Panajatovic Miljenko Valentin, Singh François, Krähenbühl Stephan, Bouitbir Jamal
Division of Clinical Pharmacology & Toxicology, University Hospital, 4031 Basel, Switzerland.
Department of Biomedicine, University of Basel, 4031 Basel, Switzerland.
Biomedicines. 2020 Sep 15;8(9):351. doi: 10.3390/biomedicines8090351.
Several studies showed an increased risk for diabetes with statin treatment. PGC-1α is an important regulator of muscle energy metabolism and mitochondrial biogenesis. Since statins impair skeletal muscle PGC-1α expression and reduced PGC-1α expression has been observed in diabetic patients, we investigated the possibility that skeletal muscle PGC1α expression influences the effect of simvastatin on muscle glucose metabolism. Mice with muscle PGC-1α knockout (KO) or PGC-1α overexpression (OE), and wild-type (WT) mice were investigated. Mice were treated orally for 3 weeks with simvastatin (5 mg/kg/day) and investigated by intraperitoneal glucose tolerance (iGTT), in vivo skeletal muscle glucose uptake, muscle glycogen content, and Glut4 and hexokinase mRNA and protein expression. Simvastatin impaired glucose metabolism in WT mice, as manifested by increased glucose blood concentrations during the iGTT, decreased skeletal muscle glucose uptake and glycogen stores. KO mice showed impaired glucose homeostasis with increased blood glucose concentrations during the iGTT already without simvastatin treatment and simvastatin induced a decrease in skeletal muscle glucose uptake. In OE mice, simvastatin treatment increased blood glucose and insulin concentrations during the iGTT, and increased skeletal muscle glucose uptake, glycogen stores, and Glut4 and hexokinase protein expression. In conclusion, simvastatin impaired skeletal muscle insulin sensitivity in WT mice, while KO mice exhibited impaired skeletal muscle insulin sensitivity already in the absence of simvastatin. In OE mice, simvastatin augmented muscular glucose uptake but impaired whole-body insulin sensitivity. Thus, simvastatin affected glucose homeostasis depending on PGC-1α expression.
多项研究表明，他汀类药物治疗会增加患糖尿病的风险。过氧化物酶体增殖物激活受体γ共激活因子1α（PGC-1α）是肌肉能量代谢和线粒体生物发生的重要调节因子。由于他汀类药物会损害骨骼肌中PGC-1α的表达，且在糖尿病患者中也观察到PGC-1α表达降低，因此我们研究了骨骼肌PGC1α表达是否会影响辛伐他汀对肌肉葡萄糖代谢的作用。我们对肌肉PGC-1α基因敲除（KO）或过表达（OE）的小鼠以及野生型（WT）小鼠进行了研究。小鼠口服辛伐他汀（5毫克/千克/天），持续3周，然后通过腹腔葡萄糖耐量试验（iGTT）、体内骨骼肌葡萄糖摄取、肌肉糖原含量以及葡萄糖转运蛋白4（Glut4）和己糖激酶的mRNA和蛋白表达进行检测。辛伐他汀损害了WT小鼠的葡萄糖代谢，表现为iGTT期间血糖浓度升高、骨骼肌葡萄糖摄取和糖原储备减少。KO小鼠在未接受辛伐他汀治疗时，iGTT期间血糖浓度就已升高，葡萄糖稳态受损，辛伐他汀还导致骨骼肌葡萄糖摄取减少。在OE小鼠中，辛伐他汀治疗使iGTT期间血糖和胰岛素浓度升高，并增加了骨骼肌葡萄糖摄取、糖原储备以及Glut4和己糖激酶蛋白表达。总之，辛伐他汀损害了WT小鼠骨骼肌的胰岛素敏感性，而KO小鼠在未使用辛伐他汀时就已表现出骨骼肌胰岛素敏感性受损。在OE小鼠中，辛伐他汀增强了肌肉葡萄糖摄取，但损害了全身胰岛素敏感性。因此，辛伐他汀对葡萄糖稳态的影响取决于PGC-1α的表达。
