TIMP-1 transgenic mice recover from diabetes induced by multiple low-dose streptozotocin
TIMP-1 transgenic mice recover from diabetes induced by multiple low-dose streptozotocin
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DOI：
10.2337/db06-0710
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发表时间：
2007-01-01
期刊：
影响因子：
7.7
通讯作者：
Xie, Yuansheng
中科院分区：
文献类型：
--
作者：
Jiang, Hongwei;Zhu, Hanyu;Xie, Yuansheng
1型糖尿病是胰岛分泌胰岛素的β细胞自身免疫破坏的结果，成人胰岛的自我复制能力太有限，在广泛的组织损伤后无法恢复。金属蛋白酶组织抑制因子(TIMP)-1抑制基质金属蛋白酶活性，调节多种细胞类型的增殖和凋亡，这取决于具体情况。在这里，我们证明了在转基因小鼠的胰岛β细胞中过表达人TIMP-1可以抵消多次小剂量链脲佐菌素(MLDS)诱导的细胞毒性和胰岛素炎。非转基因小鼠在注射链脲佐菌素2周后出现严重的高血糖、低胰岛素血症和胰腺炎，并在17周内死亡。然而，MLDS处理的转基因小鼠逐渐恢复了代谢参数并存活了下来。由于增强了贝塔细胞的复制，贝塔细胞质量平行增加。因此，我们的结果首次证明了TIMP-1在β细胞中的过表达增强了胰岛β细胞的复制，并对抗1型糖尿病，表明TIMP-1基因可能是预防甚至逆转1型糖尿病的潜在税收。
Type 1 diabetes results from autoimmune destruction of the insulin-producing beta-cells of pancreatic islets, of which the capacity for self-replication in the adult is too limited to restore following extensive tissue injury. Tissue inhibitor of metalloproteinase (TIMP)-1 inhibits matrix metalloproteinase activity and regulates proliferation and apoptosis of a variety of cells types, depending on the context. Here, we show that overexpression of human TIMP-1 in pancreatic beta-cells of transgenic mice counteracts the cytotoxicity and insulitis induced by multiple low-dose streptozotocin (MLDS). Nontransgenic mice developed severe hyperglycemia, hypoinsulinemia, and insulitis 2 weeks after streptozotocin administration and died within 17 weeks. However, MLDS-treated transgenic mice gradually normalized the metabolic parameters and survived. beta-Cell mass increased in parallel as a result of enhancement of beta-cell replication. Thus, our results have demonstrated for the first time that overexpression of TIMP-1 in beta-cells enhances the replication of pancreatic islets beta-cells and counteracts type 1 diabetes, indicating that the TIMP-1 gene may be a potential tax-get to prevent, or even reverse, type 1 diabetes.