Increased islet apoptosis in Pdx1+/- mice
Increased islet apoptosis in Pdx1+/- mice
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DOI：
10.1172/jci200316537
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发表时间：
2003-04-01
影响因子：
15.9
通讯作者：
Polonsky, KS
中科院分区：
文献类型：
--
作者：
Johnson, JD;Ahmed, NT;Polonsky, KS
50%Pdx 1（一种对胰腺发育至关重要的同源异型盒基因）的小鼠，随着年龄的增长，葡萄糖耐量恶化，胰岛素释放减少，对灌注胰腺中的葡萄糖、KCl和精氨酸的反应。令人惊讶的是，在灌流或静态孵育实验中响应于葡萄糖和其他促分泌素的胰岛素分泌在分离自Pdx 1（+/-）小鼠的胰岛中与Pdx 1（+/+）同窝对照相比是相似的。葡萄糖敏感和胰岛Ca 2+反应也正常。去极化诱发的胞吐和Ca 2+电流在单个Pdx 1（+/-）细胞与对照组没有差异，反对普遍存在的β细胞刺激分泌偶联缺陷。然而，在基础葡萄糖浓度下，分离的Pdx 1（+/-）胰岛和分散的β细胞比Pdx 1（+/+）胰岛明显更容易发生细胞凋亡。Pdx 1（+/-）胰岛Bcl（XL）和Bcl-2表达减少。在体内，细胞凋亡增加与胰岛结构异常、TUNEL阳性、活性caspase-3和淋巴细胞浸润相关。虽然在年轻小鼠中相似，但β细胞质量和胰岛数量均未随年龄增加，并且在一年内比对照组少约50%。这些结果表明，细胞凋亡的增加，胰岛数量和β细胞质量的异常调节，是部分PDX 1缺乏导致胰岛素分泌和糖尿病器官水平缺陷的关键机制。
Mice with 50% Pdx1, a homeobox gene critical for pancreatic development, had worsening glucose tolerance with age and reduced insulin release in response to glucose, KCl, and arginine from the perfused pancreas. Surprisingly, insulin secretion in perifusion or static incubation experiments in response to glucose and other secretagogues was similar in islets isolated from Pdx1(+/-) mice compared with Pdx1(+/+) littermate controls. Glucose sensing and islet Ca2+ responses were also normal. Depolarization-evoked exocytosis and Ca2+ currents in single Pdx1(+/-) cells were not different from controls, arguing against a ubiquitous beta cell stimulus-secretion coupling defect. However, isolated Pdx1(+/-) islets and dispersed beta cells were significantly more susceptible to apoptosis at basal glucose concentrations than Pdx1(+/+) islets. Bcl(XL) and Bcl-2 expression were reduced in Pdx1(+/-) islets. In vivo, increased apoptosis was associated with abnormal islet architecture, positive TUNEL, active caspase-3, and lymphocyte infiltration. Although similar in young mice, both beta cell mass and islet number failed to increase with age and were approximately 50% less than controls by one year. These results suggest that an increase in apoptosis, with abnormal regulation of islet number and beta cell mass, represents a key mechanism whereby partial PDX1 deficiency leads to an organ-level defect in insulin secretion and diabetes.