Shuang Zheng1,2, Ningxin Chen2, Xingjian Kang3, Yaomin Hu2, Sheng Shi4. 1. School of Medicine, Shanghai University, Shanghai, 200444, China. 2. Department of Endocrinology, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 200127, China. 3. School of Stomatology, Wenzhou Medical University, Wenzhou, 325000, China. 4. Department of Orthopedics, Shanghai Tenth People's Hospital, Tongji University, Shanghai, 200072, China. shisheng273@163.com.
Abstract
PURPOSE: Type 2 diabetes mellitus is characterized by insulin resistance and β-cell dysfunction. Elevated free fatty acids-induced lipotoxicity may play a vital role in the pathogenesis of β-cell insulin resistance. Exercise-stimulated myokine irisin has been reported to be closely related to T2DM. However, its function on β-cell insulin signaling and the underlying mechanisms are only partially elucidated as yet. METHODS: High-fat diet-fed C57BL/6J mice and palmitic acid-treated MIN6 cell models were utilized as lipotoxic models. Factors associated with β-cell insulin signaling transduction and inflammatory responses were assessed in these models. Furthermore, the role of irisin in β-cells and the underlying mechanisms were also explored. RESULTS: Irisin effectively decreased lipid levels in HFD mice, enhanced glucose-stimulated insulin secretion and nullified the expressions of inflammatory cytokines in vivo and in vitro experiments. Moreover, irisin improved PI3K/AKT insulin signaling pathway and inhibited TLR4/NF-κB inflammatory signaling pathway in both islets of HFD mice and PA-treated MIN6 cells. Mechanistic analysis indicated that FOXO1 might serve as a bridge between the two pathways. CONCLUSION: Irisin alleviates lipotoxicity-induced β-cell insulin resistance and inflammatory response through the activation of PI3K/AKT/FOXO1 signaling pathways and the inhibition of TLR4/NF-κB signaling pathways. Irisin might provide a novel therapeutic strategy for T2DM.
PURPOSE: Type 2 diabetes mellitus is characterized by insulin resistance and β-cell dysfunction. Elevated free fatty acids-induced lipotoxicity may play a vital role in the pathogenesis of β-cell insulin resistance. Exercise-stimulated myokine irisin has been reported to be closely related to T2DM. However, its function on β-cell insulin signaling and the underlying mechanisms are only partially elucidated as yet. METHODS: High-fat diet-fed C57BL/6J mice and palmitic acid-treated MIN6 cell models were utilized as lipotoxic models. Factors associated with β-cell insulin signaling transduction and inflammatory responses were assessed in these models. Furthermore, the role of irisin in β-cells and the underlying mechanisms were also explored. RESULTS: Irisin effectively decreased lipid levels in HFD mice, enhanced glucose-stimulated insulin secretion and nullified the expressions of inflammatory cytokines in vivo and in vitro experiments. Moreover, irisin improved PI3K/AKT insulin signaling pathway and inhibited TLR4/NF-κB inflammatory signaling pathway in both islets of HFD mice and PA-treated MIN6 cells. Mechanistic analysis indicated that FOXO1 might serve as a bridge between the two pathways. CONCLUSION: Irisin alleviates lipotoxicity-induced β-cell insulin resistance and inflammatory response through the activation of PI3K/AKT/FOXO1 signaling pathways and the inhibition of TLR4/NF-κB signaling pathways. Irisin might provide a novel therapeutic strategy for T2DM.