{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,28]],"date-time":"2026-07-28T07:02:22Z","timestamp":1785222142597,"version":"3.55.0"},"reference-count":31,"publisher":"Endocrinology Research Centre","issue":"3","license":[{"start":{"date-parts":[[2026,7,22]],"date-time":"2026-07-22T00:00:00Z","timestamp":1784678400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.probl-endojournals.ru\/jour\/about\/editorialPolicies#openAccessPolicy"}],"content-domain":{"domain":["www.probl-endojournals.ru"],"crossmark-restriction":true},"short-container-title":["Probl Endokrinol (Mosk)"],"abstract":"<jats:p>Glucagon-like peptide-1 receptor agonists (GLP-1RAs) like semaglutide have transformed type 2 diabetes mellitus (T2DM) management, yet emerging concerns highlight potential risks of accelerated sarcopenia and subsequent metabolic disruptions. This case-driven hypothesis explores a 53-year-old male with T2DM diagnosed in 2014, who experienced progressive glycemic failure despite standard therapies, including metformin, glipizide, sitagliptin, and empagliflozin. Transition to dulaglutide 1.5 mg for 1.5 years followed by semaglutide (titrated from 0.25 to 1 mg weekly starting September 2024) resulted in weight loss from 84 kg to 70 kg by September 2025, accompanied by sarcopenic symptoms (muscle weakness, reduced mobility) and refractory hyperglycemia (fasting glucose 300 mg\/dL, HbA1c 9%), persisting post-discontinuation on September 1, 2025, despite metformin and empagliflozin. We posit that semaglutide may precipitate acute sarcopenia via unexpected GLP-1R-mTOR-satellite cells axis crosstalk, disrupting AMPK-mTOR balance to suppress anabolic mTORC1\/IGF-1 signaling (potentially by 25-35%) while enhancing catabolic FOXO\/ubiquitin-proteasome and excessive autophagy pathways. This could extend to myokine reprogramming (elevated myostatin\/GDF15, reduced irisin\/IL-15), glucagon\/\u03b1-cell compensation inducing hyperglucagonemia (15-25% rise), microbiome-bile acid shifts fostering low-grade inflammation (IL-6\/TNF-\u03b1 upregulation by 10-15%), mitochondrial mass reduction (20-25% via AMPK), and NMJ disassembly, collectively impairing muscle as the primary glucose sink (reducing GLUT4-mediated uptake by 35-45%) and initiating a \u00abmuscle-glucose feedback loop\u00bb with hepatic gluconeogenesis amplification, yielding treatment-resistant hyperglycemia.<\/jats:p>\n                  <jats:p>Supporting evidence from cohorts (e.g., 24-month study showing ASMI\/grip strength declines in 432 patients), longitudinal analyses (NMJ degradation with CAF22\/NfL elevations in 141 men), secondary trials (9.3% psoas volume loss in 51 MASLD cases), and case reports (fatigue in a 74-year-old, rhabdomyolysis in a 47-year-old) aligns with this framework, as does in vitro data linking GLP-1 excess to kinesin-1\/GLUT4 inhibition and ATP depletion (20-30%). This novel hypothesis underscores sarcopenia\u2019s role in GLP-1RA-induced metabolic paradoxes, urging prospective studies on muscle-preserving interventions like resistance training or GLP-1R modulators to refine T2DM paradigms and inspire multidisciplinary research into endocrine-muscle interactions.<\/jats:p>","DOI":"10.14341\/probl13660","type":"journal-article","created":{"date-parts":[[2026,7,27]],"date-time":"2026-07-27T14:47:35Z","timestamp":1785163655000},"page":"60-65","update-policy":"https:\/\/doi.org\/10.14341\/crossmarkpolicy2018","source":"Crossref","is-referenced-by-count":0,"title":["Semaglutide-Induced Sarcopenia via GLP-1R-mTOR-Satellite Cells Axis and Muscle-Glucose Feedback Loop Potentially Leading to Refractory Hyperglycemia in Type 2 Diabetes: A Case-Driven Hypothesis"],"prefix":"10.14341","volume":"72","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3477-236X","authenticated-orcid":true,"given":"Amr","family":"Ahmed","sequence":"first","affiliation":[{"name":"The Public Health Department, Riyadh First Health Cluster, Ministry of Health"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sharifa","family":"Rodini","sequence":"additional","affiliation":[{"name":"Nurse Technician, Ministry of Health"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fahad","family":"Alrubyea","sequence":"additional","affiliation":[{"name":"Public Health Specialist, The Public Health Department, Riyadh First Health Cluster, Ministry of Health"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5480-1688","authenticated-orcid":true,"given":"Maher","family":"Akl","sequence":"additional","affiliation":[{"name":"National Research Lobachevsky State University of Nizhny Novgorod"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"5458","published-online":{"date-parts":[[2026,7,22]]},"reference":[{"key":"ref1","doi-asserted-by":"crossref","unstructured":"Zheng, Z., Zong, Y., Ma, Y. et al. 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