Department of Pharmacy, Guizhou Provincial People's Hospital, Guiyang, Guizhou, China.
The First Affiliated Hospital, Guizhou University of Traditional Chinese Medicine, Guiyang, Guizhou, China.
Exp Physiol. 2023 Jul;108(7):961-974. doi: 10.1113/EP090305. Epub 2023 May 4.
What is the central question of this study? Is there a risk of developing diabetes associated with statin treatment? What is the underlying mechanism of the increased incidence rate of new-onset diabetes in patients treated with rosuvastatin? What is the main finding and its importance? Rosuvastatin therapy reduced intraperitoneal glucose tolerance and changed the catabolism of branched-chain amino acid (BCAAs) in white adipose tissue and skeletal muscle. Protein phosphatase 2Cm knockdown completely abolished the effects of insulin and rosuvastatin on glucose absorption. This study provides mechanistic support for recent clinical data on rosuvastatin-related new-onset diabetes and underscores the logic for intervening in BCAA catabolism to prevent the harmful effects of rosuvastatin.
Accumulating evidence indicates that patients treated with rosuvastatin have an increased risk of developing new-onset diabetes. However, the underlying mechanism remains unclear. In this study, we administered rosuvastatin (10 mg/kg body weight) to male C57BL/6J mice for 12 weeks and found that oral rosuvastatin dramatically reduced intraperitoneal glucose tolerance. Rosuvastatin-treated mice showed considerably higher serum levels of branched-chain amino acids (BCAAs) than control mice. They also showed dramatically altered expression of BCAA catabolism-related enzymes in white adipose tissue and skeletal muscle, including downregulated mRNA expression of BCAT2 and protein phosphatase 2Cm (PP2Cm) and upregulated mRNA expression of branched-chain ketoacid dehydrogenase kinase (BCKDK). The levels of BCKD in the skeletal muscle were reduced in rosuvastatin-treated mice, which was associated with lower PP2Cm protein levels and increased BCKDK levels. We also investigated the effects of rosuvastatin and insulin administration on glucose metabolism and BCAA catabolism in C2C12 myoblasts. We observed that incubation with insulin enhanced glucose uptake and facilitated BCAA catabolism in C2C12 cells, which was accompanied by elevated Akt and glycogen synthase kinase 3 β (GSK3β) phosphorylation. These effects of insulin were prevented by co-incubation of the cells with 25 μM rosuvastatin. Moreover, the effects of insulin and rosuvastatin administration on glucose uptake and Akt and GSK3β signaling in C2C12 cells were abolished when PP2Cm was knocked down. Although the relevance of these data, obtained with high doses of rosuvastatin in mice, to therapeutic doses in humans remains to be elucidated, this study highlights a potential mechanism for the diabetogenic effects of rosuvastatin, and suggests that BCAA catabolism could be a pharmacological target for preventing the adverse effects of rosuvastatin.
本研究的核心问题是什么？他汀类药物治疗是否与糖尿病风险增加有关？接受瑞舒伐他汀治疗的患者中新发糖尿病发病率增加的潜在机制是什么？主要发现及其重要性是什么？瑞舒伐他汀治疗降低了腹腔内葡萄糖耐量，并改变了白色脂肪组织和骨骼肌中支链氨基酸（BCAA）的分解代谢。蛋白磷酸酶 2Cm 敲低完全消除了胰岛素和瑞舒伐他汀对葡萄糖吸收的影响。这项研究为瑞舒伐他汀相关新发糖尿病的最近临床数据提供了机制支持，并强调了干预 BCAA 分解代谢以预防瑞舒伐他汀有害影响的逻辑。
越来越多的证据表明，接受瑞舒伐他汀治疗的患者发生新发糖尿病的风险增加。然而，其潜在机制尚不清楚。在这项研究中，我们给雄性 C57BL/6J 小鼠给予瑞舒伐他汀（10mg/kg 体重）12 周，发现口服瑞舒伐他汀显著降低了腹腔内葡萄糖耐量。与对照组相比，瑞舒伐他汀治疗的小鼠血清支链氨基酸（BCAA）水平显著升高。他们还在白色脂肪组织和骨骼肌中观察到与 BCAA 分解代谢相关的酶的表达明显改变，包括 BCAT2 和蛋白磷酸酶 2Cm（PP2Cm）的 mRNA 表达下调以及分支链酮酸脱氢酶激酶（BCKDK）的 mRNA 表达上调。瑞舒伐他汀治疗小鼠的骨骼肌中 BCKD 水平降低，与 PP2Cm 蛋白水平降低和 BCKDK 水平升高有关。我们还研究了瑞舒伐他汀和胰岛素给药对 C2C12 成肌细胞葡萄糖代谢和 BCAA 分解代谢的影响。我们观察到胰岛素孵育增强了 C2C12 细胞的葡萄糖摄取并促进了 BCAA 分解代谢，这伴随着 Akt 和糖原合酶激酶 3β（GSK3β）磷酸化的增加。当细胞与 25μM 瑞舒伐他汀共孵育时，胰岛素的这些作用被阻止。此外，当敲低 PP2Cm 时，胰岛素和瑞舒伐他汀给药对 C2C12 细胞葡萄糖摄取以及 Akt 和 GSK3β 信号的影响被消除。虽然这些数据与小鼠中高剂量瑞舒伐他汀获得的数据与人类治疗剂量的相关性仍有待阐明，但本研究强调了瑞舒伐他汀致糖尿病作用的潜在机制，并表明 BCAA 分解代谢可能是预防瑞舒伐他汀不良影响的药理学靶点。
