TGFβ receptor signaling is essential for inflammation-induced but not β-cell workload-induced β-cell proliferation.
TGFβ receptor signaling is essential for inflammation-induced but not β-cell workload-induced β-cell proliferation.
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作者：
Xiao X;Wiersch J;El-Gohary Y;Guo P;Prasadan K;Paredes J;Welsh C;Shiota C;Gittes GK
保护和恢复功能性β细胞团是预防和治疗糖尿病的基本策略。因此，了解决定功能性β细胞质量的信号具有巨大的临床意义。转化生长因子β(转化生长因子β)超家族信号通路在发育和组织规范中发挥着重要作用。然而，这些通路在成人β细胞内稳态中的作用还没有很好的定义。在这里，我们去除了接受两种外科β细胞复制模型(部分胰腺切除或部分导管结扎)的小鼠的转化生长因子β受体I和II基因，分别代表了β细胞增殖、β细胞工作负荷增加和局部炎症的两个触发因素。我们的数据表明转化生长因子β受体信号对于基线β细胞的增殖是必要的。通过提供过量的葡萄糖或外源性胰岛素治疗，我们进一步证明炎症和增加的β细胞工作负荷都是β细胞增殖的刺激因素，但分别是转化生长因子β受体信号依赖和不依赖的。总而言之，通过使用胰腺特异性转化生长因子β受体缺失的小鼠模型，我们已经确定了两种不同的调节成人β细胞增殖的途径。因此，我们的研究为了解β细胞在正常生长和胰腺疾病中的增殖提供了重要信息。
Protection and restoration of a functional β-cell mass are fundamental strategies for prevention and treatment of diabetes. Consequently, knowledge of signals that determine the functional β-cell mass is of immense clinical relevance. Transforming growth factor β (TGFβ) superfamily signaling pathways play a critical role in development and tissue specification. Nevertheless, the role of these pathways in adult β-cell homeostasis is not well defined. Here, we ablated TGFβ receptor I and II genes in mice undergoing two surgical β-cell replication models (partial pancreatectomy or partial duct ligation), representing two triggers for β-cell proliferation, increased β-cell workload and local inflammation, respectively. Our data suggest that TGFβ receptor signaling is necessary for baseline β-cell proliferation. By either provision of excess glucose or treatment with exogenous insulin, we further demonstrated that inflammation and increased β-cell workload are both stimulants for β-cell proliferation but are TGFβ receptor signaling dependent and independent, respectively. Collectively, by using a pancreas-specific TGFβ receptor–deleted mouse model, we have identified two distinct pathways that regulate adult β-cell proliferation. Our study thus provides important information for understanding β-cell proliferation during normal growth and in pancreatic diseases.
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