Mäkinen Selina, Datta Neeta, Nguyen Yen H, Kyrylenko Petro, Laakso Markku, Koistinen Heikki A
Minerva Foundation Institute for Medical Research, Helsinki, Finland.
Department of Medicine, University of Helsinki, Helsinki University Central Hospital, Helsinki, Finland.
Endocr Connect. 2020 Nov;9(11):1103-1113. doi: 10.1530/EC-20-0444.
Simvastatin use is associated with muscular side effects, and increased risk for type 2 diabetes (T2D). In clinical use, simvastatin is administered in inactive lipophilic lactone-form, which is then converted to active acid-form in the body. Here, we have investigated if lactone- and acid-form simvastatin differentially affect glucose metabolism and mitochondrial respiration in primary human skeletal muscle cells.
Muscle cells were exposed separately to lactone- and acid-form simvastatin for 48 h. After pre-exposure, glucose uptake and glycogen synthesis were measured using radioactive tracers; insulin signalling was detected with Western blotting; and glycolysis, mitochondrial oxygen consumption and ATP production were measured with Seahorse XFe96 analyzer.
Lactone-form simvastatin increased glucose uptake and glycogen synthesis, whereas acid-form simvastatin did not affect glucose uptake and decreased glycogen synthesis. Phosphorylation of insulin signalling targets Akt substrate 160 kDa (AS160) and glycogen synthase kinase 3β (GSK3β) was upregulated with lactone-, but not with acid-form simvastatin. Exposure to both forms of simvastatin led to a decrease in glycolysis and glycolytic capacity, as well as to a decrease in mitochondrial respiration and ATP production.
These data suggest that lactone- and acid-forms of simvastatin exhibit differential effects on non-oxidative glucose metabolism as lactone-form increases and acid-form impairs glucose storage into glycogen, suggesting impaired insulin sensitivity in response to acid-form simvastatin. Both forms profoundly impair oxidative glucose metabolism and energy production in human skeletal muscle cells. These effects may contribute to muscular side effects and risk for T2D observed with simvastatin use.
使用辛伐他汀与肌肉副作用以及2型糖尿病（T2D）风险增加相关。在临床应用中，辛伐他汀以无活性的亲脂性内酯形式给药，然后在体内转化为活性酸形式。在此，我们研究了内酯型和酸型辛伐他汀是否对原代人骨骼肌细胞的葡萄糖代谢和线粒体呼吸有不同影响。
将肌肉细胞分别暴露于内酯型和酸型辛伐他汀48小时。预暴露后，使用放射性示踪剂测量葡萄糖摄取和糖原合成；通过蛋白质免疫印迹法检测胰岛素信号；并用海马XFe96分析仪测量糖酵解、线粒体氧消耗和ATP产生。
内酯型辛伐他汀增加葡萄糖摄取和糖原合成，而酸型辛伐他汀不影响葡萄糖摄取并降低糖原合成。胰岛素信号靶点Akt底物160 kDa（AS160）和糖原合酶激酶3β（GSK3β）的磷酸化在内酯型辛伐他汀作用下上调，但在酸型辛伐他汀作用下未上调。暴露于两种形式的辛伐他汀均导致糖酵解和糖酵解能力降低，以及线粒体呼吸和ATP产生减少。
这些数据表明，辛伐他汀的内酯型和酸型对非氧化葡萄糖代谢表现出不同影响，因为内酯型增加而酸型损害葡萄糖储存为糖原，提示对酸型辛伐他汀的胰岛素敏感性受损。两种形式均严重损害人骨骼肌细胞中的氧化葡萄糖代谢和能量产生。这些影响可能导致使用辛伐他汀时观察到的肌肉副作用和T2D风险。
