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. In vitro 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.

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