Wang Baomin, Wang Ziyan, Yang Yumei, Ho Melody Yuen Man, Yang Runyue, Yang Huizi, Liu Siyi, Lin Huige, Cheng Kenneth King Yip, Li Xiaomu
Department of Endocrinology and Metabolism, Zhongshan Hospital Fudan University, Shanghai, China.
Fudan Institute for Metabolic Diseases, Fudan University, Shanghai, China.
J Diabetes. 2025 Jun;17(6):e70100. doi: 10.1111/1753-0407.70100.
Pancreatic β-cells function deteriorates during aging, leading to increased risk of type 2 diabetes. We and others previously demonstrated that p53 activation triggers β-cell senescence and dysfunction in aging, but how its activity is controlled remains incompletely understood. Metabolites are not only by-products of metabolic pathways but also function as messengers to regulate various biological pathways. Taurine, a non-proteinogenic amino acid derived from cysteine, has demonstrated anti-aging effects in multiple cell types and tissues. Nevertheless, its role in β-cell senescence remains unclear.
Untargeted metabolomic analysis was used to determine differential metabolites in pancreatic islets of mice during aging. In vitro, β-cell lines MIN6 and INS-1E were treated with taurine and its transporter inhibitor, followed by measurement of senescence-related markers. Multiple experimental techniques, such as LC-MS/MS, co-immunoprecipitation, DARTS analysis, and LiP-MS, were used to study the mechanistic actions of taurine.
Untargeted metabolomic analysis showed that taurine and taurocholic acid were significantly upregulated in aged islets. Pretreatment with taurine inhibited naturally aging, chemically induced senescent and inflammatory program, oxidative stress, and defective insulin secretion in pancreatic β-cells. SLC6A6 transporter was required to mediate exogenous taurine uptake, and inhibition of SLC6A6 abolished the anti-senescent effects of taurine. Taurine bound with CKDN2AIP and inhibited its interaction with p53, thereby promoting p53 degradation and suppressing the p53-dependent senescent program.
Our findings suggest that increasing β-cell taurine uptake might be a feasible approach to preserve β-cell function by targeting the p53-dependent senescent response.
胰腺β细胞功能在衰老过程中会恶化，导致2型糖尿病风险增加。我们和其他人之前证明，p53激活会引发衰老过程中β细胞的衰老和功能障碍，但其活性如何被控制仍未完全了解。代谢产物不仅是代谢途径的副产物，还作为信使调节各种生物途径。牛磺酸是一种由半胱氨酸衍生而来的非蛋白质氨基酸，已在多种细胞类型和组织中显示出抗衰老作用。然而，其在β细胞衰老中的作用仍不清楚。
采用非靶向代谢组学分析来确定衰老过程中小鼠胰岛中的差异代谢产物。在体外，用牛磺酸及其转运体抑制剂处理β细胞系MIN6和INS-1E，随后测量衰老相关标志物。使用多种实验技术，如液相色谱-串联质谱、免疫共沉淀、DARTS分析和LiP-MS，来研究牛磺酸的作用机制。
非靶向代谢组学分析表明，牛磺酸和牛磺胆酸在衰老胰岛中显著上调。牛磺酸预处理可抑制胰腺β细胞的自然衰老、化学诱导的衰老和炎症程序、氧化应激以及胰岛素分泌缺陷。需要SLC6A6转运体来介导外源性牛磺酸的摄取，抑制SLC6A6可消除牛磺酸的抗衰老作用。牛磺酸与CKDN2AIP结合并抑制其与p53的相互作用，从而促进p53降解并抑制p53依赖性衰老程序。
我们的研究结果表明，通过靶向p53依赖性衰老反应增加β细胞对牛磺酸的摄取可能是一种维持β细胞功能的可行方法。
