Division of Molecular and Clinical Gerontology, Department of Molecular and Cellular Biology, Medical Institute of Bioregulation, Kyushu University, 4546 Tsurumihara, Beppu 874-0838, Japan.
Am J Physiol Heart Circ Physiol. 2009 Dec;297(6):H2188-95. doi: 10.1152/ajpheart.00421.2009. Epub 2009 Oct 23.
This study was conducted to examine telomere biology in terms of improving insulin sensitivity in a type 2 diabetic animal model: Otsuka Long-Evans Tokushima fatty (OLETF) rats. To improve insulin sensitivity, pioglitazone (PG; 10 mg.kg(-1).day(-1)) was administrated to OLETF rats from 20 to 40 wk of age, and the effects of treatment were compared with those in untreated OLETF or control Long-Evans Tokushima Otsuka fatty rats. At the end of the study, the homeostasis model assessment of insulin resistance significantly increased in OLETF rats but decreased in OLETF rats treated with PG. No shortening of telomere length was observed in the heart tissue of OLETF rats, whereas telomerase activity was decreased in OLETF heart tissue. The mRNA expression of both telomerase reverse transcriptase and telomere repeat binding factor 2 was downregulated in the hearts of OLETF rats. The protein expression of phospho-Akt, insulin-like growth factor, and endothelial nitric oxide synthase was reduced in OLETF rats. On the other hand, myocardial matrix metalloproteinase-9 expression was elevated in OLETF rats. The changes observed in OLETF rats were inhibited by PG treatment. However, protein and mRNA expression of Sirt1, a lifespan modulator, were attenuated in OLETF rat hearts, although they were enhanced in OLETF rats with PG treatment. Myocardial fibrosis was less extensive and diastolic dysfunction more greatly ameliorated in PG-treated OLETF rats than in OLETF rats. These findings suggest that improving insulin sensitivity via the activation of peroxisom proliferator-activated receptor-gamma may exert regulatory effects on cardiac telomere biology and may have desirable morphological and functional effects on the diabetic heart.
这项研究旨在探讨端粒生物学在改善 2 型糖尿病动物模型胰岛素敏感性方面的作用：Otsuka Long-Evans Tokushima fatty (OLETF) 大鼠。为了改善胰岛素敏感性，从 20 至 40 周龄开始，向 OLETF 大鼠给予吡格列酮 (PG；10mg/kg·天)，并将治疗效果与未经治疗的 OLETF 或对照 Long-Evans Tokushima Otsuka fatty 大鼠进行比较。在研究结束时，OLETF 大鼠的稳态模型评估胰岛素抵抗显著增加，但接受 PG 治疗的 OLETF 大鼠则降低。OLETF 大鼠的心脏组织中未观察到端粒长度缩短，而端粒酶活性在 OLETF 心脏组织中降低。OLETF 大鼠心脏组织中，端粒酶逆转录酶和端粒重复结合因子 2 的 mRNA 表达均下调。OLETF 大鼠的磷酸化 Akt、胰岛素样生长因子和内皮型一氧化氮合酶的蛋白表达减少。另一方面，心肌基质金属蛋白酶-9 的表达在 OLETF 大鼠中升高。PG 治疗抑制了 OLETF 大鼠中观察到的这些变化。然而，尽管在接受 PG 治疗的 OLETF 大鼠中增强，但寿命调节剂 Sirt1 的蛋白和 mRNA 表达在 OLETF 大鼠心脏中减弱。PG 治疗的 OLETF 大鼠的心肌纤维化程度较轻，舒张功能改善更大。这些发现表明，通过激活过氧化物酶体增殖物激活受体-γ来改善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。
