General Education Center, Tzu Chi College of Technology, Hualien, Taiwan.
Chronobiol Int. 2013 Jul;30(6):796-810. doi: 10.3109/07420528.2013.766204. Epub 2013 Jun 5.
Circadian rhythms are exhibited in the physiological and behavioral processes of all mammals; they are generated by intracellular levels of circadian oscillators, which are named as a set of circadian-clock genes. These genes compose the transcriptional/translational feedback loops to regulate not only circadian rhythmicity, but also energy metabolism. Previous studies have shown that obesity and diabetes cause the dysregulation of the circadian-clock system, and vice versa. However, some diabetes subjects are lean with insulin resistance and the mechanisms of insulin resistance without obesity are much less well known. Therefore, whether insulin resistance alone is enough to influence the expression of circadian-clock genes is uncertain. This study employs a neonatal streptozotocin (STZ)-treated paradigm in mice to model the molecular and physiological progress of nonobese insulin resistance. A single injection of STZ into 2-d-old male C57BL/6 mice induces nonobese, hyperglycemic and hyperinsulinemic conditions, and the levels of gene expression in the liver by a real-time quantitative polymerase chain reaction are then measured. Although the levels of Bmal1 (brain and muscle Arnt-like protein-1), Per2 (period 2), and Cry1 (cryptochrome 1) mRNA expression in the liver change during the progress of insulin resistance conditions, the gene expression patterns still show circadian rhythmicity. This study suggests that changes in the hepatic circadian-clock gene expression mark an early event in the metabolic disruption associated with insulin resistance. Furthermore, 2 wks of treatment with the thiazolidinedione, pioglitazone, fully resolve the dysfunction in metabolic parameters and the changes in circadian-clock gene expression from early insulin resistance conditions. These results indicate that the circadian-clock system is sensitive to insulin resistance, and that treatment with thiazolidinediones can resolve changes in the circadian-clock system in a timely manner. Thus, strengthening the peripheral circadian-clock system may counteract the adverse physiological consequences in the metabolic syndrome.
昼夜节律表现在所有哺乳动物的生理和行为过程中；它们是由细胞内的昼夜振荡器水平产生的，这些振荡器被命名为一组昼夜节律钟基因。这些基因构成了转录/翻译反馈环，不仅调节昼夜节律性，还调节能量代谢。先前的研究表明，肥胖和糖尿病导致昼夜节律钟系统失调，反之亦然。然而，一些糖尿病患者体重偏瘦但存在胰岛素抵抗，而肥胖患者的胰岛素抵抗机制则知之甚少。因此，胰岛素抵抗本身是否足以影响昼夜节律钟基因的表达尚不确定。本研究采用新生链脲佐菌素（STZ）处理的小鼠模型来模拟非肥胖型胰岛素抵抗的分子和生理进展。在 2 日龄雄性 C57BL/6 小鼠中单次注射 STZ 会导致非肥胖、高血糖和高胰岛素血症，并通过实时定量聚合酶链反应测量肝脏中的基因表达水平。尽管肝脏中 Bmal1（脑和肌肉 ARNT 样蛋白-1）、Per2（周期 2）和 Cry1（隐色素 1）mRNA 表达水平在胰岛素抵抗条件下的进展过程中发生变化，但基因表达模式仍显示昼夜节律性。本研究表明，肝脏昼夜节律钟基因表达的变化标志着与胰岛素抵抗相关的代谢紊乱的早期事件。此外，2 周的噻唑烷二酮类药物吡格列酮治疗可完全解决代谢参数的功能障碍和早期胰岛素抵抗条件下昼夜节律钟基因表达的变化。这些结果表明，昼夜节律钟系统对胰岛素抵抗敏感，噻唑烷二酮类药物治疗可以及时解决昼夜节律钟系统的变化。因此，增强外周昼夜节律钟系统可能有助于抵抗代谢综合征的不良生理后果。
