母鼠甲减对子代胰岛β细胞甲状腺激素受体和胰岛素分泌功能的影响及机制

The recent researches found that maternal hypothyroidism led to glucose intolerance and reduced insulin secretion capacity in rat. The adaptive expression changes in gene of thyroid hormone receptor (THR) of fetal islets caused by maternal hypothyroidism were suggested to be the underling mechanism. As to the key role of THR in regulating proliferation and secretion of islets, we speculate that the expression change of THR in fetal islets caused by maternal hypothyroidism is an important factor of increased risk of adult type 2 diabetes (T2DM). We, therefore, plan to establish the female model in different hypothyroid levels with the TSH gene knockout mice, develop the matched group of normal phenotype fetuses by hypothyroid dams according to the Mendelian genetic law, and detect the trace expression of TRbeta in islets of different phases with flow cytometry and immunofluorescence double staining, in order to investigate the effects of maternal hypothyroidism on the THR expression in fetal islets and the influences of abnormal THR expression in fetuses on the function of postnatal islets, and preliminarily clarify the mechanism of increased risk of adult T2DM caused by maternal hypothyroidism.

甲状腺功能减退母亲所育胎儿成年后胰岛细胞功能受损，其机制不明。甲状腺激素受体β（TRβ）在胰岛β细胞核内的表达量对这类细胞的增殖及分泌功能有着重要的调控作用。课题组前期体外实验发现，甲状腺激素水平降低可导致人胚胎（E47天）胰岛细胞株T6PNE核内TRβ表达量下调，但孕期甲减对子代出生前后各阶段胰岛β细胞TRβ表达和胰岛素分泌功能的影响尚不清楚。本项目将采用体外、体内实验相结合，从分子水平、细胞水平和整体三个水平，利用TSH受体基因敲除小鼠先天低甲状腺激素、高TSH的特性，人工培育不同程度的甲减母鼠模型；以孟德尔遗传定律为依据，培养甲减母鼠孕育正常胎鼠的组合模型，研究：⑴ 孕期母体不同甲状腺激素水平对胚胎胰岛β细胞核内TRβ表达的影响；⑵ 胚胎期胰岛β细胞核内不同TRβ表达，对出生前后各生长阶段胰岛β细胞增殖、胰岛素分泌功能的影响。探讨孕期甲减所致胎儿成年后糖尿病风险增加的机制。

甲状腺功能减退母亲所育胎儿成年后胰岛细胞功能受损，其机制不明。甲状腺激素受体β（TRβ）在胰岛β细胞核内的表达量对这类细胞的增殖及分泌功能有着重要的调控作用。课题组前期体外实验发现，甲状腺激素水平降低可导致人胚胎（E47天）胰岛细胞株T6PNE核内TRβ表达量下调，但孕期甲减对子代出生后各阶段胰岛β细胞TRβ表达和胰岛素分泌功能的影响尚不清楚。. 本项目利用丙硫氧嘧啶（PTU）建立母鼠甲减模型，采用体内、体外实验相结合的方式，初步证实了孕期母体低甲状腺激素通过降低仔鼠胰岛β细胞中TRβ的表达，进而抑制仔鼠各生长阶段胰岛β细胞增殖、胰岛素分泌功能，初步探明孕期甲减所致子代糖尿病风险增加的机制。本课题为研究糖尿病的发病机制提供了潜在的新思路。