Defective IGF2 and IGF1R protein production in embryonic pancreas precedes beta cell mass anomaly in the Goto-Kakizaki rat model of type 2 diabetes
Defective IGF2 and IGF1R protein production in embryonic pancreas precedes beta cell mass anomaly in the Goto-Kakizaki rat model of type 2 diabetes
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DOI：
10.1007/s00125-007-0676-2
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发表时间：
2007-07-01
期刊：
影响因子：
8.2
通讯作者：
Serradas, P.
中科院分区：
文献类型：
--
作者：
Calderari, S.;Gangnerau, M.-N.;Serradas, P.
目的/假设Goto-Kakizaki（GK）大鼠是2型糖尿病的自发模型。在胎儿年龄晚期可检测到缺陷性β细胞群，这是高脂血症发作的先兆。我们的假设是，胚胎IGF生产缺陷可能参与糖尿病GK大鼠的β细胞质量异常。为了验证这一点，我们评估了在胰腺器官发生过程中：（1）GK大鼠胚胎（E）13.5和E18.5的β细胞发育，（2）E13.5和E18.5的IGF 2和IGF 1受体（IGF 1 R）胰腺蛋白的产生，（3）E13.5的GK胰腺原基体的体外发育，（4）E13.5的GK胰腺原基体的体外发育，（5）E13.5的GK胰腺原基体的体外发育，（6）E13.5的GK胰腺原基体的体外发育。（4）IGF 2对β细胞数量的影响。材料与方法采用免疫组织化学和形态计量学方法对β细胞进行定量分析。使用蛋白质印迹分析评价IGF 2和IGF 1 R胰腺蛋白的产生。E13.5时，取胰腺背侧雏形，分离胰腺组织，培养7 d，加入或不加入重组IGF 2。结果E18.5时，胰岛β细胞数量已减少，但第一批胰岛β细胞分化正常。此外，缺陷的IGF 2和IGF 1 R蛋白生产检测GK胰腺的雏形早在E13.5。在体外维持的分离的GK胰腺原基模拟在体内观察到的GK β细胞缺乏。这最后一种方法使我们能够表明，GK β细胞是完全响应IGF 2至于他们的净增长concerned.Conclusions/解释在糖尿病GK大鼠，有缺陷的IGF 2和IGF 1 R蛋白生产在胚胎胰腺β细胞质量异常。IGF 2补充剂扩大了β细胞库。
Aims/hypothesis The Goto-Kakizaki (GK) rat is a spontaneous model of type 2 diabetes. Defective beta cell mass detectable in late fetal age precedes the onset of hyperglycaemia. Our hypothesis was that an embryonic IGF production deficiency might be involved in beta cell mass anomaly in the diabetic GK rat. To test this, we evaluated during pancreatic organogenesis: (1) the beta cell development in GK rats on embryonic day (E) 13.5 and E18.5; (2) IGF2 and IGF1 receptor (IGF1R) pancreatic protein production on E13.5 and E18.5; (3) the in vitro development of GK pancreatic rudiment on E13.5; and (4) the in vitro effect of IGF2 addition on beta cell mass.Materials and methods Beta cell quantitative analyses were determined by immunohistochemistry and morphometry. IGF2 and IGF1R pancreatic protein production was evaluated using western blot analyses. Dorsal pancreatic rudiments were dissected on E13.5, separated from surrounding mesenchyme and cultured for 7 days without or with recombinant IGF2.Results While beta cell mass was already decreased on E18.5, the differentiation of the first beta cells was in fact normal in E13.5 GK pancreas. Moreover, defective IGF2 and IGF1R protein production was detected in GK pancreatic rudiment as early as E13.5. The isolated GK pancreatic rudiment as maintained in vitro mimics the GK beta cell deficiency observed in vivo. This last approach enabled us to show that GK beta cells were fully responsive to IGF2 as far as their net growth is concerned.Conclusions/interpretation In diabetic GK rat, defective IGF2 and IGF1R protein production in embryonic pancreas precedes beta cell mass anomaly. IGF2 supplementation expands the pool of beta cells.