Reduced PDX-1 expression impairs islet response to insulin resistance and worsens glucose homeostasis
Reduced PDX-1 expression impairs islet response to insulin resistance and worsens glucose homeostasis
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DOI：
10.1152/ajpendo.00252.2004
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发表时间：
2005-04-01
影响因子：
5.1
通讯作者：
Powers, AC
中科院分区：
文献类型：
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作者：
Brissova, M;Blaha, M;Powers, AC
在2型糖尿病中，胰岛素抵抗和胰岛β细胞对胰岛素抵抗需求的反应不足会导致胰岛素分泌受损和高血糖。胰腺十二指肠同源结构域-1(PDX1)是正常胰腺发育所必需的转录因子，在胰岛正常分泌胰岛素方面也起着关键作用。为了研究PDX-1在胰岛素抵抗的胰岛补偿中的作用，我们检测了四种不同基因类型的小鼠的葡萄糖处置、胰岛素分泌和胰岛细胞质量：野生型小鼠，一个PDX-1等位基因失活的小鼠(PDX-1(+/-)，导致胰岛素分泌受损)，一个GLUT4等位基因失活的小鼠(GLUT4(+/-)，导致胰岛素抵抗)，以及PDX-1和GLUT4杂合子的小鼠(GLUT4(+/-)；PDX-1(+/-))。PDX-1和GLUT4杂合子的结合显著延长了葡萄糖清除。GLUT4(+/-)；PDX-1(+/-)小鼠出现了β细胞增生，但未能增加其β细胞胰岛素含量。这些结果表明，PDX-1杂合性(类似于正常蛋白质水平的60%)取消了β细胞对胰岛素抵抗的代偿反应，损害了葡萄糖稳态，并可能参与了2型糖尿病的发病。
In type 2 diabetes mellitus, insulin resistance and an inadequate pancreatic beta-cell response to the demands of insulin resistance lead to impaired insulin secretion and hyperglycemia. Pancreatic duodenal homeodomain-1 (PDX1), a transcription factor required for normal pancreatic development, also plays a key role in normal insulin secretion by islets. To investigate the role of PDX-1 in islet compensation for insulin resistance, we examined glucose disposal, insulin secretion, and islet cell mass in mice of four different genotypes: wild-type mice, mice with one PDX-1 allele inactivated (PDX-1(+/-), resulting in impaired insulin secretion), mice with one GLUT4 allele inactivated (GLUT4(+/-), resulting in insulin resistance), and mice heterozygous for both PDX-1 and GLUT4 (GLUT4(+/-); PDX-1(+/-)). The combination of PDX-1 and GLUT4 heterozygosity markedly prolonged glucose clearance. GLUT4(+/-); PDX-1(+/-) mice developed beta-cell hyperplasia but failed to increase their beta-cell insulin content. These results indicate that PDX-1 heterozygosity (similar to 60% of normal protein levels) abrogates the beta-cell's compensatory response to insulin resistance, impairs glucose homeostasis, and may contribute to the pathogenesis of type 2 diabetes.