Pdx1 restores β cell function in Irs2 knockout mice
Pdx1 restores β cell function in Irs2 knockout mice
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DOI：
10.1172/jci200214439
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发表时间：
2002-05-01
影响因子：
15.9
通讯作者：
White, MF
中科院分区：
文献类型：
--
作者：
Kushner, JA;Ye, J;White, MF
同源域转录因子Pdx 1是胰腺发育所必需的，包括β细胞的分化和功能。Pdx 1或上游肝细胞核因子的突变可导致常染色体形式的早发性糖尿病（年轻人成熟型糖尿病[MODY]）。在小鼠中，胰岛素/Igf信号系统的Irs 2分支介导外周胰岛素作用和胰腺细胞生长和功能。为了研究Irs 2（-/-）小鼠的β细胞衰竭是否与MODY相关转录因子的功能障碍有关，我们测量了年轻Irs 2（-/-）小鼠胰岛中Pdx 1的表达。在糖尿病发作之前，Irs 2（-/-）小鼠的胰岛中Pdx 1减少，而野生型或Irs 1（-/-）小鼠的胰岛中Pdx 1正常表达，这些小鼠不会患糖尿病。而雄性Irs 2（-/-）Pdx 1（+/+）小鼠在8至10周龄之间发生糖尿病，Pdx 1单倍不足导致新生Irs 2（-/-）小鼠发生糖尿病。相比之下，Pdx 1的转基因表达恢复了Irs 2（-/-）小鼠的β细胞质量和功能，并促进了终生的葡萄糖耐量，因为这些小鼠在没有糖尿病的情况下存活了至少20个月。我们的研究结果表明，Pdx 1的失调可能是普通2型糖尿病和MODY之间的共同联系。
The homeodomain transcription factor Pdx1 is required for pancreas development, including the differentiation and function of beta cells. Mutations in Pdx1 or upstream hepatocyte nuclear factors cause autosomal forms of early-onset diabetes (maturity-onset diabetes of the young [MODY]). In mice, the Irs2 branch of the insulin/Igf signaling system mediates peripheral insulin action and pancreatic cell growth and function. To investigate whether beta cell failure in Irs2(-/-) mice might be related to dysfunction of MODY-related transcription factors, we measured the expression of Pdx1 in islets from young Irs2(-/-) mice. Before the onset of diabetes, Pdx1 was reduced in islets from Irs2(-/-) mice, whereas it was expressed normally in islets from wild-type or Irs1(-/-) mice, which do not develop diabetes. Whereas male Irs2(-/-) Pdx1(+/+) mice developed diabetes between 8 and 10 weeks of age, haploinsufficiency for Pdx1 caused diabetes in newborn Irs2(-/-) mice. By contrast, transgenic expression of Pdx1 restored beta cell mass and function in Irs2(-/-) mice and promoted glucose tolerance throughout life, as these mice survived for at least 20 months without diabetes. Our results suggest that dysregulation of Pdx1 might represent a common link between ordinary type 2 diabetes and MODY.