Yang Xinyu, Liang Shuntao, Huang Mingyue, Yue Shijun, Jiang Dechun, Yan Dan
Department of Pharmacy, Beijing Shijitan Hospital, Capital Medical University, Beijing 100038, China.
College of Pharmacy, Hebei University of Chinese Medicine, Shijiazhuang 050200, China.
Endocrinology. 2025 Jul 8;166(9). doi: 10.1210/endocr/bqaf105.
Damage to pancreatic β-cells serves as a critical pathological basis in the progression of diabetes. Berberine (BBR), an isoquinoline alkaloid, potentially protects pancreatic β-cells, exerting hypoglycemic effects. However, the dose-response relationship and the specific protective mechanism are still unclear. Hormesis is a self-protective response triggered by mild stimuli and has been reported to determine the extent to which phytochemicals can combat diabetes. In this study, we found that BBR exhibited a typical hormetic effect in IL-1β-induced damage to pancreatic β-cells, where low doses of BBR protect cells while high doses aggravate the damage. A model-based approach was used to describe dose-response relationships, as well as to detect and estimate hormetic effects. In addition, the regulatory effect of BBR in preventing apoptosis in pancreatic β-cells was confirmed, and an appropriate dose of BBR stabilized the mitochondrial membrane potential and prevented DNA damage. Moreover, the results showed that the hormetic effect of BBR was closely related to p53 and apoptosis pathways. To further investigate the role of the p53-mediated apoptosis pathways, our study interfered with the p53 pathway, resulting in the attenuation of the hormetic effect of BBR. These results introduce the concept of hormesis to study the biphasic effects of berberine on damaged pancreatic β-cells, while also exploring the relationship between the hormetic mechanism of BBR and the p53-mediated apoptosis pathway. These findings provide clues to explore the potential application of BBR in treating diabetes.
胰腺β细胞损伤是糖尿病进展的关键病理基础。黄连素（BBR）是一种异喹啉生物碱，具有潜在的保护胰腺β细胞和降血糖作用。然而，其剂量反应关系及具体保护机制仍不清楚。毒物兴奋效应是由轻度刺激引发的一种自我保护反应，据报道它可决定植物化学物质对抗糖尿病的程度。在本研究中，我们发现BBR在白细胞介素-1β诱导的胰腺β细胞损伤中表现出典型的毒物兴奋效应，低剂量BBR保护细胞，而高剂量则加重损伤。采用基于模型的方法来描述剂量反应关系以及检测和评估毒物兴奋效应。此外，证实了BBR在预防胰腺β细胞凋亡中的调节作用，适当剂量的BBR可稳定线粒体膜电位并防止DNA损伤。而且，结果表明BBR的毒物兴奋效应与p53和凋亡途径密切相关。为进一步研究p53介导的凋亡途径的作用，我们的研究干扰了p53途径，导致BBR的毒物兴奋效应减弱。这些结果引入了毒物兴奋效应的概念来研究黄连素对受损胰腺β细胞的双相作用，同时也探索了BBR的毒物兴奋效应机制与p53介导的凋亡途径之间的关系。这些发现为探索BBR在治疗糖尿病中的潜在应用提供了线索。
