Increased β-cell Mass by Islet Transplantation and PLAG1 Overexpression Causes Hyperinsulinemic Normoglycemia and Hepatic Insulin Resistance in Mice
Increased β-cell Mass by Islet Transplantation and PLAG1 Overexpression Causes Hyperinsulinemic Normoglycemia and Hepatic Insulin Resistance in Mice
复制标题
DOI：
10.2337/db09-1446
复制
发表时间：
2010-08-01
期刊：
影响因子：
7.7
通讯作者：
Verfaillie, Catherine M.
中科院分区：
文献类型：
--
作者：
Declercq, Jeroen;Kumar, Anujith;Verfaillie, Catherine M.
抗胰岛素-据信，尽管β-细胞质量增加，但生物体仍保持血糖正常，这是因为β-细胞在每个细胞的基础上产生的胰岛素减少。然而，一些具有β-细胞增生的转基因小鼠模型表明，胰岛素产生仍然过量，并且血糖正常是由胰岛素抵抗维持的。我们通过在血糖正常的小鼠中移植过量的正常胰岛，以及在β细胞中使用靶向PLAG 1表达，这导致β-细胞扩增。在两种模型中，空腹血浆胰岛素水平增加，即使动物血糖正常。腹膜内葡萄糖耐量试验后，血浆胰岛素水平增加，这与葡萄糖清除的改善有关。在这些条件下，如高胰岛素血症正葡萄糖钳夹实验所证明的，正常胰岛素水平由肝胰岛素抵抗维持。结论-总之，我们证明，当移植过量的β细胞时，每个β细胞的胰岛素产生没有充分降低，导致高胰岛素血症和肝胰岛素抵抗。这一观察结果对于设计基于干细胞的胰岛替代疗法可能很重要。糖尿病59：1957-1965，2010年
OBJECTIVE-It is believed that an organism remains normoglycemic despite an increase in the beta-cell mass because of decreased insulin production by beta-cells on a per-cell basis However, some transgenic mouse models with beta-cell hyperplasia suggest that insulin production remains excessive and that normoglycemia is maintained by insulin resistanceMETHODS-Here, we investigated the effect of an increased beta-cell mass on glycemia and insulin resistance by grafting excess normal islets in normoglycemic mice, as well as using targeted PLAG1 expression in beta-cells, which leads to beta-cell expansion.RESULTS-In both models, fasting plasma insulin levels were increased, even though animals were normoglycemic. After an intraperitoneal glucose tolerance test, plasma insulin levels increased, which was associated with improved glucose clearing Under these conditions, normoglycemia is maintained by hepatic insulin resistance as demonstrated by hyperinsulinemic euglycemic clamp experiments.CONCLUSIONS-In conclusion, we demonstrate that when excess beta-cells are grafted, insulin production on a per beta-cell basis is not sufficiently decreased, leading to hyperinsulinemia and hepatic insulin resistance. This observation might be important for the design of stem cell-based islet replacement therapies. Diabetes 59:1957-1965, 2010