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

作者：Ahmed A, Rodini S, Alrubyea F, Akl M · 发表于：Problemy endokrinologii · 年份：2026 · DOI：10.14341/probl13660 · 研究领域：Diabetes Mellitus, Type 2、Glucagon-Like Peptides、Sarcopenia、Hyperglycemia、Hypoglycemic Agents、Semaglutide、Humans、Male、Middle Aged、TOR Serine-Threonine Kinases、Glucagon-Like Peptide-1 Receptor、Satellite Cells, Skeletal Muscle

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/α-cell compensation inducing hyperglucagonemia (15-25% rise), microbiome-bile acid shifts fostering low-grade inflammation (IL-6/TNF-α upregulation by 10-15%), mitochondrial mass reduction (20-25% via AMPK), ...