Hepatocyte growth factor is essential for amelioration of hyperglycemia in streptozotocin-induced diabetic mice receiving a marginal mass of intrahepatic islet grafts
Hepatocyte growth factor is essential for amelioration of hyperglycemia in streptozotocin-induced diabetic mice receiving a marginal mass of intrahepatic islet grafts
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DOI：
10.1097/00007890-200001270-00004
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发表时间：
2000-01-27
期刊：
影响因子：
6.2
通讯作者：
Ikeda, S
中科院分区：
文献类型：
--
作者：
Nakano, M;Yasunami, Y;Ikeda, S
研究背景：寻找一种提高胰岛移植后胰岛素非依赖性的方法是临床胰岛移植的关键。在本研究中，我们确定肝细胞生长因子（HGF）是否对链脲佐菌素（STZ，200 mg/kg）诱导的糖尿病小鼠（C57 BL/6）接受肝内胰岛同系移植边缘质量的高血糖具有良好的改善作用。将分离的同系胰岛移植到受体的肝脏中。HGF与硫酸葡聚糖（DS）在相对于胰岛移植的第0、2、4、6和8天每天一次腹腔内施用。结果发现，在本模型中，250个胰岛的数量是作为供体胰岛的边缘质量，其中接受250个胰岛的14只糖尿病小鼠中有2只在移植后90天血糖恢复正常。用HGF（100 μ g）和DS（200 μ g）联合治疗所有小鼠（n=5）均产生正常血糖。形态学研究以及腹腔葡萄糖耐量试验显示HGF的有益作用。令我们惊讶的是，接受250个胰岛并单独用DS治疗的9只小鼠中有6只血糖正常。额外的抗HGF抗体处理（100 μ g，第-1，0，2，4，6和8天）消除了DS的作用，表明DS的作用是通过内源性HGF介导的。以肾包膜下间隙为胰岛移植部位时，DS的作用不明显。肝内移植后小鼠血浆HGF水平明显升高，而肾包膜下移植后无明显变化。这些发现表明，HGF是必不可少的STZ诱导的糖尿病小鼠的高血糖症的改善时，边缘质量的胰岛移植到肝脏。由于肝脏是临床胰岛移植的部位，移植后不能实现胰岛素非依赖性是成功移植的主要障碍，HGF可能有助于克服临床胰岛移植的这一重要问题。
Background, It is crucial for clinical islet transplantation to find a procedure to improve the success rate of insulin independence after islet transplantation. In the present study, we determined whether hepatocyte growth factor (HGF) has a favorable effect on amelioration of hyperglycemia in streptozotocin (STZ, 200 mg/kg)-induced diabetic mice (C57BL/6) receiving a marginal mass of intrahepatic islet isografts.Methods. Isolated syngeneic islets were transplanted into the liver of recipients. HGF with dextran sulfate (DS) was administered intraperitoneally once a day at day 0, 2, 4, 6, and 8 relative to islet transplantation. DS has been known to enhance the effect of HGF,Results, It was found that the number of 250 islets was a marginal mass as donor islets in this model, in which 2 out of 14 diabetic mice receiving 250 islets became normoglycemic by 90 days after transplantation. The treatment with HGF (100 mu g) in conjunction with DS (200 mu g) produced normoglycemia in all mice (n=5), Morphological study as well as intraperitoneal glucose tolerance test revealed the beneficial effects of HGF. To our surprise, six out of nine mice receiving 250 islets and treated with DS alone became normoglycemic. Additional anti-HGF antibody treatment (100 mu g, day -1, 0, 2, 4, 6, and 8) abolished the effects of DS, indicating that the effect by DS is mediated via the endogenous HGF. The effects of DS were not observed when the renal subcapsular space was the site of islet transplantation. There was a significant increase in plasma HGF levels in mice after the intrahepatic grafts but not the renal subcapsular one.Conclusions. These findings demonstrate that HGF is essential for amelioration of hyperglycemia in STZ-induced diabetic mice when a marginal mass of islets was grafted into the liver. As the liver is the site of clinical islet transplantation and the inability to achieve insulin independence after transplantation is a major obstacle for successful transplantation, HGF may facilitate to overcome such an important issue for clinical islet transplantation.