Department of Stem Cell and Regenerative Biology, Harvard Stem Cell Institute, Cambridge, MA 02138, USA.
Proc Natl Acad Sci U S A. 2012 Mar 6;109(10):3915-20. doi: 10.1073/pnas.1201149109. Epub 2012 Feb 15.
Diabetes is a pathological condition characterized by relative insulin deficiency, persistent hyperglycemia, and, consequently, diffuse micro- and macrovascular disease. One therapeutic strategy is to amplify insulin-secretion capacity by increasing the number of the insulin-producing β cells without triggering a generalized proliferative response. Here, we present the development of a small-molecule screening platform for the identification of molecules that increase β-cell replication. Using this platform, we identify a class of compounds [adenosine kinase inhibitors (ADK-Is)] that promote replication of primary β cells in three species (mouse, rat, and pig). Furthermore, the replication effect of ADK-Is is cell type-selective: treatment of islet cell cultures with ADK-Is increases replication of β cells but not that of α cells, PP cells, or fibroblasts. Short-term in vivo treatment with an ADK-I also increases β-cell replication but not exocrine cell or hepatocyte replication. Therefore, we propose ADK inhibition as a strategy for the treatment of diabetes.
糖尿病是一种病理状况，其特征为相对胰岛素缺乏、持续高血糖，进而导致弥漫性微血管和大血管疾病。一种治疗策略是通过增加产生胰岛素的β细胞数量来放大胰岛素分泌能力，而不会引发广泛的增殖反应。在这里，我们介绍了一种用于鉴定增加β细胞复制的分子的小分子筛选平台。使用该平台，我们鉴定出一类化合物（腺苷激酶抑制剂（ADK-Is）），可促进三种物种（小鼠、大鼠和猪）的原代β细胞复制。此外，ADK-Is 的复制作用具有细胞类型选择性：用 ADK-Is 处理胰岛细胞培养物会增加β细胞的复制，但不会增加α细胞、PP 细胞或成纤维细胞的复制。ADK-I 的短期体内治疗也会增加β细胞的复制，但不会增加外分泌细胞或肝细胞的复制。因此，我们提出 ADK 抑制作为治疗糖尿病的一种策略。
