{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,30]],"date-time":"2026-07-30T09:01:30Z","timestamp":1785402090214,"version":"3.56.0"},"reference-count":31,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2026,6,9]],"date-time":"2026-06-09T00:00:00Z","timestamp":1780963200000},"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"}]},{"award":["CSH-2021-C-017"],"award-info":[{"award-number":["CSH-2021-C-017"]}],"id":[{"id":"https:\/\/ror.org\/01abtsn51","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National Science and Technology Council","award":["114-2320-B-040-016"],"award-info":[{"award-number":["114-2320-B-040-016"]}]},{"name":"National Science and Technology Council","award":["114-2314-B-040-030-MY3"],"award-info":[{"award-number":["114-2314-B-040-030-MY3"]}]},{"name":"National Science and Technology Council","award":["114-2320-B-040-012-MY3"],"award-info":[{"award-number":["114-2320-B-040-012-MY3"]}]},{"award":["114-2320-B-040-016"],"award-info":[{"award-number":["114-2320-B-040-016"]}],"id":[{"id":"https:\/\/ror.org\/02kv4zf79","id-type":"ROR","asserted-by":"publisher"}]},{"award":["114-2314-B-040-030-MY3"],"award-info":[{"award-number":["114-2314-B-040-030-MY3"]}],"id":[{"id":"https:\/\/ror.org\/02kv4zf79","id-type":"ROR","asserted-by":"publisher"}]},{"award":["114-2320-B-040-012-MY3"],"award-info":[{"award-number":["114-2320-B-040-012-MY3"]}],"id":[{"id":"https:\/\/ror.org\/02kv4zf79","id-type":"ROR","asserted-by":"publisher"}]},{"name":"National Chung Hsing University and Chung Shan Medical University","award":["NCHU\u2010CSMU\u201011411"],"award-info":[{"award-number":["NCHU\u2010CSMU\u201011411"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Background\/Objectives: Type 2 diabetes (T2D)-associated sarcopenia is characterized by impaired insulin signaling, lipotoxicity, oxidative stress, and progressive muscle loss. Although liraglutide improves glucose control and reduces lipid burden, its ability to preserve muscle integrity under diabetic lipotoxic conditions remains limited. This study investigated whether \u03b2-hydroxy-\u03b2-methylbutyrate (HMB) could enhance liraglutide-mediated protection against high-glucose plus free fatty acid (HG+FFA)-induced injury in skeletal muscle cells. Methods: Differentiated C2C12 myotubes were exposed to HG+FFA to establish a sublethal lipotoxic model and treated with liraglutide, HMB, or their combination. Cell viability, lipid accumulation, myotube morphology, insulin signaling, glucose uptake, mitochondrial function, reactive oxygen species (ROS), antioxidant gene expression, and atrophy-related signaling were assessed. Results: HG+FFA induced marked lipid droplet accumulation, impaired insulin signaling, reduced glucose uptake, disrupted mitochondrial membrane potential, increased ROS production, suppressed antioxidant gene expression, and promoted an atrophic phenotype characterized by increased atrogin-1 and MuRF1 and reduced myogenic markers. Liraglutide alone reduced large lipid droplets and partially improved insulin signaling but showed limited efficacy in preserving the myotube phenotype. HMB alone exerted modest effects on lipid accumulation but preserved myotube area. Notably, combined HMB and liraglutide treatment more effectively reduced lipid burden, restored insulin signaling and glucose uptake, attenuated mitochondrial dysfunction and oxidative stress, restored antioxidant gene expression, and preserved MyHC-positive area and myotube diameter while suppressing atrogin-1\/MuRF1 activation. These protective effects were largely attenuated by rapamycin, indicating at least partial dependence on mTOR-associated signaling. Conclusions: Overall, HMB and liraglutide exert complementary protective effects against diabetic lipotoxic and atrophic stress, supporting the potential utility of this combination strategy for T2D-associated sarcopenia.<\/jats:p>","DOI":"10.3390\/nu18121865","type":"journal-article","created":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T00:58:12Z","timestamp":1781053092000},"page":"1865","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["HMB and Liraglutide Confer Complementary Protection Against Lipotoxic and Atrophic Alterations in High-Glucose Plus Free Fatty Acid-Treated C2C12 Myotubes"],"prefix":"10.3390","volume":"18","author":[{"given":"Li-Yuan","family":"Chen","sequence":"first","affiliation":[{"name":"Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan"},{"name":"Department of Physical Therapy, Chung Shan Medical University, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9408-3542","authenticated-orcid":false,"given":"Shao-Hsing","family":"Weng","sequence":"additional","affiliation":[{"name":"Institute of Medicine, Chung Shan Medical University, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hsin-Hua","family":"Li","sequence":"additional","affiliation":[{"name":"Department of Exercise Health Science, National Taiwan University of Sport, Taichung 404, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Chen-Hsing","family":"Su","sequence":"additional","affiliation":[{"name":"Department of Neurosurgery, 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":"Kuei-Chuan","family":"Chan","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Chung Shan Medical University Hospital, Taichung 402, Taiwan"},{"name":"School of Medicine, Chung Shan Medical University, 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, Chung Shan Medical University Hospital, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0180-1822","authenticated-orcid":false,"given":"Hui-Chih","family":"Hung","sequence":"additional","affiliation":[{"name":"Department of Life Sciences, National Chung Hsing University, Taichung 402, Taiwan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5771-6101","authenticated-orcid":false,"given":"Sheng-Chieh","family":"Lin","sequence":"additional","affiliation":[{"name":"School of Medicine, Chung Shan Medical University, Taichung 402, Taiwan"},{"name":"Department of Orthopedics, Chung Shan Medical University Hospital, Taichung 402, 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"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,9]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","unstructured":"Liu, Z., Guo, Y., and Zheng, C. 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