Department of Cardiology, Beijing Chaoyang Hospital, Beijing, China.
Department of Cardiology, Second Affiliated Hospital of Shantou University Medical College, Shantou, Guangdong, China.
J Cell Mol Med. 2021 Jul;25(14):6733-6745. doi: 10.1111/jcmm.16677. Epub 2021 May 30.
High uric acid (HUA) is associated with insulin resistance (IR) in cardiomyocytes. We investigated whether metformin protects against HUA-induced IR in cardiomyocytes. We exposed primary cardiomyocytes to HUA, and cellular glucose uptake was quantified by measuring the uptake of 2-NBDG, a fluorescent glucose analog. Western blot was used to examine the levels of signalling protein. Membrane of glucose transporter type 4 (GLUT4) was analysed by immunofluorescence. We monitored the impact of metformin on HUA-induced IR and in myocardial tissue of an acute hyperuricaemia mouse model established by potassium oxonate treatment. Treatment with metformin protected against HUA-reduced glucose uptake induced by insulin in cardiomyocytes. HUA directly inhibited the phosphorylation of Akt and the translocation of GLUT4 induced by insulin, which was blocked by metformin. Metformin promoted phosphorylation of AMP-activated protein kinase (AMPK) and restored the insulin-stimulated glucose uptake in HUA-induced IR cardiomyocytes. As a result of these effects, in a mouse model of acute hyperuricaemia, metformin improved insulin tolerance and glucose tolerance, accompanied by increased AMPK phosphorylation, Akt phosphorylation and translocation of GLUT4 in myocardial tissues. As expected, AICAR, another AMPK activator, had similar effects to metformin, demonstrating the important role of AMPK activation in protecting against IR induced by HUA in cardiomyocytes. Metformin protects against IR induced by HUA in cardiomyocytes and improves insulin tolerance and glucose tolerance in an acute hyperuricaemic mouse model, along with the activation of AMPK. Consequently, metformin may be an important potential new treatment strategy for hyperuricaemia-related cardiovascular disease.
高尿酸（HUA）与心肌细胞胰岛素抵抗（IR）有关。我们研究了二甲双胍是否可以预防 HUA 诱导的心肌细胞 IR。我们将原代心肌细胞暴露于 HUA 中，并通过测量荧光葡萄糖类似物 2-NBDG 的摄取来定量测定细胞葡萄糖摄取。使用 Western blot 检测信号蛋白水平。通过免疫荧光分析葡萄糖转运蛋白 4（GLUT4）的膜。我们监测了二甲双胍对 HUA 诱导的 IR 的影响，以及黄嘌呤氧化酶处理建立的急性高尿酸血症小鼠模型心肌组织中的影响。二甲双胍治疗可预防 HUA 降低胰岛素诱导的心肌细胞葡萄糖摄取。HUA 直接抑制胰岛素诱导的 Akt 磷酸化和 GLUT4 的易位，而二甲双胍可阻断这一作用。二甲双胍促进 AMP 激活的蛋白激酶（AMPK）磷酸化，并恢复 HUA 诱导的 IR 心肌细胞中胰岛素刺激的葡萄糖摄取。由于这些作用，在急性高尿酸血症小鼠模型中，二甲双胍改善了胰岛素耐量和葡萄糖耐量，同时伴有心肌组织中 AMPK 磷酸化、Akt 磷酸化和 GLUT4 易位的增加。正如预期的那样，另一种 AMPK 激活剂 AICAR 具有与二甲双胍相似的作用，表明 AMPK 激活在保护心肌细胞免受 HUA 诱导的 IR 方面起着重要作用。二甲双胍可预防心肌细胞中 HUA 诱导的 IR，并改善急性高尿酸血症小鼠模型中的胰岛素耐量和葡萄糖耐量，同时激活 AMPK。因此，二甲双胍可能是治疗与高尿酸血症相关心血管疾病的重要新潜在治疗策略。
