{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,23]],"date-time":"2026-10-23T04:00:53Z","timestamp":1792728053647,"version":"4.5.0"},"reference-count":33,"publisher":"MDPI AG","issue":"15","license":[{"start":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T00:00:00Z","timestamp":1785283200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Key Research and Development Program","award":["2025JC-YBQN-1070"],"award-info":[{"award-number":["2025JC-YBQN-1070"]}]},{"name":"Key Research and Development Program","award":["2025SF-YBXM-409"],"award-info":[{"award-number":["2025SF-YBXM-409"]}]},{"name":"Non-profit Central Research Institute Fund","award":["2023-PT320-10"],"award-info":[{"award-number":["2023-PT320-10"]}]},{"name":"Shaanxi Health Scientific Research Innovation Team for Comprehensive Treatment of Complex Facial Injuries","award":["2024TD-07"],"award-info":[{"award-number":["2024TD-07"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Int. J. Mol. Sci.","IJMS"],"abstract":"<jats:p>People with diabetes often have a high rate of oral implant failure and unstable long-term treatment effects. It is urgent to find the potential mechanisms and effective cure methods to address the increasing demand for dental restoration in recent years. This paper aims to find an influential factor, and a probable treatment resulting from it, to improve poor osseointegration and achieve favorable bone regeneration. To find out the influential factor of poor diabetic osseointegration, we compared marginal bone loss among patients taking different hypoglycemic drugs. To verify our pre-clinical findings, we performed in vitro experiments as well as micro-CT, fluorescence intensity, and histopathological analysis methods after establishing a diabetic rat model controlled by different systemic hypoglycemic drugs. To enhance implant osseointegration and find out the underlying mechanism, we proposed the GelMA\u2013alogliptin hydrogel system and tested the scratch wound healing, cell adhesion, CCK-8, live-dead cell staining, osteogenesis, qPCR, and Western blot methods based on diabetic rat-derived BMSCs, HUVECs and BMMS, as well as the in vivo experiments in diabetic rats. People with diabetes under DPP4i (alogliptin) exhibit the lowest marginal bone loss. The systemic alogliptin and locally delivered peri-implant GelMA\u2013alogliptin hydrogel treatment promoted bone regeneration around diabetic implants, enhanced diabetic-derived BMSC activity and migration through GLP1R\/GSK3\u03b2\/\u03b2-catenin and induced osteogenic differentiation, and promoted vascular regeneration and inflammation control. Alogliptin has positive effects on the oral implant health of people with diabetes. A locally delivered GelMA\u2013alogliptin hydrogel system exhibits competitive ability to improve diabetic bone microenvironment and enhance implant osseointegration.<\/jats:p>","DOI":"10.3390\/ijms27156800","type":"journal-article","created":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T13:53:31Z","timestamp":1785333211000},"page":"6800","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Alogliptin Enhances Implant Osseointegration in Diabetes Through an Osteogenic\u2013Angiogenic Immunomodulatory Procedure"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1761-7245","authenticated-orcid":false,"given":"Xiangdong","family":"Liu","sequence":"first","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Air Force Medical University, Xi\u2019an 710032, China"},{"name":"State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zijun","family":"Chen","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Oral Implants, School of Stomatology, Air Force Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu","family":"Yang","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Oral Implants, School of Stomatology, Air Force Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei","family":"Ma","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Oral Implants, School of Stomatology, Air Force Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yiwen","family":"Liu","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Air Force Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yingliang","family":"Song","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Military Stomatology and National Clinical Research Center for Oral Diseases and Shaanxi Engineering Research Center for Dental Materials and Advanced Manufacture, Department of Oral Implants, School of Stomatology, Air Force Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mingchao","family":"Ding","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Tian","sequence":"additional","affiliation":[{"name":"State Key Laboratory of Oral & Maxillofacial Reconstruction and Regeneration, National Clinical Research Center for Oral Diseases, Shaanxi Clinical Research Center for Oral Diseases, Department of Oral and Maxillofacial Surgery, School of Stomatology, The Fourth Military Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5269-1331","authenticated-orcid":false,"given":"Mingkai","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Pharmacology, School of Pharmacy, Air Force Medical University, Xi\u2019an 710032, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"40","DOI":"10.1111\/prd.12270","article-title":"Diabetes as a potential risk for periodontitis: Association studies","volume":"83","author":"Genco","year":"2020","journal-title":"Periodontol. 2000"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1111\/prd.12293","article-title":"Patient compliance as a risk factor for the outcome of implant treatment","volume":"81","author":"Cortellini","year":"2019","journal-title":"Periodontol. 2000"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"e2235995","DOI":"10.1001\/jamanetworkopen.2022.35995","article-title":"Association of Sodium-Glucose Cotransporter-2 Inhibitors with Incident Atrial Fibrillation in Older Adults with Type 2 Diabetes","volume":"5","author":"Zhuo","year":"2022","journal-title":"JAMA Netw. Open"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"20420188211042145","DOI":"10.1177\/20420188211042145","article-title":"Therapeutics for type-2 diabetes mellitus: A glance at the recent inclusions and novel agents under development for use in clinical practice","volume":"12","author":"Shah","year":"2021","journal-title":"Ther. Adv. Endocrinol. Metab."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"107843","DOI":"10.1016\/j.diabres.2019.107843","article-title":"Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: Results from the International Diabetes Federation Diabetes Atlas, 9(th) edition","volume":"157","author":"Saeedi","year":"2019","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1111\/clr.12391","article-title":"Peri-implant evaluation in type 2 diabetes mellitus patients: A 3-year study","volume":"26","author":"Guardia","year":"2015","journal-title":"Clin. Oral Implant. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"142","DOI":"10.4103\/0975-5950.127642","article-title":"Dental implant survival in diabetic patients; review and recommendations","volume":"4","author":"Dubey","year":"2013","journal-title":"Natl. J. Maxillofac. Surg."},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Liu, X., Liu, Y., Liu, H., Li, H., Yang, J., Hu, P., Xiao, X., and Liu, D. (2021). Dipeptidyl-Peptidase-IV Inhibitors, Imigliptin and Alogliptin, Improve Beta-Cell Function in Type 2 Diabetes. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.694390"},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"Zhang, Y.S., Zheng, Y.D., Yuan, Y., Chen, S.C., and Xie, B.C. (2021). Effects of Anti-Diabetic Drugs on Fracture Risk: A Systematic Review and Network Meta-Analysis. Front. Endocrinol., 12.","DOI":"10.3389\/fendo.2021.735824"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1007\/s11892-020-01361-5","article-title":"Impact of Type 2 Diabetes Mellitus and Antidiabetic Medications on Bone Metabolism","volume":"20","author":"Lee","year":"2020","journal-title":"Curr. Diab. Rep."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"849","DOI":"10.1161\/CIRCULATIONAHA.117.028136","article-title":"Cardiovascular Actions and Clinical Outcomes with Glucagon-Like Peptide-1 Receptor Agonists and Dipeptidyl Peptidase-4 Inhibitors","volume":"136","author":"Nauck","year":"2017","journal-title":"Circulation"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"672","DOI":"10.1007\/s12020-021-02664-7","article-title":"Exendin-4, a glucagon-like peptide receptor agonist, facilitates osteoblast differentiation via connexin43","volume":"72","author":"Chen","year":"2021","journal-title":"Endocrine"},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"1031","DOI":"10.1089\/dna.2018.4397","article-title":"Liraglutide Promotes the Osteogenic Differentiation in MC3T3-E1 Cells via Regulating the Expression of Smad2\/3 Through PI3K\/Akt and Wnt\/beta-Catenin Pathways","volume":"37","author":"Gao","year":"2018","journal-title":"DNA Cell Biol."},{"key":"ref_14","first-page":"12408","article-title":"Liraglutide regulates proliferation, differentiation, and apoptosis of preosteoblasts through a signaling network of Notch\/Wnt\/Hedgehog signaling pathways","volume":"24","author":"Hou","year":"2020","journal-title":"Eur. Rev. Med. Pharmacol. Sci."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"109796","DOI":"10.1016\/j.biopha.2019.109796","article-title":"Anagliptin stimulates osteoblastic cell differentiation and mineralization","volume":"129","author":"Dong","year":"2020","journal-title":"Biomed. Pharmacother."},{"key":"ref_16","doi-asserted-by":"crossref","unstructured":"Sghaireen, M.G., Alduraywish, A.A., Srivastava, K.C., Shrivastava, D., Patil, S.R., Al Habib, S., Hamza, M., Ab Rahman, S., Lynch, E., and Alam, M.K. (2020). Comparative Evaluation of Dental Implant Failure among Healthy and Well-Controlled Diabetic Patients-A 3-Year Retrospective Study. Int. J. Environ. Res. Public Health, 17.","DOI":"10.3390\/ijerph17145253"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"291","DOI":"10.2337\/dc16-2380","article-title":"Basal Glucose Can Be Controlled, but the Prandial Problem Persists\u2014It\u2019s the Next Target!","volume":"40","author":"Riddle","year":"2017","journal-title":"Diabetes Care"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Medenica, S., Bogdanovic, J., Vekic, J., Vojinovic, T., Babic, I., Bogdanovi\u0107, L., Maggio, V., El Tanani, M., and Rizzo, M. (2025). Incretin-Based Therapies and Cancer: What\u2019s New?. Medicina, 61.","DOI":"10.3390\/medicina61040678"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"651","DOI":"10.1089\/met.2024.0127","article-title":"Efficacy of Alogliptin\/Metformin Fixed-Dose Combination Tablets and Vildagliptin\/Metformin Fixed-Dose Combination Tablets on Glycemic Control in Real-World Clinical Practice for the Patients with Type 2 Diabetes: A Multicenter, Open-Label, Randomized, Parallel Group, Comparative Trial","volume":"22","author":"Abe","year":"2024","journal-title":"Metab. Syndr. Relat. Disord."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"137996","DOI":"10.1016\/j.neulet.2024.137996","article-title":"Effects of Apelin-13 on auditory system in STZ-induced diabetic rats","volume":"842","year":"2024","journal-title":"Neurosci. Lett."},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Yang, J., Huang, C., Wu, S., Xu, Y., Cai, T., Chai, S., Yang, Z., Sun, F., and Zhan, S. (2017). The effects of dipeptidyl peptidase-4 inhibitors on bone fracture among patients with type 2 diabetes mellitus: A network meta-analysis of randomized controlled trials. PLoS ONE, 12.","DOI":"10.1371\/journal.pone.0187537"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"136","DOI":"10.2186\/jpr.JPR_D_24_00086","article-title":"Optimizing implant osseointegration, soft tissue responses, and bacterial inhibition: A comprehensive narrative review on the multifaceted approach of the UV photofunctionalization of titanium","volume":"69","author":"Park","year":"2025","journal-title":"J. Prosthodont. Res."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e70014","DOI":"10.1111\/dme.70014","article-title":"LncRNA CASC2 mediates SOCS6 mRNA stabilization via U2AF2 recruitment to modulate macrophage polarisation in diabetic retinopathy","volume":"42","author":"Xiao","year":"2025","journal-title":"Diabet. Med. A J. Br. Diabet. Assoc."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"e15386","DOI":"10.1111\/dme.15386","article-title":"Bone marrow mesenchymal stem cell-derived exosomal miR-221-3p promotes angiogenesis and wound healing in diabetes via the downregulation of forkhead box P1","volume":"41","author":"Qiu","year":"2024","journal-title":"Diabet. Med. A J. Br. Diabet. Assoc."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"e15507","DOI":"10.1111\/dme.15507","article-title":"Heat shock-pretreated bone marrow mesenchymal stem cells accelerate wound healing in a diabetic foot ulcer rat model","volume":"42","author":"Lin","year":"2025","journal-title":"Diabet. Med. A J. Br. Diabet. Assoc."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"35","DOI":"10.1016\/j.diabres.2013.11.015","article-title":"Streptozotocin-induced diabetes in rats diminishes the size of the osteoprogenitor pool in bone marrow","volume":"103","author":"Weinberg","year":"2014","journal-title":"Diabetes Res. Clin. Pract."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"183","DOI":"10.1177\/00220345241286490","article-title":"Wnt\/\u03b2-catenin Promotes Cementum Apposition in Periodontal Regeneration","volume":"104","author":"Ono","year":"2025","journal-title":"J. Dent. Res."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"403","DOI":"10.1186\/s13018-025-05685-4","article-title":"Epimedin B protects against bone loss and inflammation in diabetic osteoporosis rats by regulating OPG\/RANKL pathway","volume":"20","author":"Zhang","year":"2025","journal-title":"J. Orthop. Surg. Res."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"70","DOI":"10.1007\/s40520-025-02991-z","article-title":"Denosumab for osteoporosis treatment: When, how, for whom, and for how long. A pragmatical approach","volume":"37","author":"Lamy","year":"2025","journal-title":"Aging Clin. Exp. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"2008515","DOI":"10.1002\/adfm.202008515","article-title":"Recapitulation of In Situ Endochondral Ossification Using an Injectable Hypoxia-Mimetic Hydrogel","volume":"31","author":"Sun","year":"2021","journal-title":"Adv. Funct. Mater."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"17131","DOI":"10.1021\/acsnano.3c04816","article-title":"Amyloid Fibril and Clay Nanosheet Dual-Nanoengineered DNA Dynamic Hydrogel for Vascularized Bone Regeneration","volume":"17","author":"Yang","year":"2023","journal-title":"ACS Nano"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"7089","DOI":"10.2147\/IJN.S124584","article-title":"Delivery of antagomiR204-conjugated gold nanoparticles from PLGA sheets and its implication in promoting osseointegration of titanium implant in type 2 diabetes mellitus","volume":"12","author":"Liu","year":"2017","journal-title":"Int. J. Nanomed."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"1493","DOI":"10.1007\/s00125-024-06172-x","article-title":"Bone metabolism in diabetes: A clinician\u2019s guide to understanding the bone-glucose interplay","volume":"67","author":"Sheu","year":"2024","journal-title":"Diabetologia"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6800\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,29]],"date-time":"2026-07-29T13:54:03Z","timestamp":1785333243000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/27\/15\/6800"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,29]]},"references-count":33,"journal-issue":{"issue":"15","published-online":{"date-parts":[[2026,8]]}},"alternative-id":["ijms27156800"],"URL":"https:\/\/doi.org\/10.3390\/ijms27156800","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,29]]}}}