Sphingolipids are thought to promote skeletal muscle insulin resistance. 1-Deoxysphingolipids (dSL) are atypical sphingolipids that are increased in plasma of individuals with type 2 diabetes and cause β-cell dysfunction in vitro. However, their role in human skeletal muscle in unknown. We found that dSL species are significantly elevated in muscle of individuals with obesity and type 2 diabetes compared to athletes and lean individuals and are inversely related to insulin sensitivity. Furthermore, we observed a significant reduction in muscle dSL content in individuals with obesity who completed a combined weight loss and exercise intervention. Increased dSL content in primary human myotubes caused a decrease in insulin sensitivity associated with increased inflammation, decreased AMP-activated kinase (AMPK) phosphorylation, and altered insulin signaling. Our findings reveal a central role for dSL in human muscle insulin resistance and suggest dSL as therapeutic targets for the treatment and prevention of type 2 diabetes.

中文翻译：

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脱氧鞘脂——与人类胰岛素抵抗相关的非典型骨骼肌脂质，可降低体外胰岛素敏感性

鞘脂被认为可促进骨骼肌胰岛素抵抗。1-脱氧鞘脂 (dSL) 是一种非典型鞘脂，在 2 型糖尿病患者的血浆中含量增加，并在体外引起 β 细胞功能障碍。然而，它们在人体骨骼肌中的作用尚不清楚。我们发现，与运动员和瘦人相比，肥胖和 2 型糖尿病患者的肌肉中 dSL 种类显着升高，并且与胰岛素敏感性呈负相关。此外，我们观察到完成减肥和运动干预的肥胖个体的肌肉 dSL 含量显着降低。人类原代肌管中 dSL 含量的增加导致胰岛素敏感性降低，与炎症增加、AMP 激活激酶 (AMPK) 磷酸化降低、并改变胰岛素信号。我们的研究结果揭示了 dSL 在人类肌肉胰岛素抵抗中的核心作用，并建议 dSL 作为治疗和预防 2 型糖尿病的治疗靶点。