{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,16]],"date-time":"2026-10-16T20:29:23Z","timestamp":1792182563604,"version":"4.4.0"},"reference-count":53,"publisher":"Wiley","issue":"21","license":[{"start":{"date-parts":[[2024,7,4]],"date-time":"2024-07-04T00:00:00Z","timestamp":1720051200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["22177007"],"award-info":[{"award-number":["22177007"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["bpspubs.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["British J Pharmacology"],"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:sec><jats:title>Background and Purpose<\/jats:title><jats:p>Metal\u2010based therapeutic agents are limited by the required concentration of metal\u2010based agents. Hereby, we determined if combination with 17\u03b2\u2010oestradiol (E2) could reduce such levels and the therapy still be effective in type 2 diabetes mellitus (T2DM).<\/jats:p><\/jats:sec><jats:sec><jats:title>Experimental Approach<\/jats:title><jats:p>The metal\u2010based agent (vanadyl acetylacetonate [VAC])\u2013 17\u03b2\u2010oestradiol (E2) combination is administered using the membrane\u2010permeable graphene quantum dots (GQD), the vehicle, to form the active GQD\u2013E2\u2013VAC complexes, which was characterized by fluorescence spectra, infrared spectra and X\u2010ray photoelectron spectroscopy. In <jats:italic>db<\/jats:italic>\/<jats:italic>db<\/jats:italic> type 2 diabetic mice, the anti\u2010diabetic effects of GQD\u2013E2\u2013VAC complexes were evaluated using blood glucose levels, oral glucose tolerance test (OGTT), serum insulin levels, homeostasis model assessment (homeostasis model assessment of insulin resistance [HOMA\u2010IR] and homeostasis model assessment of \u03b2\u2010cell function [HOMA\u2010\u03b2]), histochemical assays and western blot.<\/jats:p><\/jats:sec><jats:sec><jats:title>Key Results<\/jats:title><jats:p>In diabetic mice, GQD\u2013E2\u2013VAC complex had comprehensive anti\u2010diabetic effects, including control of hyperglycaemia, improved insulin sensitivity, correction of hyperinsulinaemia and prevention of \u03b2\u2010cell loss. Co\u2010regulation of thioredoxin interacting protein (TXNIP) activation by the combination of metal complex and 17\u03b2\u2010oestradiol contributed to the enhanced anti\u2010diabetic effects. Furthermore, a potent mitochondrial protective antioxidant, coniferaldehyde, significantly potentiates the protective effects of GQD\u2013E2\u2013VAC complexes.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion and Implications<\/jats:title><jats:p>A metal complex\u2013E2 combinatorial approach achieved simultaneously the protection of \u03b2 cells and insulin enhancement at an unprecedented low dose, similar to the daily intake of dietary metals in vitamin supplements. This study demonstrates the positive effects of combination and multi\u2010modal therapies towards type 2 diabetes treatment.<\/jats:p><\/jats:sec>","DOI":"10.1111\/bph.16485","type":"journal-article","created":{"date-parts":[[2024,7,5]],"date-time":"2024-07-05T05:15:22Z","timestamp":1720156522000},"page":"4214-4228","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Combination therapy enhances efficacy and overcomes toxicity of metal\u2010based anti\u2010diabetic agent"],"prefix":"10.1111","volume":"181","author":[{"given":"Bing","family":"Shang","sequence":"first","affiliation":[{"name":"State Key Laboratory of Natural and Biomimetic Drugs and Department of Chemical Biology, School of Pharmaceutical Sciences Peking University Health Science Center  Beijing China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yaqiong","family":"Dong","sequence":"additional","affiliation":[{"name":"Institute of 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