Transforming Growth Factor Beta Superfamily Signaling in Pancreas Biology

转化生长因子-β/Smad3信号调节胰岛素基因转录和胰岛β细胞功能 胰岛β细胞功能障碍是2型糖尿病发病机制的标志性特征。因此，了解调节β细胞功能的信号具有巨大的临床意义。转化生长因子-β信号通路在胰腺发育过程中发挥着重要作用，但在成人胰腺中的作用尚不清楚。我们最近明确了转化生长因子-β途径在调节胰岛素基因转录和β细胞功能中的重要作用。我们发现转化生长因子-β信号效应分子Smad3占据了胰岛素基因的启动子并抑制了胰岛素基因的转录。相反，Smad3小干扰RNA缓解了胰岛素转录抑制，提高了胰岛素水平。腺病毒Smad3转导到原代人类和非人类灵长类胰岛可抑制胰岛素含量，而显性阴性的Smad3可提高胰岛素水平。与此一致的是，Smad3基因缺陷小鼠表现出中度高胰岛素血症和轻度低血糖。此外，在体内，Smad3缺乏会导致糖耐量的改善和葡萄糖刺激的胰岛素分泌增加。在体外灌流试验中，SMAD3缺陷的胰岛表现出改善的葡萄糖估计的胰岛素释放。有趣的是，Smad3缺陷的胰岛包含一个激活的胰岛素受体信号通路，而转化生长因子-β信号调节与β细胞功能相关的基因的表达。综上所述，这些研究强调了转化生长因子-β/Smad3信号是胰岛素基因转录和β细胞功能的重要调节因子，并提示转化生长因子-β信号通路的组成部分在糖尿病中可能是失调的。

Transforming Growth Factor-beta/Smad3 Signaling Regulates Insulin Gene Transcription and Pancreatic Islet beta-Cell Function. Pancreatic islet beta-cell dysfunction is a signature feature of Type 2 diabetes pathogenesis. Consequently, knowledge of signals that regulate beta-cell function is of immense clinical relevance. Transforming growth factor (TGF)-beta signaling plays a critical role in pancreatic development although the role of this pathway in the adult pancreas is obscure. We recently defined an important role of the TGF-beta pathway in regulation of insulin gene transcription and beta-cell function. We showed that the TGF-beta signaling effector Smad3 occupies the insulin gene promoter and represses insulin gene transcription. In contrast, Smad3 small interfering RNAs relieve insulin transcriptional repression and enhance insulin levels. Transduction of adenoviral Smad3 into primary human and non-human primate islets suppresses insulin content, whereas, dominant-negative Smad3 enhances insulin levels. Consistent with this, Smad3-deficient mice exhibit moderate hyperinsulinemia and mild hypoglycemia. Moreover, Smad3 deficiency results in improved glucose tolerance and enhanced glucose-stimulated insulin secretion in vivo. In ex vivo perifusion assays, Smad3-deficient islets exhibit improved glucosestimulated insulin release. Interestingly, Smad3-deficient islets harbor an activated insulin-receptor signaling pathway and TGF-beta signaling regulates expression of genes involved in beta-cell function. Together, these studies emphasize TGF-beta/Smad3 signaling as an important regulator of insulin gene transcription and beta-cell function and suggest that components of the TGF-beta signaling pathway may be dysregulated in diabetes.