Insulin-like growth factor I (IGF-I)-stimulated pancreatic β-cell growth is glucose-dependent -: Synergistic activation of insulin receptor substrate-mediated signal transduction pathways by glucose and IGF-I in INS-1 CELLS
Insulin-like growth factor I (IGF-I)-stimulated pancreatic β-cell growth is glucose-dependent -: Synergistic activation of insulin receptor substrate-mediated signal transduction pathways by glucose and IGF-I in INS-1 CELLS
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DOI：
10.1074/jbc.273.28.17771
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发表时间：
1998-07-10
影响因子：
4.8
通讯作者：
Rhodes, CJ
中科院分区：
文献类型：
--
作者：
Hügl, SR;White, MF;Rhodes, CJ
营养物和某些生长因子刺激胰腺β细胞有丝分裂发生，然而，尚未定义适当的促有丝分裂信号转导途径。在葡萄糖敏感性胰腺β细胞系INS-1中，发现葡萄糖（6 - 18 mM）独立地增加INS-1细胞增殖（在15 mM葡萄糖下> 20倍）。胰岛素样生长因子I（IGF-I）诱导的INS-1细胞增殖仅在生理相关浓度范围内具有葡萄糖依赖性IGF-I和葡萄糖的组合是协同的，在15mM葡萄糖+10nM IGF-I下使INS-1细胞增殖增加> 20倍，葡萄糖代谢与磷脂酰肌醇S'-激酶（PI 3'-激酶）激活对于葡萄糖和IGF-I刺激的INS-1细胞增殖都是必需的，IGF-I和15 mM葡萄糖增加了酪氨酸磷酸化介导的Grb 2/mSOS和PI 3 '-激酶向IRS-2和pp60的募集，葡萄糖和IGF-I也诱导了Shc与Grb 2/mSOS、葡萄糖（3 - 18 mM）和IGF-I的结合，与此相反，p70（S6K）随着葡萄糖浓度的增加（在6和18 mM之间）被激活，并且在与INS-1细胞增殖速率相关的相同葡萄糖浓度范围内被IGF I增强。因此，葡萄糖和IGF-I诱导的β细胞增殖是通过信号传导机制介导的，该机制由促分裂原活化蛋白激酶促进，但依赖于IRS介导的PI 3 '-激酶活性诱导和下游p70 S6K活化。IGF-I介导的INS-1细胞增殖的葡萄糖依赖性强调β细胞信号传导机制在与糖酵解代谢通量紧密相关方面是相当独特的。
Nutrients and certain growth factors stimulate pancreatic beta-cell mitogenesis, however, the appropriate mitogenic signal transduction pathways have not been defined, In the glucose sensitive pancreatic beta-cell line, INS-I, it was found that glucose (6-18 mM) independently increased INS-1 cell proliferation (>20-fold at 15 mM glucose). Insulin-like growth factor I (IGF-I)-induced INS-1 cell proliferation was glucose-dependent only in the physiologically relevant concentration range (6-18 mm glucose), The combination of IGF-I and glucose was synergistic, increasing INS-1 cell-proliferation >20-fold at 15 mM glucose + 10 nM IGF-I, Glucose metabolism and phosphatidylinositol S'-kinase (PI 3'-kinase) activation were necessary for both glucose and IGF-I-stimulated INS-1 cell proliferation, IGF-I and 15 mM glucose increased tyrosine phosphorylation mediated recruitment of Grb2/mSOS and PI 3'-kinase to IRS-2 and pp60, Glucose and IGF-I also induced Shc association with Grb2/ mSOS, Glucose (3-18 mM) and IGF-I, independently of glucose, activated mitogen-activated protein kinase but this did not correlate with IGF-I-induced beta-cell proliferation, In contrast, p70(S6K) was activated with increasing glucose concentration (between 6 and 18 mM), and potentiated by IGF I in the same glucose concentration range which correlated with INS-1 cell proliferation rate. Thus, glucose and IGF-I-induced beta-cell proliferation were mediated via a signaling mechanism that was facilitated by mitogen-activated protein kinase but de pendent on IRS-mediated induction of PI 3'-kinase activity and downstream activation of p70S6K. The glucose dependence of IGF-I mediated INS-1 cell proliferation emphasizes beta-cell signaling mechanisms are rather unique in being tightly linked to glycolytic metabolic flux.