{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,26]],"date-time":"2026-06-26T00:57:54Z","timestamp":1782435474955,"version":"3.54.5"},"reference-count":30,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2023,6,17]],"date-time":"2023-06-17T00:00:00Z","timestamp":1686960000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004699","name":"Chung Shan Medical University Hospital","doi-asserted-by":"publisher","award":["CSH-2021-C-017"],"award-info":[{"award-number":["CSH-2021-C-017"]}],"id":[{"id":"10.13039\/501100004699","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004699","name":"Chung Shan Medical University Hospital","doi-asserted-by":"publisher","award":["CSH-2020-C-009"],"award-info":[{"award-number":["CSH-2020-C-009"]}],"id":[{"id":"10.13039\/501100004699","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004699","name":"Chung Shan Medical University Hospital","doi-asserted-by":"publisher","award":["111-2320-B-040-017-MY3"],"award-info":[{"award-number":["111-2320-B-040-017-MY3"]}],"id":[{"id":"10.13039\/501100004699","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004699","name":"Chung Shan Medical University Hospital","doi-asserted-by":"publisher","award":["111-2314-B-040-029-MY3"],"award-info":[{"award-number":["111-2314-B-040-029-MY3"]}],"id":[{"id":"10.13039\/501100004699","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100004699","name":"Chung Shan Medical University Hospital","doi-asserted-by":"publisher","award":["112-2320-B-040-003-MY3"],"award-info":[{"award-number":["112-2320-B-040-003-MY3"]}],"id":[{"id":"10.13039\/501100004699","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Taiwan National Science and Technology Council","award":["CSH-2021-C-017"],"award-info":[{"award-number":["CSH-2021-C-017"]}]},{"name":"Taiwan National Science and Technology Council","award":["CSH-2020-C-009"],"award-info":[{"award-number":["CSH-2020-C-009"]}]},{"name":"Taiwan National Science and Technology Council","award":["111-2320-B-040-017-MY3"],"award-info":[{"award-number":["111-2320-B-040-017-MY3"]}]},{"name":"Taiwan National Science and Technology Council","award":["111-2314-B-040-029-MY3"],"award-info":[{"award-number":["111-2314-B-040-029-MY3"]}]},{"name":"Taiwan National Science and Technology Council","award":["112-2320-B-040-003-MY3"],"award-info":[{"award-number":["112-2320-B-040-003-MY3"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Obesity is strongly associated with insulin sensitivity in type 2 diabetes (T2D), mainly because free fatty acids (FFAs) are released from excess fat tissue. Long-term exposure to high levels of FFAs and glucose leads to glucolipotoxicity, causing damage to pancreatic \u03b2-cells, thus accelerating the progression of T2D. Therefore, the prevention of \u03b2-cell dysfunction and apoptosis is essential to prevent the development of T2D. Unfortunately, there are currently no specific clinical strategies for protecting \u03b2-cells, highlighting the need for effective therapies or preventive approaches to improve the survival of \u03b2-cells in T2D. Interestingly, recent studies have shown that the monoclonal antibody denosumab (DMB), used in osteoporosis, displays a positive effect on blood glucose regulation in patients with T2D. DMB acts as an osteoprotegerin (OPG) by inhibiting the receptor activator of the NF-\u03baB ligand (RANKL), preventing the maturation and function of osteoclasts. However, the exact mechanism by which the RANK\/RANKL signal affects glucose homeostasis has not been fully explained. The present study used human 1.4 \u00d7 107 \u03b2-cells to simulate the T2D metabolic condition of high glucose and free fatty acids (FFAs), and it investigated the ability of DMB to protect \u03b2-cells from glucolipotoxicity. Our results show that DMB effectively attenuated the cell dysfunction and apoptosis caused by high glucose and FFAs in \u03b2-cells. This may be caused by blocking the RANK\/RANKL pathway that reduced mammalian sterile 20-like kinase 1 (MST1) activation and indirectly increased pancreatic and duodenal homeobox 1 (PDX-1) expression. Furthermore, the increase in inflammatory cytokines and ROS caused by the RANK\/RANKL signal also played an important role in glucolipotoxicity-induced cytotoxicity, and DMB can also protect \u03b2-cells by reducing the mechanisms mentioned above. These findings provide detailed molecular mechanisms for the future development of DMB as a potential protective agent of \u03b2-cells.<\/jats:p>","DOI":"10.3390\/ijms241210289","type":"journal-article","created":{"date-parts":[[2023,6,19]],"date-time":"2023-06-19T01:31:14Z","timestamp":1687138274000},"page":"10289","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":12,"title":["Denosumab Attenuates Glucolipotoxicity-Induced \u03b2-Cell Dysfunction and Apoptosis by Attenuating RANK\/RANKL Signals"],"prefix":"10.3390","volume":"24","author":[{"given":"Sheng-Chieh","family":"Lin","sequence":"first","affiliation":[{"name":"Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan"},{"name":"Department of Orthopaedics, Chung Shan Medical University Hospital, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7574-028X","authenticated-orcid":false,"given":"Sing-Hua","family":"Tsou","sequence":"additional","affiliation":[{"name":"Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien-Yin","family":"Kuo","sequence":"additional","affiliation":[{"name":"Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan"},{"name":"Department of Surgery, Chung Shan Medical University Hospital, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wei-Liang","family":"Chen","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Division of Gastroenterology and Hepatology, Chung Shan Medical University Hospital, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8170-9879","authenticated-orcid":false,"given":"Kuan-Wen","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Orthopaedic Surgery, National Taiwan University Hospital, Taipei 100, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4553-3727","authenticated-orcid":false,"given":"Chih-Li","family":"Lin","sequence":"additional","affiliation":[{"name":"Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan"},{"name":"Department of Medical Research, Chung Shan Medical University Hospital, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chien-Ning","family":"Huang","sequence":"additional","affiliation":[{"name":"Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan"},{"name":"Department of Internal Medicine, Division of Endocrinology and Metabolism, Chung Shan Medical University Hospital, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2023,6,17]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Henderson, G.C. 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