Department of Endocrinology, The Affiliated People's Hospital of Ningbo University, Ningbo, 315040, Zhejiang, China.
Department of Chemoradiotherapy Centre, The Affiliated People's Hospital of Ningbo University, Ningbo, 315040, Zhejiang, China.
Inflamm Res. 2021 Jun;70(6):695-704. doi: 10.1007/s00011-021-01467-w. Epub 2021 May 12.
Diabetes mellitus (DM) is defined as a group of metabolic diseases characterized by hyperglycemia, which results from a deficiency in insulin secretion and/or insulin action. In diabetic patients, type 2 diabetes mellitus (T2DM) is in the majority. We explored the effects of circANKRD36 on streptozotocin (STZ)-induced insulin resistance and inflammation in diabetic rats with the aim of uncovering the underlying mechanism.
STZ was used to induce the in vivo T2DM rat model. After circANKRD36 interference, blood glucose, insulin and adiponectin were respectively detected. Hematoxylin and eosin (H&E), enzyme-linked immunosorbent assay (ELISA) and terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling assay (TUNEL) were conducted to examine inflammation and apoptosis in T2DM rats, and western blot was used for detecting apoptosis-related proteins. The binding relationships among circANKRD36, miR-145 and XBP1 were examined by luciferase reporter assay.
Results showed that circANKRD36 was expressed at a high level in T2DM rats, while silencing circANKRD36 led to decreased blood glucose and insulin, accompanied by increased adiponectin level, and ameliorating insulin resistance. Silencing circANKRD36 alleviated the inflammation and suppressed cell apoptosis in the pancreatic tissues of T2DM rats, which was abated by miR-145 inhibitor. The binding of miR-145 to XBP1 was then confirmed. Additionally, miR-145 inhibitor increased the level of XBP1 in T2DM rats, which was decreased in the presence of circANKRD36 silencing.
This study is the first to prove that silencing circANKRD36 inhibits STZ-induced insulin resistance and inflammation in diabetic rats by targeting miR- 145 via XBP1. The results warrant the importance of circRNAs as drug target and thereby pave way for the development of newer therapeutic measures for T2DM.
糖尿病（DM）被定义为一组以高血糖为特征的代谢性疾病，这是由于胰岛素分泌和/或胰岛素作用的缺陷所致。在糖尿病患者中，2 型糖尿病（T2DM）占多数。我们探讨了 circANKRD36 对链脲佐菌素（STZ）诱导的糖尿病大鼠胰岛素抵抗和炎症的影响，旨在揭示其潜在机制。
使用 STZ 诱导体内 T2DM 大鼠模型。在进行 circANKRD36 干扰后，分别检测血糖、胰岛素和脂联素。通过苏木精和伊红（H&E）、酶联免疫吸附测定（ELISA）和末端脱氧核苷酸转移酶介导的 dUTP-生物素缺口末端标记（TUNEL）检测 T2DM 大鼠的炎症和细胞凋亡，并用 Western blot 检测凋亡相关蛋白。通过荧光素酶报告实验检测 circANKRD36、miR-145 和 XBP1 之间的结合关系。
结果表明，circANKRD36 在 T2DM 大鼠中表达水平较高，而沉默 circANKRD36 可降低血糖和胰岛素水平，同时提高脂联素水平，改善胰岛素抵抗。沉默 circANKRD36 可减轻 T2DM 大鼠胰腺组织的炎症和抑制细胞凋亡，而 miR-145 抑制剂可减弱这一作用。随后证实了 miR-145 与 XBP1 的结合。此外，miR-145 抑制剂增加了 T2DM 大鼠中 XBP1 的水平，而沉默 circANKRD36 可降低其水平。
本研究首次证明，通过靶向 XBP1 抑制 miR-145，沉默 circANKRD36 可抑制 STZ 诱导的糖尿病大鼠胰岛素抵抗和炎症。该结果证明了 circRNAs 作为药物靶点的重要性，为 T2DM 的新型治疗措施的发展铺平了道路。
