Pancreatic-specific inactivation of IGF-I gene causes enlarged pancreatic islets and significant resistance to diabetes
Pancreatic-specific inactivation of IGF-I gene causes enlarged pancreatic islets and significant resistance to diabetes
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DOI：
10.2337/diabetes.53.12.3131
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发表时间：
2004-12-01
期刊：
影响因子：
7.7
通讯作者：
Liu, JL
中科院分区：
文献类型：
--
作者：
Lu, YR;Herrera, PL;Liu, JL
IGF-I刺激胰岛生长的教条受到了IGF或IGF-IR(IGF受体)基因的联合靶向以及β细胞特异性IGF-IR基因缺陷的挑战，这种缺陷不会导致胰岛细胞的生长缺陷。为了评估局部产生的IGF-I的生理作用，我们通过与Pdx1-Cre和IGF-I/loxP小鼠杂交，建立了胰腺特异性IGF-I基因缺陷(PID)。除了血糖水平降低和胰岛细胞团扩大2.3倍外，PID小鼠是正常的。当用小剂量链脲佐菌素攻击时，对照组小鼠在6天后出现高血糖，并保持在高水平至少2个月。相比之下，PID小鼠在12天后才表现出边缘高血糖，并在整个实验过程中保持不变。在链脲佐菌素作用15天后，PID小鼠表现出显著更高的胰岛素产生水平。此外，链脲佐菌素诱导的P细胞凋亡(转移酶介导的dUTP缺口末端标记[TUNEL]法)可被显著阻止。最后，PID小鼠表现出由高脂饮食诱导的2型糖尿病的延迟发病，伴随着胰岛超大，胰岛素mRNA水平升高，并保持对胰岛素的敏感性。我们的结果表明，胰腺内局部产生的IGF-I抑制胰岛细胞的生长；它的缺乏为β细胞提供了保护环境，并具有抗击糖尿病的潜力。
The dogma that IGF-I stimulates pancreatic islet growth has been challenged by combinational targeting of IGF or IGF-IR (IGF receptor) genes as well as beta-cell-specific IGF-IR gene deficiency, which caused no defect in islet cell growth. To assess the physiological role of locally produced IGF-I, we have developed pancreatic-specific IGF-I gene deficiency (PID) by crossing Pdx1-Cre and IGF-I/loxP mice. PID mice are normal except for decreased blood glucose level and a 2.3-fold enlarged islet cell mass. When challenged with low doses of streptozotocin, control mice developed hyperglycemia after 6 days that was maintained at high levels for at least 2 months. In contrast, PID mice only exhibited marginal hyperglycemia after 12 days, maintained throughout the experiment. Fifteen days after streptozotocin, PID mice demonstrated significantly higher levels of insulin production. Furthermore, streptozotocin-induced P-cell apoptosis (transferase-mediated dUTP nick-end labeling [TUNEL] assay) was significantly prevented in PID mice. Finally, PID mice exhibited a delayed onset of type 2 diabetes induced by a high-fat diet, accompanied by super enlarged pancreatic islets, increased insulin mRNA levels, and preserved sensitivity to insulin. Our results suggest that locally produced IGF-I within the pancreas inhibits islet cell growth; its deficiency provides a protective environment to the beta-cells and potential in combating diabetes.