Makino Naoki, Sasaki Makoto, Maeda Toyoki, Mimori Kosi
Division of Molecular and Clinical Gerontology, Department of Molecular and Cellular Biology;
Exp Clin Cardiol. 2010 Winter;15(4):e128-33.
The present study examined telomere biology in the context of insulin sensitivity in Otsuka Long-Evans Tokushima Fatty (OLETF) rats, a type 2 diabetic animal model. To improve insulin sensitivity, pioglitazone (PG; 10 mg/kg/day) was administered to OLETF rats between 20 weeks and 40 weeks of age, and the effects of the treatment were compared with those in untreated OLETF rats or control Long-Evans Tokushima Otsuka rats. The homeostasis model assessment of insulin resistance index significantly increased in OLETF rats, but decreased in PG-treated OLETF rats. Telomere lengths were not shortened in heart tissues of OLETF rats; however, telomerase activity was decreased in heart tissues of OLETF rats. Messenger RNA expression for both telomerase reverse transcriptase and telomere repeat binding factor 2 was downregulated in the hearts of OLETF rats. Protein expression of phosphorylated Akt, insulin-like growth factor and endothelial nitric oxide synthase were all reduced in OLETF rats. The changes observed in OLETF rats were inhibited by PG treatment. Myocardial fibrosis was less extensive and diastolic dysfunction improved in PG-treated OLETF rats versus untreated OLETF rats. These findings suggest that improving insulin sensitivity via the activation of peroxisome proliferator-activated receptor-gamma may exert regulatory effects on cardiac telomere biology, and may have desirable morphological and functional effects on the diabetic heart.
本研究在2型糖尿病动物模型大冢长- Evans德岛肥胖（OLETF）大鼠的胰岛素敏感性背景下，研究了端粒生物学。为提高胰岛素敏感性，在20周龄至40周龄的OLETF大鼠中给予吡格列酮（PG；10 mg/kg/天），并将治疗效果与未治疗的OLETF大鼠或对照长- Evans德岛大冢大鼠进行比较。OLETF大鼠的胰岛素抵抗指数稳态模型评估显著升高，但PG治疗的OLETF大鼠则降低。OLETF大鼠心脏组织中的端粒长度未缩短；然而，OLETF大鼠心脏组织中的端粒酶活性降低。OLETF大鼠心脏中端粒酶逆转录酶和端粒重复结合因子2的信使核糖核酸表达均下调。OLETF大鼠中磷酸化Akt、胰岛素样生长因子和内皮型一氧化氮合酶的蛋白表达均降低。PG治疗可抑制OLETF大鼠中观察到的这些变化。与未治疗的OLETF大鼠相比，PG治疗的OLETF大鼠心肌纤维化程度较轻，舒张功能障碍改善。这些发现表明，通过激活过氧化物酶体增殖物激活受体γ来提高胰岛素敏感性，可能对心脏端粒生物学发挥调节作用，并可能对糖尿病心脏产生理想的形态和功能影响。
