Tavernier, J., and Peelman, F. (2019). The Small GTPase Arf6: An Overview of Its Mechanisms of Action and of Its Role in Host-Pathogen Interactions and Innate Immunity. Int. J. Mol. Sci., 20.","DOI":"10.3390\/ijms20092209"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"jcs259609","DOI":"10.1242\/jcs.259609","article-title":"AMPK promotes Arf6 activation in a kinase-independent manner upon glucose starvation","volume":"135","author":"Chen","year":"2022","journal-title":"J. Cell Sci."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1080\/21541248.2016.1259710","article-title":"The small GTPase ARF6 regulates protein trafficking to control cellular function during development and in disease","volume":"10","author":"Grossmann","year":"2019","journal-title":"Small GTPases"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"1559","DOI":"10.1042\/BST20221355","article-title":"The ARF GTPase regulatory network in collective invasion and metastasis","volume":"51","author":"Nikolatou","year":"2023","journal-title":"Biochem. Soc. Trans."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"583","DOI":"10.1007\/s12640-019-00047-5","article-title":"Endothelial PPAR\u03b3 Is Crucial for Averting Age-Related Vascular Dysfunction by Stalling Oxidative Stress and ROCK","volume":"36","author":"Uddin","year":"2019","journal-title":"Neurotox. Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"31","DOI":"10.1080\/09537104.2018.1535703","article-title":"Small GTPases in platelet membrane trafficking","volume":"30","author":"Walsh","year":"2019","journal-title":"Platelets"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"4089","DOI":"10.1016\/j.apsb.2023.06.008","article-title":"Arf6 as a therapeutic target: Structure, mechanism, and inhibitors","volume":"13","author":"Sun","year":"2023","journal-title":"Acta Pharm. Sin. B"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"52","DOI":"10.1210\/er.2009-0022","article-title":"Small G proteins in islet beta-cell function","volume":"31","author":"Kowluru","year":"2010","journal-title":"Endocr. Rev."},{"key":"ref_30","doi-asserted-by":"crossref","unstructured":"Stalin, A., Hesham, A.E., Mishra, A., Zou, Q., and Ignacimuthu, S. (2024). Editorial: Herbal medical products for metabolic diseases\u2014New integrated pharmacological approaches. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1464176"},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"e1036","DOI":"10.1002\/iid3.1036","article-title":"Identification of ferroptosis-related genes in type 2 diabetes mellitus based on machine learning","volume":"11","author":"Wang","year":"2023","journal-title":"Immun. Inflamm. Dis."},{"key":"ref_32","doi-asserted-by":"crossref","unstructured":"Deepa Maheshvare, M., Raha, S., K\u00f6nig, M., and Pal, D. (2023). A pathway model of glucose-stimulated insulin secretion in the pancreatic \u03b2-cell. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1185656"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"e1670","DOI":"10.1210\/clinem\/dgae474","article-title":"A Longitudinal Study of Glucose Tolerance in Cystic Fibrosis: The Central Role of Beta Cell Functional Mass","volume":"110","author":"Piona","year":"2025","journal-title":"J. Clin. Endocrinol. Metab."},{"key":"ref_34","first-page":"CD013334","article-title":"Low-carbohydrate versus balanced-carbohydrate diets for reducing weight and cardiovascular risk","volume":"1","author":"Naude","year":"2022","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1177\/1721727X231154152","article-title":"Pancreatic Beta-cell Dysfunction in Type 2 Diabetes","volume":"21","author":"Khin","year":"2023","journal-title":"Eur. J. Inflamm."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"129","DOI":"10.1016\/j.cellsig.2018.02.002","article-title":"Cysteinyl leukotriene receptor 1 regulates glucose-stimulated insulin secretion (GSIS)","volume":"46","author":"Guo","year":"2018","journal-title":"Cell. Signal."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"597","DOI":"10.1007\/s10495-017-1354-6","article-title":"Exposure to chronic hyperglycemic conditions results in Ras-related C3 botulinum toxin substrate 1 (Rac1)-mediated activation of p53 and ATM kinase in pancreatic \u03b2-cells","volume":"22","author":"Sidarala","year":"2017","journal-title":"Apoptosis Int. J. Program. Cell Death"},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"323","DOI":"10.1080\/21541248.2020.1815508","article-title":"Roles of GTP and Rho GTPases in pancreatic islet beta cell function and dysfunction","volume":"12","author":"Kowluru","year":"2021","journal-title":"Small GTPases"},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"1583","DOI":"10.1093\/nar\/gkad023","article-title":"Simultaneous inhibition of endocytic recycling and lysosomal fusion sensitizes cells and tissues to oligonucleotide therapeutics","volume":"51","author":"Finicle","year":"2023","journal-title":"Nucleic Acids Res."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"e13086","DOI":"10.15252\/emmm.202013086","article-title":"Drug-like sphingolipid SH-BC-893 opposes ceramide-induced mitochondrial fission and corrects diet-induced obesity","volume":"13","author":"Jayashankar","year":"2021","journal-title":"EMBO Mol. Med."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"e14618","DOI":"10.15252\/emmm.202114618","article-title":"Fuse your mitochondria, lose appetite: An anorexic, anti-obesity sphingolipid","volume":"13","author":"Muley","year":"2021","journal-title":"EMBO Mol. Med."},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Ruze, R., Liu, T., Zou, X., Song, J., Chen, Y., Xu, R., Yin, X., and Xu, Q. (2023). Obesity and type 2 diabetes mellitus: Connections in epidemiology, pathogenesis, and treatments. Front. Endocrinol., 14.","DOI":"10.3389\/fendo.2023.1161521"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"114","DOI":"10.1080\/21541248.2019.1635403","article-title":"Paradoxical regulation of glucose-induced Rac1 activation and insulin secretion by RhoGDI\u03b2 in pancreatic \u03b2-cells","volume":"12","author":"Thamilselvan","year":"2021","journal-title":"Small GTPases"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"154863","DOI":"10.1016\/j.metabol.2021.154863","article-title":"Rheb1 promotes glucose-stimulated insulin secretion in human and mouse \u03b2-cells by upregulating GLUT expression","volume":"123","author":"Yang","year":"2021","journal-title":"Metab. Clin. Exp."},{"key":"ref_45","first-page":"525","article-title":"GFP transgenic animals in biomedical research: A review of potential disadvantages","volume":"68","author":"Hiripi","year":"2019","journal-title":"Physiol. Res."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"13320","DOI":"10.1073\/pnas.2232129100","article-title":"ADP-ribosylation factor 6 regulates insulin secretion through plasma membrane phosphatidylinositol 4,5-bisphosphate","volume":"100","author":"Lawrence","year":"2003","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"599","DOI":"10.1083\/jcb.200104019","article-title":"Activation of ARF6 by ARNO stimulates epithelial cell migration through downstream activation of both Rac1 and phospholipase D","volume":"154","author":"Santy","year":"2001","journal-title":"J. Cell Biol."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"637","DOI":"10.1242\/jcs.180141","article-title":"PI3K regulates endocytosis after insulin secretion by mediating signaling crosstalk between Arf6 and Rab27a","volume":"129","author":"Yamaoka","year":"2016","journal-title":"J. Cell Sci."},{"key":"ref_49","doi-asserted-by":"crossref","first-page":"769","DOI":"10.1007\/s12035-018-1099-4","article-title":"Brain Glucose-Sensing Mechanism and Energy Homeostasis","volume":"56","author":"Salazar","year":"2019","journal-title":"Mol. Neurobiol."},{"key":"ref_50","doi-asserted-by":"crossref","first-page":"9872","DOI":"10.1080\/21655979.2021.1996314","article-title":"Astragalus polysaccharide improve the proliferation and insulin secretion of mouse pancreatic \u03b2 cells induced by high glucose and palmitic acid partially through promoting miR-136-5p and miR-149-5p expression","volume":"12","author":"Deng","year":"2021","journal-title":"Bioengineered"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"2","DOI":"10.1016\/S2213-8587(24)00315-2","article-title":"The promise and hope of GLP-1 receptor agonists","volume":"13","author":"Sumithran","year":"2025","journal-title":"Lancet Diabetes Endocrinol."},{"key":"ref_52","doi-asserted-by":"crossref","first-page":"101107","DOI":"10.1016\/j.molmet.2020.101107","article-title":"Review: Glucose-sensitive insulin","volume":"46","year":"2021","journal-title":"Mol. Metab."},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Li, Y., Yang, B., Shi, C., Tan, Y., Ren, L., Mokrani, A., Li, Q., and Liu, S. (2023). Integrated analysis of mRNAs and lncRNAs reveals candidate marker genes and potential hub lncRNAs associated with growth regulation of the Pacific Oyster, Crassostrea gigas. BMC Genom., 24.","DOI":"10.1186\/s12864-023-09543-7"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"E425","DOI":"10.1152\/ajpendo.00534.2020","article-title":"Separating insulin-mediated and non-insulin-mediated glucose uptake during and after aerobic exercise in type 1 diabetes","volume":"320","author":"Nguyen","year":"2021","journal-title":"Am. J. Physiol. Endocrinol. Metab."},{"key":"ref_55","doi-asserted-by":"crossref","unstructured":"Elenjickal, E.J., Valson, A.T., Varughese, S., Vincent, L., Fernando, E., and Natarajan, G. (2024). Editorial: Novel pathophysiologic mechanisms and reno-protective pharmacotherapies in diabetic kidney disease. Front. Pharmacol., 15.","DOI":"10.3389\/fphar.2024.1531748"},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"1867","DOI":"10.2147\/DDDT.S58459","article-title":"Liraglutide and obesity: A review of the data so far","volume":"9","author":"Ladenheim","year":"2015","journal-title":"Drug Des. Dev. Ther."},{"key":"ref_57","doi-asserted-by":"crossref","unstructured":"Hsu, S.K., Cheng, K.C., Mgbeahuruike, M.O., Lin, Y.H., Wu, C.Y., Wang, H.D., Yen, C.H., Chiu, C.C., and Sheu, S.J. (2021). New Insight into the Effects of Metformin on Diabetic Retinopathy, Aging and Cancer: Nonapoptotic Cell Death, Immunosuppression, and Effects beyond the AMPK Pathway. Int. J. Mol. Sci., 22.","DOI":"10.3390\/ijms22179453"},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.ejmech.2019.04.025","article-title":"Synthetic heterocyclic candidates as promising \u03b1-glucosidase inhibitors: An overview","volume":"176","author":"Dhameja","year":"2019","journal-title":"Eur. J. Med. Chem."},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"4237","DOI":"10.1038\/s41467-022-31103-y","article-title":"A critical role of the mechanosensor PIEZO1 in glucose-induced insulin secretion in pancreatic \u03b2-cells","volume":"13","author":"Ye","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1007\/s11892-009-0087-5","article-title":"Bile acid sequestrants for lipid and glucose control","volume":"10","author":"Staels","year":"2010","journal-title":"Curr. Diabetes Rep."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"1355","DOI":"10.1111\/bph.12025","article-title":"ARF6 and GASP-1 are post-endocytic sorting proteins selectively involved in the intracellular trafficking of dopamine D2 receptors mediated by GRK and PKC in transfected cells","volume":"168","author":"Cho","year":"2013","journal-title":"Br. J. Pharmacol."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"115220","DOI":"10.1016\/j.ejmech.2023.115220","article-title":"Discovery of PIM-1 kinase inhibitors based on the 2,5-disubstituted 1,3,4-oxadiazole scaffold against prostate cancer: Design, synthesis, in vitro and in vivo cytotoxicity investigation","volume":"250","author":"Castanet","year":"2023","journal-title":"Eur. J. Med. Chem."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"2821","DOI":"10.1007\/s12325-021-01710-0","article-title":"Weight Loss and Maintenance Related to the Mechanism of Action of Glucagon-Like Peptide 1 Receptor Agonists","volume":"38","author":"Ard","year":"2021","journal-title":"Adv. Ther."},{"key":"ref_64","doi-asserted-by":"crossref","unstructured":"Cheng, X., Sun, P., Yan, J., Zhai, X., Liu, W., Li, D., Hong, J., Cao, Z., and Jiang, B. (2026). Genome-wide identification and expression analysis of the ARF gene family in wax gourd (Benincasa hispida). BMC Plant Biol., 26.","DOI":"10.1186\/s12870-026-08779-1"},{"key":"ref_65","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1136\/gut.47.1.112","article-title":"Glucagon-like peptide-2 enhances intestinal epithelial barrier function of both transcellular and paracellular pathways in the mouse","volume":"47","author":"Benjamin","year":"2000","journal-title":"Gut"},{"key":"ref_66","first-page":"465","article-title":"Rapid beneficial effect of the IL-6 receptor blockade on insulin resistance and insulin sensitivity in non-diabetic patients with rheumatoid arthritis","volume":"37","author":"Genre","year":"2019","journal-title":"Clin. Exp. Rheumatol."},{"key":"ref_67","doi-asserted-by":"crossref","first-page":"111165","DOI":"10.1016\/j.jbc.2026.111165","article-title":"ARF6 controls VSMC phenotypic switching upon lipid stimulation to promote inflammatory signaling contributing to the progression of atherosclerosis","volume":"302","author":"Campbell","year":"2026","journal-title":"J. Biol. Chem."},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"941","DOI":"10.1038\/nature05415","article-title":"Inhibition of cytohesins by SecinH3 leads to hepatic insulin resistance","volume":"444","author":"Hafner","year":"2006","journal-title":"Nature"},{"key":"ref_69","doi-asserted-by":"crossref","first-page":"C921","DOI":"10.1152\/ajpcell.00541.2009","article-title":"ADP-ribosylation factor 6 modulates adrenergic stimulated lipolysis in adipocytes","volume":"298","author":"Liu","year":"2010","journal-title":"Am. J. Physiol. Cell Physiol."},{"key":"ref_70","doi-asserted-by":"crossref","first-page":"1030","DOI":"10.1093\/abbs\/gmt092","article-title":"TLR4 is required for the obesity-induced pancreatic beta cell dysfunction","volume":"45","author":"Li","year":"2013","journal-title":"Acta Biochim. Biophys. Sin."}],"container-title":["Metabolites"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2218-1989\/16\/7\/508\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,21]],"date-time":"2026-07-21T11:07:22Z","timestamp":1784632042000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2218-1989\/16\/7\/508"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,21]]},"references-count":70,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["metabo16070508"],"URL":"https:\/\/doi.org\/10.3390\/metabo16070508","relation":{},"ISSN":["2218-1989"],"issn-type":[{"value":"2218-1989","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,21]]}}}