Department of Geriatric Medicine, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, Kunming, China.
Endokrynol Pol. 2023;74(3):277-284. doi: 10.5603/EP.a2023.0035. Epub 2023 Jun 19.
Irisin is closely related to type 2 diabetes mellitus (T2DM) and other metabolic diseases. It can improve the homeostasis of T2DM. MiR-133a-3p is decreased in the peripheral blood of patients with T2DM. Forkhead box protein O1 (FOXO1) is widely expressed in beta-cells and affects the occurrence of diabetes through transcriptional regulation and signalling pathway regulation.
The miR-133a-3p inhibitor was constructed to verify the effect of irisin on pyroptosis through miR-133a-3p. Next, we predicted the presence of targeted binding sequences between FOXO1 and miR-133a-3p by bioinformatics software, which was then confirmed with a double fluorescence assay. Finally, the FOXO1 overexpression vector was used to further verify the effect of irisin through the miR-133a-3p/FOXO1 axis.
We first observed that irisin inhibited the protein levels of N-terminal gasdermin D (GSDMD-N) and cleaved caspase-1 and the secretion of interleukins (IL): IL-1beta and IL-18 in Min6 cells treated with high glucoes (HG). Irisin inhibited pyroptosis of Min6 cells treated with HG by reinforcing miR-133a-3p. Then, FOXO1 was validated to be the target gene of miR-133a. Both miR-133a-3p inhibitor and overexpression of FOXO1 restrained the force of irisin on pyroptosis in HG-induced Min6 cells.
We explored the protective effect of irisin on HG-induced pyroptosis of islet b-cells in vitro and explained its mechanism of inhibiting pyroptosis through the miR-133a-3p/FOXO1 axis, to provide a theoretical basis for finding new molecular targets to delay beta-cell failure and the treatment of T2DM.
鸢尾素与 2 型糖尿病（T2DM）和其他代谢性疾病密切相关，它可以改善 T2DM 的内稳态。miR-133a-3p 在 T2DM 患者的外周血中减少。叉头框蛋白 O1（FOXO1）广泛表达于β细胞，通过转录调控和信号通路调控影响糖尿病的发生。
构建 miR-133a-3p 抑制剂，通过 miR-133a-3p 验证鸢尾素对细胞焦亡的作用。接下来，我们通过生物信息学软件预测 FOXO1 和 miR-133a-3p 之间靶向结合序列的存在，然后通过双荧光测定法进行验证。最后，使用 FOXO1 过表达载体进一步通过 miR-133a-3p/FOXO1 轴验证鸢尾素的作用。
我们首先观察到，在高糖（HG）处理的 Min6 细胞中，鸢尾素抑制 N 端 Gasdermin D（GSDMD-N）和切割的半胱天冬酶-1的蛋白水平以及白细胞介素（IL）：IL-1beta 和 IL-18 的分泌。鸢尾素通过增强 miR-133a-3p 抑制 HG 处理的 Min6 细胞的细胞焦亡。然后，验证 FOXO1 是 miR-133a-3p 的靶基因。miR-133a-3p 抑制剂和 FOXO1 的过表达均抑制了 HG 诱导的 Min6 细胞中鸢尾素对细胞焦亡的作用。
我们在体外探索了鸢尾素对胰岛β细胞 HG 诱导的细胞焦亡的保护作用，并通过 miR-133a-3p/FOXO1 轴解释了其抑制细胞焦亡的机制，为寻找新的分子靶点以延缓β细胞衰竭和治疗 T2DM 提供了理论依据。
