Centre for Biomolecular Interactions Bremen, University of Bremen, Leobener Strasse NW2, Bremen, Germany.
Diabetologia. 2012 Dec;55(12):3296-307. doi: 10.1007/s00125-012-2693-z. Epub 2012 Sep 4.
AIMS/HYPOTHESIS: Diabetes is characterised by loss and dysfunction of the beta cell. A major goal of diabetes therapy is to promote the formation of new beta cells. Polymorphisms of T cell factor 7-like 2 (TCF7L2) are associated with type 2 diabetes, negatively regulating beta cell survival and function. Here, we provide evidence for a role of TCF7L2 in beta cell proliferation and regeneration.
Pancreatic sections from three mouse models (high-fat diet, exendin-4 and streptozotocin-treated mice) and from healthy individuals and patients with type 2 diabetes were used to investigate the association of beta cell regeneration and TCF7L2 levels. To analyse a direct effect of TCF7L2 on duct cell to beta cell conversion, TCF7L2 was overexpressed in isolated exocrine cells.
TCF7L2 levels correlated with beta cell compensation during high-fat diet feeding. TCF7L2 was increased together with pancreatic duct cell proliferation and differentiation. Small islet-like cell clusters (ICCs) that contained TCF7L2 originated in the vicinity of the ductal epithelium. In human isolated exocrine tissue, TCF7L2 overexpression induced proliferation of pancreatic duct cells and ICC formation next to duct cells, an effect dependent on the JAK2/STAT3 pathway.
CONCLUSIONS/INTERPRETATION: The present study demonstrates that TCF7L2 overexpression fosters beta cell regeneration. Our findings imply correlation of TCF7L2 levels and new beta cell formation.
目的/假设：糖尿病的特征是β细胞的丧失和功能障碍。糖尿病治疗的主要目标是促进新的β细胞的形成。T 细胞因子 7 样 2（TCF7L2）的多态性与 2 型糖尿病相关，负调节β细胞的存活和功能。在这里，我们提供了 TCF7L2 在β细胞增殖和再生中的作用的证据。
使用三种小鼠模型（高脂肪饮食、exendin-4 和链脲佐菌素处理的小鼠）以及健康个体和 2 型糖尿病患者的胰腺切片，研究β细胞再生和 TCF7L2 水平之间的关系。为了分析 TCF7L2 对导管细胞向β细胞转化的直接影响，在分离的外分泌细胞中过表达 TCF7L2。
TCF7L2 水平与高脂肪饮食喂养期间β细胞代偿相关。TCF7L2 与胰腺导管细胞增殖和分化一起增加。含有 TCF7L2 的小胰岛样细胞簇（ICCs）起源于导管上皮附近。在人类分离的外分泌组织中，TCF7L2 的过表达诱导了胰腺导管细胞的增殖和 ICC 的形成，紧邻导管细胞，这种效应依赖于 JAK2/STAT3 途径。
结论/解释：本研究表明 TCF7L2 的过表达促进了β细胞的再生。我们的发现意味着 TCF7L2 水平与新的β细胞形成相关。
