Department of Structural and Functional Biology, Biology Institute, State University of Campinas, Cidade Universitária Zeferino Vaz, Rua Monteiro Lobato, 255, Campinas, SP, CEP 13083-862, Brazil.
J Transl Med. 2019 Aug 27;17(1):285. doi: 10.1186/s12967-019-2045-6.
HMG-CoA reductase inhibitors (statins) are cholesterol-lowering drugs widely used to treat hypercholesterolemia and prevent cardiovascular disease. Statins are generally well tolerated, but adverse reactions may occur, particularly myopathy and new onset of diabetes. The exact mechanism of statin-induced myopathy and diabetes has not been fully elucidated. We have previously shown that treatment of hypercholesterolemic (LDLr) mice with pravastatin for 2 months decreased pancreatic islet insulin secretion and increased oxidative stress and cell death, but no glucose intolerance was observed. The purpose of the current work was to study long-term pravastatin effects on glucose homeostasis, insulin sensitivity, muscle protein turnover and cell viability.
LDLr mice were treated with pravastatin for 3, 6 and 10 months. Glucose tolerance, insulin resistance and glucose-stimulated insulin secretion were evaluated. The rates of protein synthesis and degradation were determined in gastrocnemius muscle after 10 months of treatment. Insulin signalling, oxidative stress and cell death were analysed in vitro using C2C12 myotubes.
After 6 and 10 months of treatment, these mice became glucose intolerant, and after 10 months, they exhibited marked insulin resistance. Reduced islet glucose-stimulated insulin secretion was observed after the 3rd month of treatment. Mice treated for 10 months showed significantly decreased body weight and increased muscle protein degradation. In addition, muscle chymotrypsin-like proteasomal activity and lysosomal cathepsin were markedly elevated. C2C12 myotubes exposed to increasing concentrations of pravastatin presented dose-dependent impairment of insulin-induced Akt phosphorylation, increased apoptotic markers (Bax protein and cleaved caspase-3) and augmented superoxide anion production.
In addition to reduced insulin secretion, long-term pravastatin treatment induces insulin resistance and muscle wasting. These results suggest that the diabetogenic effect of statins is linked to the appearance of myotoxicity induced by oxidative stress, impaired insulin signalling, proteolysis and apoptosis.
羟甲基戊二酰辅酶 A 还原酶抑制剂（他汀类药物）是广泛用于治疗高胆固醇血症和预防心血管疾病的降胆固醇药物。他汀类药物通常耐受性良好，但可能会出现不良反应，特别是肌病和新发糖尿病。他汀类药物引起的肌病和糖尿病的确切机制尚未完全阐明。我们之前已经表明，用普伐他汀治疗 2 个月的高脂血症（LDLr）小鼠会降低胰岛胰岛素分泌，并增加氧化应激和细胞死亡，但未观察到葡萄糖耐量异常。本研究的目的是研究普伐他汀对葡萄糖稳态、胰岛素敏感性、肌肉蛋白质周转和细胞活力的长期影响。
用普伐他汀治疗 LDLr 小鼠 3、6 和 10 个月。评估葡萄糖耐量、胰岛素抵抗和葡萄糖刺激的胰岛素分泌。在治疗 10 个月后测定比目鱼肌的蛋白质合成和降解率。使用 C2C12 肌管体外分析胰岛素信号转导、氧化应激和细胞死亡。
治疗 6 和 10 个月后，这些小鼠出现葡萄糖不耐受，治疗 10 个月后出现明显的胰岛素抵抗。治疗 3 个月后观察到胰岛葡萄糖刺激的胰岛素分泌减少。治疗 10 个月的小鼠体重明显减轻，肌肉蛋白降解增加。此外，肌肉糜蛋白酶样蛋白酶体活性和溶酶体组织蛋白酶显著升高。暴露于普伐他汀浓度增加的 C2C12 肌管表现出剂量依赖性的胰岛素诱导的 Akt 磷酸化受损，增加的凋亡标志物（Bax 蛋白和裂解的 caspase-3）和增强的超氧阴离子产生。
除了胰岛素分泌减少外，长期普伐他汀治疗还会引起胰岛素抵抗和肌肉消耗。这些结果表明，他汀类药物的致糖尿病作用与氧化应激、胰岛素信号转导受损、蛋白水解和细胞凋亡引起的肌毒性的出现有关。
