Transgenic overexpression of hepatocyte growth factor in the β-cell markedly improves islet function and islet transplant outcomes in mice
Transgenic overexpression of hepatocyte growth factor in the β-cell markedly improves islet function and islet transplant outcomes in mice
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DOI：
10.2337/diabetes.50.12.2752
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发表时间：
2001-12-01
期刊：
影响因子：
7.7
通讯作者：
Stewart, AF
中科院分区：
文献类型：
--
作者：
García-Ocaña, A;Vasavada, RC;Stewart, AF
人类胰岛移植的最新进展突出表明需要扩大可用于移植的β细胞库。我们开发了三种转基因模型，其中使用大鼠胰岛素启动子 (RIP) 将生长因子（肝细胞生长因子 [HGF]、胎盘催乳素或甲状旁腺激素相关蛋白）靶向 β 细胞。每一个都显示出胰岛大小和数量的增加，并且每一个都显示出胰岛素介导的低血糖。在这三种模型中，RIP-HGF 小鼠在基础条件下表现出最不令人印象深刻的表型。在这项研究中，我们证明这种温和的基础表型具有误导性，而 RIP-HGF 小鼠具有独特且有益的表型。与正常胰岛相比，RIP-HGF 胰岛每个 β 细胞含有更多的胰岛素（正常胰岛与 RIP-HGF 胰岛中分别为 50 +/- 5 和 78 +/- 9 ng/胰岛当量 [IE]，P < 0.025），在体内响应葡萄糖而分泌更多胰岛素（正常与正常胰岛中分别为 0.66 +/- 0.06 与 0.91 +/- 0.10 ng/ml）。 RIP-HGF 小鼠，P < 0.05）和体外（22.2 mmol/l 葡萄糖：640 +/- 120.1 对比 1,615 +/- 196.9 pg。mug 蛋白(-1)。正常与 RIP-HGF 胰岛相比 30 分钟(-1)，P < 0.01），具有两到三倍高的 GLUT2 和葡萄糖激酶稳态 mRNA 水平，取 更有效地增加和代谢葡萄糖，最重要的是，移植后功能至少提高两倍。这些发现表明，HGF 对 β 细胞有丝分裂、葡萄糖感应、β 细胞分化标志物和移植物存活具有令人惊讶的积极影响。作为体内胰岛质量和功能增强剂，它似乎具有独特且意想不到的有效特性。
Recent advances in human islet transplantation have highlighted the need for expanding the pool of beta -cells available for transplantation. We have developed three transgenic models in which growth factors (hepatocyte growth factor [HGF], placental lactogen, or parathyroid hormone-related protein) have been targeted to the beta -cell using rat insulin promoter (RIP). Each displays an increase in islet size and islet number, and each displays insulin-mediated hypoglycemia. Of these three models, the RIP-HGF mouse displays the least impressive phenotype under basal conditions. In this study, we show that this mild basal phenotype is misleading and that RIP-HGF mice have a unique and salutary phenotype. Compared with normal islets, RIP-HGF islets contain more insulin per beta -cell (50 +/- 5 vs. 78 +/- 9 ng/islet equivalent [IE] in normal vs. RIP-HGF islets, P < 0.025), secrete more insulin in response to glucose in vivo (0.66 +/- 0.06 vs. 0.91 +/- 0.10 ng/ml in normal vs. RIP-HGF mice, P < 0.05) and in vitro (at 22.2 mmol/l glucose: 640 +/- 120.1 vs. 1,615 +/- 196.9 pg . mug protein(-1) . 30 min(-1) in normal vs. RIP-HGF islets, P < 0.01), have two- to threefold higher GLUT2 and glucokinase steady-state mRNA levels, take up and metabolize glucose more effectively, and most importantly, function at least twice as effectively after transplantation. These findings indicate that HGF has surprisingly positive effects on -cell mitogenesis, glucose sensing, beta -cell markers of differentiation, and transplant survival. It appears to have a unique and unanticipated effective profile as an islet mass- and function-enhancing agent in vivo.