Wenjing Zhang, Jiahua Wu, Yuchen Zhao, Nan Wu, Shuiya Sun, Sunyue He, Xihua Lin, Jiaqiang Zhou
Our findings suggest that elevated 7-ketocholesterol is associated with β-cell dysfunction in T2D patients and appears to impair insulin secretion by inducing oxidative stress in pancreatic β-cells, positioning 7-ketocholesterol as a potential contributor to diabetes progression.
AIMS: Glucolipotoxicity-induced β-cell dysfunction is a key factor in the pathogenesis of type 2 diabetes (T2D). While cholesterol is known to contribute to this dysfunction, the specific role of its major oxidation product, 7-ketocholesterol, remains unclear.
METHODS: We quantified serum 7-ketocholesterol levels using UPLC-MS in a cohort comprising individuals with T2D and normal glucose tolerance (NGT). Using INS-1 cells and primary islets, we investigated the effects of 7-ketocholesterol on β-cell function (including glucose-stimulated insulin secretion [GSIS], perfusion and calcium dynamics) and the underlying mechanisms related to oxidative stress (reactive oxygen species [ROS], mitochondrial membrane potential [MMP], ATP) and gene/protein expression. The antioxidant N-Acetyl-L-cysteine (NAC) was employed to rescue the observed dysfunction.
RESULTS: Cohort analysis showed serum 7-ketocholesterol levels were significantly elevated in T2D patients compared to NGT controls (0.070 ± 0.035 vs. 0.051 ± 0.021 µmol/L), and this elevation correlated negatively with early-phase insulin secretion. In INS-1 cells and primary islets, 7-ketocholesterol exposure impaired GSIS and disrupted intracellular calcium signaling. Furthermore, 7-ketocholesterol induced marked oxidative stress, characterized by increased ROS production, loss of MMP, and reduced ATP levels. Mechanistically, 7-ketocholesterol promoted NRF2 nuclear translocation and upregulated the expression of antioxidant genes, including Gpx4 and Sod1. Critically, co-treatment with NAC attenuated 7-ketocholesterol-induced oxidative stress and restored insulin secretion and calcium signaling.
CONCLUSION: Our findings suggest that elevated 7-ketocholesterol is associated with β-cell dysfunction in T2D patients and appears to impair insulin secretion by inducing oxidative stress in pancreatic β-cells, positioning 7-ketocholesterol as a potential contributor to diabetes progression.