Transgenic mice overexpressing insulin-like growth factor-II in β cells develop type 2 diabetes
Transgenic mice overexpressing insulin-like growth factor-II in β cells develop type 2 diabetes
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DOI：
10.1172/jci5656
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发表时间：
2000-03-01
影响因子：
15.9
通讯作者：
Bosch, F
中科院分区：
文献类型：
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作者：
Devedjian, JC;George, M;Bosch, F
在胚胎发育过程中，胰岛素样生长因子-II（IGF-II）参与胰岛生长和分化的调节。为了研究胰岛增生和高胰岛素血症在2型糖尿病发展中的作用，我们在大鼠胰岛素I启动子的控制下产生了在β细胞中表达IGF-II的转基因小鼠（C57 BL 6/SJL）。与对照小鼠的胰岛相比，转基因小鼠的胰岛显示出高水平的IGF-II mRNA和蛋白。转基因小鼠的胰腺酶显示β细胞质量（约3倍）和胰岛素mRNA水平增加。然而，转基因胰岛内的细胞组织被破坏，胰高血糖素产生细胞随机分布在整个核心。我们还观察到转基因小鼠胰岛中葡萄糖刺激的胰岛素分泌和葡萄糖利用增强。这些小鼠表现出高胰岛素血症，轻度高血糖症，葡萄糖和胰岛素耐量试验改变，当喂食高脂肪饮食时，约30%的这些动物发展为明显的糖尿病。此外，从与C57 KsJ小鼠的N1回交获得的转基因小鼠显示出高胰岛增生和胰岛素抵抗，但它们也发生脂肪肝和肥胖。这些结果表明，胰岛素样生长因子-II在胰岛中的局部过度表达可能导致2型糖尿病，胰岛增生和胰岛素分泌过多可能发生在这种疾病的发病机制的早期。
During embryonic development, insulin-like growth factor-II (IGF-II) participates in the regulation of islet growth and differentiation. We generated transgenic mice (C57BL6/SJL) expressing IGF-II in beta cells under control of the rat Insulin I promoter in order to study the role of islet hyperplasia and hyperinsulinemia in the development of type 2 diabetes. In contrast to islets from control mice, islets from transgenic mice displayed high levels of IGF-II mRNA and protein. Pancreases from transgenic mice showed an increase in beta-cell mass (about 3-fold) and in insulin mRNA levels. However, the organization of cells within transgenic islets was disrupted, with glucagon-producing cells randomly distributed throughout the core. We also observed enhanced glucose-stimulated insulin secretion and glucose utilization in islets from transgenic mice. These mice displayed hyperinsulinemia, mild hyperglycemia, and altered glucose and insulin tolerance tests, and about 30% of these animals developed overt diabetes when fed a high-fat diet. Furthermore, transgenic mice obtained from the N1 backcross to C57KsJ mice showed high islet hyperplasia and insulin resistance, but they also developed fatty liver and obesity. These results indicate that local overexpression of IGF-II in islets might lead to type 2 diabetes and that islet hyperplasia and hypersecretion of insulin might occur early in the pathogenesis of this disease.