Veedu Anuranjana Putiya, Kunhipurayil Divya, Beegum Fathima, George Krupa Thankam, Kanwal Abhinav, Shenoy Rekha Raghuveer, Nandakumar Krishnadas
Department of Pharmacology, Manipal College of Pharmaceutical Sciences, Manipal Academy of Higher Education, Manipal, Karnataka 576104, India.
Department of Pharmacology, All India Institute of Medical Sciences, Bathinda, Punjab 151005, India.
Biomed Rep. 2025 Mar 24;22(5):91. doi: 10.3892/br.2025.1969. eCollection 2025 May.
The widespread use of statin therapy for hypercholesterolemia has raised concerns due to its associated risk of inducing diabetes. Biochanin-A (BA), an isoflavone, exhibits potential in preventing diabetes and hyperlipidemia, yet its efficacy in mitigating statin-induced diabetes remains unexplored. This gap prompts a crucial inquiry: Can BA reduce the risk of diabetes associated with statin therapy? The present study investigated the molecular mechanisms behind atorvastatin's diabetogenic nature and evaluated the potential of BA to counteract these effects. Insulin resistance was assessed using L6 skeletal muscle cells and pancreatic beta cell apoptosis in MIN-6 cells. Our hypothesis posits that atorvastatin exacerbates free fatty acid accumulation, leading to the downregulation of sirtuin-1 (SIRT-1) and decreased uncoupling protein (UCP) 3 expression, culminating in insulin resistance. Conversely, BA is assumed to positively modulate SIRT-1 and downregulate UCP2, thus offering a protective effect. studies using L6 and MIN-6 cells revealed that BA has increased cell viability and shown optimal protection against the toxicity induced by atorvastatin in both cell lines at different concentrations. BA effectively inhibited the reduction in glucose uptake caused by atorvastatin. Pre-treatment with BA upregulated proteins that are involved in the insulin-signaling pathway and reversed the expression levels of UCPs induced by atorvastatin. BA also enhanced insulin release, preserved mitochondrial function, and prevented atorvastatin-induced apoptosis. Furthermore, BA improved SIRT-1 expression, potentially through the nicotinamide phospho-ribosyl-transferase-nicotinamide adenine dinucleotide + SIRT1-pathway, revealing that BA may play a role in modulating cellular processes in statin-associated SIRT-1 downregulation. BA can be considered a promising molecule to counteract statin-induced diabetes, suggesting a prospective therapeutic role in enhancing the safety profile of statin therapy. This research lays the groundwork for future clinical evaluations of BA as an adjunctive treatment for patients at risk of statin-induced diabetes.
他汀类药物疗法在高胆固醇血症治疗中的广泛应用引发了人们对其诱发糖尿病相关风险的担忧。生物活性成分A（BA）是一种异黄酮，在预防糖尿病和高脂血症方面具有潜力，但其减轻他汀类药物诱发糖尿病的功效尚未得到研究。这一空白引发了一个关键问题：BA能否降低与他汀类药物疗法相关的糖尿病风险？本研究调查了阿托伐他汀致糖尿病特性背后的分子机制，并评估了BA抵消这些影响的潜力。使用L6骨骼肌细胞评估胰岛素抵抗，并在MIN-6细胞中评估胰腺β细胞凋亡。我们的假设是，阿托伐他汀会加剧游离脂肪酸积累，导致沉默调节蛋白-1（SIRT-1）下调和解偶联蛋白（UCP）3表达降低，最终导致胰岛素抵抗。相反，BA被认为可正向调节SIRT-1并下调UCP2，从而提供保护作用。使用L6和MIN-6细胞的研究表明，BA提高了细胞活力，并在不同浓度下对两种细胞系中阿托伐他汀诱导的毒性表现出最佳保护作用。BA有效抑制了阿托伐他汀引起的葡萄糖摄取减少。BA预处理上调了参与胰岛素信号通路的蛋白质，并逆转了阿托伐他汀诱导的UCPs表达水平。BA还增强了胰岛素释放，保留了线粒体功能，并防止了阿托伐他汀诱导的细胞凋亡。此外，BA可能通过烟酰胺磷酸核糖基转移酶-烟酰胺腺嘌呤二核苷酸+SIRT1途径改善了SIRT-1表达，表明BA可能在调节他汀类药物相关SIRT-1下调中的细胞过程中发挥作用。BA可被视为抵消他汀类药物诱发糖尿病的有前景分子，提示其在提高他汀类药物疗法安全性方面具有潜在治疗作用。本研究为未来将BA作为他汀类药物诱发糖尿病风险患者的辅助治疗进行临床评估奠定了基础。
