Adenosine kinase inhibition selectively promotes rodent and porcine islet β-cell replication
Adenosine kinase inhibition selectively promotes rodent and porcine islet β-cell replication
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DOI：
10.1073/pnas.1201149109
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发表时间：
2012-03-06
影响因子：
11.1
通讯作者：
Melton, Douglas A.
中科院分区：
文献类型：
--
作者：
Annes, Justin P.;Ryu, Jennifer Hyoje;Melton, Douglas A.
糖尿病是一种以相对胰岛素缺乏、持续高血糖、弥漫性微血管和大血管疾病为特征的病理状态。一种治疗策略是通过增加产生胰岛素的β细胞的数量来增强胰岛素分泌能力，而不引发普遍的增殖反应。在这里，我们提出了一个小分子筛选平台的开发，用于鉴定增加β细胞复制的分子。利用这个平台，我们鉴定了一类化合物[腺苷激酶抑制剂（ADK-Is）]，可以促进三种物种（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可增加β细胞的复制，但不能增加α细胞、PP细胞或成纤维细胞的复制。短期体内ADK-I治疗也能增加β细胞的复制，但不能增加外分泌细胞或肝细胞的复制。因此，我们提出抑制ADK作为治疗糖尿病的一种策略。
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 beta 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 beta-cell replication. Using this platform, we identify a class of compounds [ adenosine kinase inhibitors (ADK-Is)] that promote replication of primary beta 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 beta cells but not that of alpha cells, PP cells, or fibroblasts. Short-term in vivo treatment with an ADK-I also increases beta-cell replication but not exocrine cell or hepatocyte replication. Therefore, we propose ADK inhibition as a strategy for the treatment of diabetes.