Amelioration of insulin resistance in streptozotocin diabetic mice by transgenic overexpression of GLUT4 driven by an adipose-specific promoters
Amelioration of insulin resistance in streptozotocin diabetic mice by transgenic overexpression of GLUT4 driven by an adipose-specific promoters
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DOI：
10.1210/en.138.4.1604
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发表时间：
1997-04-01
期刊：
影响因子：
4.8
通讯作者：
Kahn, BB
中科院分区：
文献类型：
--
作者：
Tozzo, E;Gnudi, L;Kahn, BB
在糖尿病啮齿类动物和人类中，脂肪细胞中葡萄糖转运蛋白4（GLUT 4）的表达受到抑制，与胰岛素抵抗相关。在脂肪中选择性过表达GLUT4的转基因小鼠增强了体内葡萄糖的处理，并大量增加了脂肪细胞中的葡萄糖转运。为了确定过表达是否可以在糖尿病中维持以及是否可以预防胰岛素抵抗，我们用链脲佐菌素使野生型和转基因小鼠患糖尿病。12 - 14天后，在进食状态下，两个糖尿病组的血糖均高于21.4 mM，血浆胰岛素为1.06 ng/ml或更低。非转基因和转基因糖尿病小鼠的体重减少，性腺脂肪垫重量和脂肪细胞大小减少52 - 75%。与非糖尿病患者相比。非转基因小鼠和转基因小鼠脂肪细胞的基础和最大刺激脂解速率相似，但异丙肾上腺素非转基因糖尿病小鼠的艾德（50）、GLUT 4蛋白Nas降低34%，胰岛素刺激葡萄糖转运降低46%。相比之下，在转基因糖尿病小鼠的脂肪细胞中，GLUT 4保持21倍过表达，导致基础增加1倍，胰岛素刺激的葡萄糖转运增加10倍。注射胰岛素（0.7 mU/g BW）可使转基因糖尿病小鼠的血糖降低35%（P <0.05），而对非转基因糖尿病小鼠无影响。因此，由脂肪特异性启动子驱动的GLUT4的高水平过表达可以在胰岛素缺乏性糖尿病中维持，即使脂肪细胞代谢显著改变。脂肪细胞中GLUT4的过表达在细胞水平阻止胰岛素抵抗葡萄糖转运，并改善体内胰岛素作用，即使是明显的糖尿病。
In diabetic rodents and humans, glucose transporter 4 (GLUT4) expression is suppressed in adipocytes in association with insulin resistance. Transgenic mice overexpressing GLUT4 selectively in fat have enhanced glucose disposal in vivo and massively increased glucose transport in adipocytes. To determine whether overexpression can be maintained in diabetes and whether it can prevent insulin resistance, we rendered wild-type and transgenic mice diabetic with streptozotocin. After 12-14 days, blood glucose was more than 21.4 mM and plasma insulin was 1.06 ng/ml or less in both diabetic groups in the fed state. Body weight was reduced and gonadal fat pad weight and adipocyte size were 52-75% smaller in both nontransgenic and transgenic diabetic mice? compared with nondiabetic. Basal and maximally-stimulated rates of lipolysis were similar in adipocytes from nontransgenic and transgenic mice, but the ED(50) for isoproterenol nontransgenic diabetic mice, GLUT4 protein Nas reduced 34%, with a 46% reduction in insulin stimulated glucose transport. In contrast, in adipocytes of transgenic diabetic mice, GLUT4 remained 21-fold overexpressed, resulting in al-fold increased basal and 10-fold increased insulin stimulated glucose transport. Injection of insulin (0.7 mU/g BW) resulted in a 35% decrease in blood glucose in transgenic diabetic mice (P < 0.05), with no effect in nontransgenic diabetic mice. Thus, high-level overexpression of GLUT4 driven by a fat specific promoter can be maintained with insulinopenic diabetes, even when fat cell metabolism is markedly altered. Overexpression of GLUT4 in adipocytes prevents insulin resistant glucose transport at the cellular level and improves insulin action in vivo, even with overt diabetes.