Overexpression of miR-297b-5p in Mouse Insulin-Secreting Cells Promotes Metformin-Mediated Protection Against Stearic Acid-Induced Senescence by Targeting Igf1r

Abstract

Background: 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. Methods: 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. Results: 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. Conclusions: 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.

Keywords

• stearic acid
• β-cell senescence
• mirna
• metformin
• type 2 diabetes