Background

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.

Methods

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

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.

Conclusion

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.

中文翻译：

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沉默circANKRD36通过XBP1靶向miR-145抑制链脲佐菌素诱导的糖尿病大鼠胰岛素抵抗和炎症

背景

糖尿病（DM）被定义为一组以高血糖为特征的代谢性疾病，其由胰岛素分泌和/或胰岛素作用不足引起。在糖尿病患者中，2 型糖尿病 (T2DM) 占大多数。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，目的是揭示潜在机制。

方法

STZ用于诱导体内T2DM大鼠模型。circANKRD36干扰后分别检测血糖、胰岛素和脂联素。苏木精和伊红（H&E）、酶联免疫吸附试验（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试验（TUNEL）用于检测 T2DM 大鼠的炎症和细胞凋亡，并使用蛋白质印迹法检测细胞凋亡-相关蛋白质。通过荧光素酶报告基因测定检查circANKRD36、miR-145和XBP1之间的结合关系。

结果

结果表明，circANKRD36在T2DM大鼠中高水平表达，而沉默circANKRD36导致血糖和胰岛素降低，伴随脂联素水平升高，改善胰岛素抵抗。沉默circANKRD36可减轻T2DM大鼠胰腺组织的炎症并抑制细胞凋亡，而miR-145抑制剂可减轻这种情况。然后证实了 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，而在 circANKRD36 沉默的情况下，XBP1 水平降低。

结论

该研究首次证明沉默 circANKRD36 通过 XBP1 靶向 miR-145 来抑制糖尿病大鼠 STZ 诱导的胰岛素抵抗和炎症。这些结果证明了 circRNA 作为药物靶点的重要性，从而为开发新的 T2DM 治疗措施铺平了道路。