INSERM UMR-S 872, Centre de Recherche des Cordeliers, 15 rue de l'Ecole de Médecine, 75006 Paris, France.
Diabetologia. 2011 Feb;54(2):350-9. doi: 10.1007/s00125-010-1898-2. Epub 2010 Sep 21.
AIMS/HYPOTHESIS: Prenatal exposure to excess glucocorticoids associates with low birthweight in rodents, primates and humans and its involvement in programming glucose homeostasis is suspected. Our aim was to further dissect the role of glucocorticoids on beta cell development and function in mice.
Using the model of maternal general food restriction during the last week of pregnancy, we thoroughly studied in the CD1 mouse-mothers and fetal and adult offspring--the pancreatic, metabolic and molecular consequences of maternal undernutrition associated with excess glucocorticoids. The specific involvement of the glucocorticoid receptor (GR) was studied in mutant fetuses lacking GR in pancreatic precursors or mature beta cells.
Maternal general food restriction in the mouse is associated with decreased maternal glucose and increased corticosterone levels. Fetuses from underfed dams had increased corticosterone levels, decreased pancreatic endocrine gene expression but increased exocrine gene expression and a lower beta cell mass. The offspring of these dams had a low birthweight, permanent postnatal growth retardation and, as adults, impaired glucose tolerance, decreased beta cell mass (-50%) and massively reduced islet expression (-80%) of most of the genes involved in beta cell function (e.g. Pdx1, Sur1 [also known as Abcc8], insulin). Moreover, using mutant fetuses lacking GR in pancreatic precursors or beta cells we show that the deleterious effect of undernutrition on fetal beta cell development requires the presence of the GR in pancreatic precursor cells.
CONCLUSIONS/INTERPRETATION: These results demonstrate the crucial role of excess fetal glucocorticoids and the importance of GR signalling in progenitor cells to programme beta cell mass and dysfunction.
目的/假设：在啮齿动物、灵长类动物和人类中，产前暴露于过量糖皮质激素与低出生体重有关，其参与葡萄糖稳态的编程作用也受到怀疑。我们的目的是进一步剖析糖皮质激素对小鼠β细胞发育和功能的作用。
利用妊娠最后一周母体一般性食物限制的模型，我们在 CD1 小鼠-母亲及其胎儿和成年后代中深入研究了与糖皮质激素过量相关的母体营养不良对胰腺、代谢和分子的影响。我们还研究了在胰腺前体细胞或成熟β细胞中缺乏 GR 的突变胎儿中，GR 的特定作用。
在小鼠中，母体一般性食物限制与母体葡萄糖降低和皮质酮水平升高有关。来自低营养母体的胎儿皮质酮水平升高，胰腺内分泌基因表达减少，但外分泌基因表达增加，β细胞数量减少。这些母鼠的后代出生体重低，出生后永久性生长迟缓，成年后葡萄糖耐量受损，β细胞数量减少（-50%），胰岛中大多数参与β细胞功能的基因（如 Pdx1、Sur1[也称为 Abcc8]、胰岛素）的表达减少（-80%）。此外，利用在胰腺前体细胞或β细胞中缺乏 GR 的突变胎儿，我们表明，营养不良对胎儿β细胞发育的有害影响需要 GR 在胰腺前体细胞中存在。
结论/解释：这些结果表明，胎儿糖皮质激素过多和 GR 信号在祖细胞中对β细胞数量和功能障碍编程的关键作用。
