Nutrition, glucocorticoids and pancreas development
Nutrition, glucocorticoids and pancreas development
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DOI：
10.1159/000091513
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发表时间：
2006-01-01
期刊：
影响因子：
--
通讯作者：
Blondeau, B
中科院分区：
文献类型：
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作者：
Bréant, B;Gesina, E;Blondeau, B
低出生体重是高血压、心血管疾病、肥胖、胰岛素抵抗和糖尿病的有力预测因素。胎儿营养不良以及由此导致的低出生体重会增加患这些疾病的风险，其机制尚不清楚。为了研究β细胞发育中的原发性缺陷的假设，我们设计了一种营养不良的大鼠模型，涉及母体食物摄入的总体减少。在该模型中，宫内发育迟缓的胎儿具有减少的β细胞质量，其持续到成年并最终导致葡萄糖耐受不良，从而模仿代谢综合征的特征。母体营养不良导致糖皮质激素浓度升高，进而导致胎儿β细胞质量减少。我们的数据还表明，糖皮质激素的关键作用时，营养供应正常。通过将体外研究与在整个生物体或特定胰腺细胞群中缺乏糖皮质激素受体的小鼠中的体内研究相结合，我们已经表明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间β细胞群扩增至关重要。糖皮质激素在激素基因表达开始之前作用于前体细胞，并且可能通过改变特定转录因子（主要是Pdx-1）的平衡来编程β细胞分化。因此，糖皮质激素应被视为胰腺发育的重要激素，在正常营养和营养不良的情况下。为了研究这是否也是人类胰腺发育的情况下，我们研究了糖皮质激素受体的表达和转录因子Pdx-1的胰腺标本从非常早期到晚期的发展阶段的人胚胎。在β细胞个体发育方面，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胰腺发育过程中可能发挥的作用一致。
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.