Bréant B, Gesina E, Blondeau B
INSERM Unit 690, Robert Debré Hospital, Paris, France.
Horm Res. 2006;65 Suppl 3:98-104. doi: 10.1159/000091513. Epub 2006 Apr 10.
Low birth weight is strongly predictive of hypertension, cardiovascular diseases, obesity, insulin resistance and diabetes. The mechanisms by which fetal undernutrition and, hence, low birth weight increase the risk of developing these diseases are unclear. To investigate the hypothesis of a primary defect in beta-cell development, we designed a rat model of undernutrition, involving an overall reduction in maternal food intake. In this model, fetuses with intrauterine growth retardation have a decreased beta-cell mass, which persists into adulthood and ultimately causes glucose intolerance, thereby mimicking features of the metabolic syndrome. Maternal undernutrition causes elevations in glucocorticoid concentrations, which, in turn, cause a reduction in beta-cell mass in the fetus. Our data also suggest a key role of glucocorticoids when nutrient supply is normal. By combining in-vitro studies with in-vivo investigations in mice lacking the glucocorticoid receptor in the whole organism or in specific pancreatic cell populations, we have shown that the glucocorticoid receptor is critical for ensuring pancreatic architecture and survival, as well as for beta-cell mass expansion during a critical developmental window. Glucocorticoids act on precursor cells before the onset of hormone gene expression and are likely to programme beta-cell differentiation by modifying the balance of specific transcription factors, mostly Pdx-1. Glucocorticoids should therefore be considered as important hormones in pancreatic development, in situations of both normal nutrition and undernutrition. To investigate whether this is also the case in human pancreatic development, we studied the expression of the glucocorticoid receptor and that of the transcription factor Pdx-1 on pancreatic specimens from very early to late stages of development of the human embryo. In terms of beta-cell ontogeny, expression of the glucocorticoid receptor in the pancreas coincides with that of the transcription factor Pdx-1 in beta cells. These results are consistent with a possible role for glucocorticoids during human pancreatic development.
低出生体重强烈预示着高血压、心血管疾病、肥胖症、胰岛素抵抗和糖尿病。胎儿营养不足进而导致低出生体重增加患这些疾病风险的机制尚不清楚。为了研究β细胞发育存在原发性缺陷这一假说，我们设计了一种营养不足的大鼠模型，即母体食物摄入量全面减少。在这个模型中，患有子宫内生长迟缓的胎儿β细胞数量减少，这种情况会持续到成年并最终导致葡萄糖不耐受，从而模拟代谢综合征的特征。母体营养不足会导致糖皮质激素浓度升高，进而导致胎儿β细胞数量减少。我们的数据还表明，在营养供应正常时糖皮质激素也起着关键作用。通过将体外研究与对全身或特定胰腺细胞群缺乏糖皮质激素受体的小鼠进行体内研究相结合，我们发现糖皮质激素受体对于确保胰腺结构和存活以及在关键发育窗口期β细胞数量的增加至关重要。糖皮质激素在激素基因表达开始之前作用于前体细胞，并可能通过改变特定转录因子（主要是Pdx-1）的平衡来调控β细胞分化。因此，无论是在正常营养还是营养不足的情况下，糖皮质激素都应被视为胰腺发育中的重要激素。为了研究人类胰腺发育中是否也是这种情况，我们研究了人类胚胎从发育早期到晚期胰腺标本中糖皮质激素受体和转录因子Pdx-1的表达。就β细胞个体发生而言，胰腺中糖皮质激素受体的表达与β细胞中转录因子Pdx-1的表达一致。这些结果与糖皮质激素在人类胰腺发育中可能发挥的作用相符。
