Department of Nutrition and Food Hygiene (National Key Discipline), Public Health College, Harbin Medical University, 150081 Harbin, Heilongjiang, China.
Department of Fundamental Neurosciences, University of Lausanne, 1005 Lausanne, Switzerland.
Front Biosci (Landmark Ed). 2023 Aug 28;28(8):181. doi: 10.31083/j.fbl2808181.
A long-term consumption of saturated fat significantly increases the concentration of saturated fatty acids in serum, which accelerates the appearance of senescence markers in β-cells and leads to their dysfunction. An understanding of the mechanisms underlying β-cell senescence induced by stearic acid and the exploration of effective agents preventing it remains largely unclear. Here, we aimed to investigate the protective effect of metformin against stearic acid-treated β-cell senescence and to assess the involvement of miR-297b-5p in this process.
To identify senescence, we measured senescence-associated β-galactosidase activity and the expression of senescence-related genes. Gain and loss of function approaches were applied to explore the role of miR-297b-5p in stearic acid-induced β-cell senescence. Bioinformatics analysis and a luciferase activity assay were used to predict the downstream targets of miR-297b-5p.
Stearic acid markedly induced senescence and suppressed miR-297b-5p expression in mouse β-TC6 cells, which were significantly alleviated by metformin. After transfection of miR-297b-5p mimics, stearic acid-evoked β-cell senescence was remarkably prevented. Insulin-like growth factor-1 receptor was identified as a direct target of miR-297b-5p. Inhibition of the insulin-like growth factor-1 receptor prevented stearic acid-induced β-cell senescence and dysfunction. Moreover, metformin alleviates the impairment of the miR-297b-5p inhibitor in β-TC6 cells. Additionally, long-term consumption of a high-stearic-acid diet significantly increased senescence and reduced miR-297b-5p expression in mouse islets.
These findings imply that metformin alleviates β-cell senescence by stearic acid through upregulating miR-297b-5p to suppress insulin-like growth factor-1 receptor expression, thereby providing a potential target to not only prevent high fat-diet-induced β-cell dysfunction but also for metformin therapy in type 2 diabetes.
长期摄入饱和脂肪会显著增加血清中饱和脂肪酸的浓度，这会加速β细胞衰老标志物的出现，并导致其功能障碍。然而，对于硬脂酸诱导的β细胞衰老的潜在机制以及探索有效的预防药物仍知之甚少。本研究旨在探讨二甲双胍对硬脂酸处理的β细胞衰老的保护作用，并评估 miR-297b-5p 在这一过程中的作用。
通过测量衰老相关β-半乳糖苷酶活性和衰老相关基因的表达来鉴定衰老。通过增益和缺失功能的方法来探讨 miR-297b-5p 在硬脂酸诱导的β细胞衰老中的作用。通过生物信息学分析和荧光素酶活性测定来预测 miR-297b-5p 的下游靶基因。
硬脂酸显著诱导小鼠β-TC6 细胞衰老并抑制 miR-297b-5p 的表达，而二甲双胍可显著减轻这种作用。转染 miR-297b-5p 模拟物后，硬脂酸诱导的β细胞衰老明显得到预防。胰岛素样生长因子 1 受体被鉴定为 miR-297b-5p 的直接靶基因。抑制胰岛素样生长因子 1 受体可预防硬脂酸诱导的β细胞衰老和功能障碍。此外，二甲双胍可减轻 miR-297b-5p 抑制剂对β-TC6 细胞的损伤。此外，长期高硬脂酸饮食显著增加了小鼠胰岛的衰老并降低了 miR-297b-5p 的表达。
这些发现表明，二甲双胍通过上调 miR-297b-5p 抑制胰岛素样生长因子 1 受体的表达来减轻硬脂酸诱导的β细胞衰老，从而为预防高脂肪饮食诱导的β细胞功能障碍以及二甲双胍治疗 2 型糖尿病提供了一个潜在的靶点。
