Wang Yan, Yang Ling-Zhi, Yang Da-Gui, Zhang Qing-Yi, Deng Zhuo-Na, Wang Kao, Mao Xing-Jian
Department of Clinical Laboratory, The People's Hospital of Dujiangyan, Chengdu 611830, China.
Ann Palliat Med. 2020 Mar;9(2):394-404. doi: 10.21037/apm.2020.02.28. Epub 2020 Mar 13.
Type 2 diabetes mellitus (T2DM) is a major cause of death with an increasing incidence at an epidemic rate. The existing treatments for T2DM lack long-term effective blood glucose control. In this study, the effects of miR-21 antagomir on T2DM and the related mechanism were investigated using streptozotocin (STZ)-induced T2DM rats.
30 T2DM rats were randomly divided into 3 groups (n=10): T2DM group, T2DM rats with miR-21 antagomir group, T2DM rats with NC antagomir group. The expression of miR-21 in rats was detected by qRT-PCR. blood glucose, triacylglycerol (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-Cho), insulin, adiponectin, ITT and GTT were detected. The expression of TIMP3 in si-TIMP3 rats and the expression of TIMP3 in T2DM rats with miR-21 antagomir and si-TIMP3 was detected by Western blotting.
We found that miR-21 antagomir reduced blood glucose concentration in T2DM rats. MiR21 antagomir improved lipid metabolic disorder by decreasing the levels of triacylglycerol (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-Cho) and increasing the level of high-density lipoprotein cholesterol (HDL-Cho). Also, miR-21 antagomir reduced the value of homeostasis model assessment of insulin resistance (HOMA-IR), hemoglobin A1c (HbAc1), plasma insulin, and up-regulated the plasma adiponectin. These results, combined with insulin tolerance tests (ITT) and glucose tolerance tests (GTT) results, showed that miR-21 improved insulin resistance in STZ-induced T2DM rats. Then the target relationship between miR-21 and tissue inhibitor of metalloproteinases 3 (TIMP3) was proved by luciferase reporter assay. More impressively, miR-21 significantly increased the expression level of TIMP3 in STZ-induced T2DM rats.
Our study taken together has shown that miR-21 antagomir improved insulin resistance and lipid metabolism disorder in STZ-induced T2DM rats by up-regulating the expression level of TIMP3. This study suggested that miR-21 antagomir could be used as an effective therapeutic strategy and the underlying mechanism was revealed.
2型糖尿病（T2DM）是主要的死亡原因，其发病率正以流行速度上升。现有的T2DM治疗方法缺乏长期有效的血糖控制。在本研究中，使用链脲佐菌素（STZ）诱导的T2DM大鼠研究了miR-21拮抗剂对T2DM的影响及其相关机制。
将30只T2DM大鼠随机分为3组（n = 10）：T2DM组、miR-21拮抗剂处理的T2DM大鼠组、阴性对照拮抗剂处理的T2DM大鼠组。通过qRT-PCR检测大鼠中miR-21的表达。检测血糖、三酰甘油（TG）、总胆固醇（TC）、低密度脂蛋白胆固醇（LDL-Cho）、胰岛素、脂联素、胰岛素耐量试验（ITT）和葡萄糖耐量试验（GTT）。通过蛋白质免疫印迹法检测si-TIMP3大鼠中TIMP3的表达以及miR-21拮抗剂和si-TIMP3处理的T2DM大鼠中TIMP3的表达。
我们发现miR-21拮抗剂降低了T2DM大鼠的血糖浓度。miR-21拮抗剂通过降低三酰甘油（TG）、总胆固醇（TC）、低密度脂蛋白胆固醇（LDL-Cho）水平并提高高密度脂蛋白胆固醇（HDL-Cho）水平改善了脂质代谢紊乱。此外，miR-21拮抗剂降低了胰岛素抵抗稳态模型评估值（HOMA-IR）、糖化血红蛋白（HbAc1）、血浆胰岛素水平，并上调了血浆脂联素水平。这些结果与胰岛素耐量试验（ITT）和葡萄糖耐量试验（GTT）结果相结合，表明miR-21改善了STZ诱导的T2DM大鼠的胰岛素抵抗。然后通过荧光素酶报告基因检测证实了miR-21与金属蛋白酶组织抑制剂3（TIMP3）之间的靶向关系。更令人印象深刻的是，miR-21显著提高了STZ诱导的T2DM大鼠中TIMP3的表达水平。
我们的研究表明，miR-21拮抗剂通过上调TIMP3的表达水平改善了STZ诱导的T2DM大鼠的胰岛素抵抗和脂质代谢紊乱。本研究表明miR-21拮抗剂可作为一种有效的治疗策略，并揭示了其潜在机制。
