Lv Xiaoyan, Zhao Yali, Yang Xuehan, Han Hao, Ge Yue, Zhang Meishuang, Zhang Hansi, Zhang Ming, Chen Li
Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, China.
Department of Clinical Laboratory, The Second Hospital of Jilin University, Changchun, China.
Front Pharmacol. 2021 Sep 22;12:720866. doi: 10.3389/fphar.2021.720866. eCollection 2021.
Pancreatic β-cell dysfunction is a key link during the progression of type 2 diabetes (T2DM), and SIRT1 participates in the regulation of various physiological activities of islet β-cells. However, as a key link in signal transduction, it is not clear how SIRT1 is regulated. By TargetScan prediction, we found that miR-204, which is enriched in islets, has highly complementary binding sites with SIRT1. Therefore, we speculate that miR-204 may be the upstream regulatory target of SIRT1 in islets and thus participate in the occurrence of β-cell dysfunction. In this study, we explored the association between miR-204 and β-cell dysfunction, the therapeutic effects of berberine (BBR) on β-cell function and the possible mechanisms. We found that miR-204 increased and SIRT1 mRNA and protein levels decreased significantly in islets both and . MIN6 cells induced by palmitic acid exhibited increased apoptosis, and the accumulation of insulin and ATP in the supernatant decreased. Importantly, palmitic acid treatment combined with miR-204 silencing showed opposite changes. MiR-204 overexpression in MIN6 cells increased apoptosis and decreased insulin and ATP production and SIRT1 expression. SIRT1 overexpression reversed the damage to β-cells caused by miR-204. The BBR treatment effectively improved insulin synthesis, reduced miR-204 levels, and increased SIRT1 expression in islet tissue in diabetic mice. Overexpression of miR-204 reversed the protective effect of BBR on apoptosis and insulin secretion in MIN6 cells. Our study identifies a novel correlation between miR-204 and β-cell dysfunction in T2DM and shows that administration of BBR leads to remission of β-cell dysfunction by regulating the miR-204/SIRT1 pathway.
胰腺β细胞功能障碍是2型糖尿病（T2DM）进展过程中的关键环节，而SIRT1参与胰岛β细胞各种生理活动的调节。然而，作为信号转导中的关键环节，SIRT1是如何被调控的尚不清楚。通过TargetScan预测，我们发现富含于胰岛中的miR-204与SIRT1具有高度互补的结合位点。因此，我们推测miR-204可能是胰岛中SIRT1的上游调控靶点，从而参与β细胞功能障碍的发生。在本研究中，我们探讨了miR-204与β细胞功能障碍之间的关联、黄连素（BBR）对β细胞功能的治疗作用及其可能机制。我们发现，在[具体情况1]和[具体情况2]时，胰岛中miR-204升高，SIRT1 mRNA和蛋白水平显著降低。棕榈酸诱导的MIN6细胞凋亡增加，上清液中胰岛素和ATP的积累减少。重要的是，棕榈酸处理联合miR-204沉默显示出相反的变化。MIN6细胞中miR-204过表达增加了细胞凋亡，降低了胰岛素和ATP的产生以及SIRT1的表达。SIRT过表达逆转了miR-204对β细胞的损伤。BBR治疗有效改善了糖尿病小鼠胰岛组织中的胰岛素合成，降低了miR-204水平，并增加了SIRT1表达。miR-204过表达逆转了BBR对MIN6细胞凋亡和胰岛素分泌的保护作用。我们的研究确定了T2DM中miR-204与β细胞功能障碍之间的新关联，并表明给予BBR通过调节miR-204/SIRT1途径导致β细胞功能障碍的缓解。
