Li Tianrong, Yang Jingjing, Tan Anjun, Chen Hewen
Department of Geriatric Medicine, The First People's Hospital of Yunnan Province, The Affiliated Hospital of Kunming University of Science and Technology, No. 157 Jinbi Road, Kunming, Yunnan, 650032, China.
Diabetol Metab Syndr. 2023 Nov 22;15(1):239. doi: 10.1186/s13098-023-01216-5.
Irisin plays a key role in metabolic diseases, including type 2 diabetes mellitus (T2DM). However, the mechanism underlying the link between irisin and the development of T2DM, particularly in pancreatic islet β-cells, remains unknown.
In vitro, Min6 cells were treated with high glucose (HG) to generate T2DM cell models. GSDMD-N staining, Western blotting assays, and ELISA were performed to measure the expression levels of GSDMD, caspase 1, IL-1β, and IL-18. Next, the NLRP3 stimulator, ATP, was used to assess the effect of irisin on NLRP3 inflammasome. To evaluate the function of the Nrf2-TrX/TXNIP signaling axis, the Nrf2 inhibitor ML385 was used. For in vivo assessment, we first established T2DM model mice. Then, hematoxylin and eosin (H&E) staining was performed to observe the islet morphology, and the immunofluorescence technique was used to examine the mass of α and β cells. To confirm the role of the Nrf2-TrX/TXNIP signaling axis, ML385 was injected into the mice. Immunofluorescence of Nrf2, caspase 1, and GSDMD was detected in the islet cells of the model mice to verify the results.
We found that irisin treatment significantly decreased the expression of GSDMD-N (P31) and cleaved caspase-1 (p20), decreased caspase1 activity, and inhibited the secretion of IL-1β and IL-18 in HG-treated Min6 cells. We also found that irisin inhibited oxidative stress and NLRP3 expression by activating the Nrf2-TrX/TXNIP signaling axis. Additionally, in the T2DM model mice, irisin enhanced the function of islet cells, decreased insulin resistance, and preserved the morphology of pancreatic islets.
We showed in this study that irisin can be used for treating pyroptosis in HG-induced islet β-cells and T2DM model mice. We also found that irisin inhibits pyroptosis and oxidative stress by inhibiting the NLRP3-GSDMD pathway and activating the Nrf2-TrX/TXNIP signaling axis.
鸢尾素在包括2型糖尿病（T2DM）在内的代谢性疾病中起关键作用。然而，鸢尾素与T2DM发生之间联系的潜在机制，尤其是在胰岛β细胞中的机制，仍不清楚。
在体外，用高糖（HG）处理Min6细胞以建立T2DM细胞模型。进行GSDMD-N染色、蛋白质印迹分析和酶联免疫吸附测定以测量GSDMD、半胱天冬酶1、白细胞介素-1β和白细胞介素-18的表达水平。接下来，使用NLRP3刺激剂ATP来评估鸢尾素对NLRP3炎性小体的影响。为了评估Nrf2-TrX/TXNIP信号轴的功能，使用了Nrf2抑制剂ML385。对于体内评估，我们首先建立了T2DM模型小鼠。然后，进行苏木精-伊红（H&E）染色以观察胰岛形态，并使用免疫荧光技术检测α细胞和β细胞的数量。为了证实Nrf2-TrX/TXNIP信号轴的作用，将ML385注射到小鼠体内。在模型小鼠的胰岛细胞中检测Nrf2、半胱天冬酶1和GSDMD的免疫荧光以验证结果。
我们发现鸢尾素处理显著降低了HG处理的Min6细胞中GSDMD-N（P31）和裂解的半胱天冬酶-1（p20）的表达，降低了半胱天冬酶1活性，并抑制了白细胞介素-1β和白细胞介素-18的分泌。我们还发现鸢尾素通过激活Nrf2-TrX/TXNIP信号轴抑制氧化应激和NLRP3表达。此外，在T2DM模型小鼠中，鸢尾素增强了胰岛细胞的功能，降低了胰岛素抵抗，并保留了胰岛的形态。
我们在本研究中表明，鸢尾素可用于治疗HG诱导的胰岛β细胞和T2DM模型小鼠中的细胞焦亡。我们还发现鸢尾素通过抑制NLRP3-GSDMD途径和激活Nrf2-TrX/TXNIP信号轴来抑制细胞焦亡和氧化应激。
