GLP-1 signalling compensates for impaired insulin signalling in regulating beta cell proliferation in βIRKO mice
GLP-1 signalling compensates for impaired insulin signalling in regulating beta cell proliferation in βIRKO mice
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DOI：
10.1007/s00125-017-4303-6
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发表时间：
2017-08-01
期刊：
影响因子：
8.2
通讯作者：
Kulkarni, Rohit N.
中科院分区：
文献类型：
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作者：
Kawamori, Dan;Shirakawa, Jun;Kulkarni, Rohit N.
目的/假设我们的目的是在GLP-1调节受损的β细胞功能的治疗潜力的背景下，研究胰岛素和胰高血糖素样肽（GLP）-1信号通路在体内β细胞周期动力学调节中的潜在相互作用。表现出β细胞功能障碍和β细胞质量的年龄依赖性降低的（β IRKO）小鼠用二肽基肽酶-4抑制剂vildagelide处理。在此之后，葡萄糖稳态和β细胞增殖进行了评估和潜在的分子机制investigated.Results在循环GLP-1水平的持续升高，由治疗的基因敲除小鼠6周，显着改善葡萄糖耐量继发于增强胰岛素分泌和β细胞增殖。用GLP-1类似物exendin-4处理β IRKO β细胞系，除了细胞周期蛋白D2外，还促进Akt磷酸化和细胞周期蛋白A、D1和E的蛋白表达2 - 3倍。胰腺从vildagliptin治疗的β IRKO小鼠表现出增加细胞周期蛋白D1的表达，而细胞周期蛋白D2的表达imported.Conclusions/解释激活GLP-1信号传导补偿受损的生长因子（胰岛素）信号传导和增强细胞周期蛋白的表达，以促进β细胞增殖。总之，这些数据表明GLP-1相关疗法在功能失调的β细胞模型中增强β细胞增殖和促进有益结果的潜力。
Aims/hypothesis We aimed to investigate potential interactions between insulin and glucagon-like peptide (GLP)-1 signalling pathways in the regulation of beta cell-cycle dynamics in vivo, in the context of the therapeutic potential of GLP-1 to modulate impaired beta cell function.Methods Beta cell-specific insulin receptor knockout (beta IRKO) mice, which exhibit beta cell dysfunction and an age-dependent decrease in beta cell mass, were treated with the dipeptidyl peptidase-4 inhibitor vildagliptin. Following this, glucose homeostasis and beta cell proliferation were evaluated and underlying molecular mechanisms were investigated.Results The sustained elevation in circulating GLP-1 levels, caused by treatment of the knockout mice with vildagliptin for 6 weeks, significantly improved glucose tolerance secondary to enhanced insulin secretion and proliferation of beta cells. Treating beta IRKO beta cell lines with the GLP-1 analogue, exendin-4, promoted Akt phosphorylation and protein expression of cyclins A, D1 and E two-to threefold, in addition to cyclin D2. Pancreases from the vildagliptin-treated beta IRKO mice exhibited increased cyclin D1 expression, while cyclin D2 expression was impaired.Conclusions/interpretation Activation of GLP-1 signalling compensates for impaired growth factor (insulin) signalling and enhances expression of cyclins to promote beta cell proliferation. Together, these data indicate the potential of GLP-1-related therapies to enhance beta cell proliferation and promote beneficial outcomes in models with dysfunctional beta cells.