Nutrition, Glucocorticoids and Pancreas Development

Abstract

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.