Marková I, Zídek V, Musilová A, Šimáková M, Mlejnek P, Kazdová L, Pravenec M
Institute of Physiology, Czech Academy of Sciences, Prague, Czech Republic.
Physiol Res. 2010;59(4):509-516. doi: 10.33549/physiolres.931852. Epub 2009 Nov 20.
It has been suggested that thiazolidinediones (TZDs) ameliorate insulin resistance in muscle tissue by suppressing muscle lipid storage and the activity of novel protein kinase C (nPKC) isoforms. To test this hypothesis, we analyzed long-term metabolic effects of pioglitazone and the activation of nPKC-epsilon and -theta isoforms in an animal model of the metabolic syndrome, the spontaneously hypertensive rat (a congenic SHR strain with wild type Cd36 gene) fed a diet with 60 % sucrose from the age of 4 to 8 months. Compared to untreated controls, pioglitazone treatment was associated with significantly increased basal (809+/-36 vs 527+/-47 nmol glucose/g/2h, P<0.005) and insulin-stimulated glycogenesis (1321+/-62 vs 749+/-60 nmol glucose/g/2h, P<0.0001) in isolated gastrocnemius muscles despite increased concentrations of muscle triglycerides (3.83+/-0.33 vs 2.25+/-0.12 micromol/g, P<0.005). Pioglitazone-treated rats exhibited significantly increased membrane/total (cytosolic plus membrane) ratio of both PKC-epsilon and PKC-theta isoforms compared to untreated controls. These results suggest that amelioration of insulin resistance after long-term pioglitazone treatment is associated with increased activation of PKC-epsilon and -theta isoforms in spite of increased lipid concentration in skeletal muscles.
有人提出噻唑烷二酮类药物（TZDs）通过抑制肌肉脂质储存和新型蛋白激酶C（nPKC）亚型的活性来改善肌肉组织中的胰岛素抵抗。为了验证这一假设，我们在代谢综合征动物模型——自发性高血压大鼠（一种具有野生型Cd36基因的同源SHR品系）中分析了吡格列酮的长期代谢效应以及nPKC-ε和-θ亚型的激活情况，该大鼠从4个月大到8个月大期间喂食含60%蔗糖的饮食。与未治疗的对照组相比，尽管肌肉甘油三酯浓度升高（3.83±0.33 vs 2.25±0.12 μmol/g，P<0.005），但吡格列酮治疗使分离的腓肠肌中的基础糖原生成（809±36 vs 527±47 nmol葡萄糖/g/2小时，P<0.005）和胰岛素刺激的糖原生成显著增加（1321±62 vs 749±60 nmol葡萄糖/g/2小时，P<0.0001）。与未治疗的对照组相比，吡格列酮治疗的大鼠PKC-ε和PKC-θ亚型的膜/总（胞质加膜）比率显著增加。这些结果表明，长期吡格列酮治疗后胰岛素抵抗的改善与PKC-ε和-θ亚型的激活增加有关，尽管骨骼肌中的脂质浓度增加。
