Glucocorticoids impair fetal β-cell development in rats

Abstract

In rats, poor fetal growth due to maternal food restriction during pregnancy is associated with decreased beta-cell mass at birth and glucose intolerance in adulthood. Overexposure to glucocorticoids in utero can induce intrauterine growth retardation in humans and animals and subsequent glucose intolerance in rodents. The aims of this study were to investigate whether glucocorticoid overexposure mediates the effect of undernutrition on beta-cell mass and to study their potential role in normally nourished rats. Undernutrition significantly increased maternal and fetal corticosterone levels. Twenty-one-day-old fetuses with undernutrition showed growth retardation and decreased pancreatic insulin content; adrenalectomy and subcutaneous corticosterone implants in their dams prevented the maternal corticosterone increase and restored fetal beta-cell mass. In fetuses with normal nutrition, fetal corticosterone levels were negatively correlated to fetal weight and insulin content; fetal beta-cell mass increased from 355 +/- 48 microg in sham to 516 +/- 160 microg after maternal adrenalectomy; inhibition of steroid production by metyrapone induced a further increase to 757 +/- 125 microg. Our data support the new concept of a negative role of glucocorticoids in fetal beta-cell development.

Glucocorticoid signalling affects pancreatic development through both direct and indirect effects

“…Several studies have suggested that fetal overexposure to glucocorticoids can alter pancreatic development and thereby programme consequences for glucose homeostasis in the adult [28,29,34]. From our previous work investigating the direct effects of glucocorticoids on pancreatic development, by inactivating the GR either in all pancreatic progenitors (GR Pdx-Cre mice) or specifically in insulin-producing cells (GR RIP-Cre mice), we concluded that the GR is not necessary for beta cell development but rather prevents it through a direct effect on pancreatic progenitors [29].…”

“…We have previously shown that undernutrition during the last week of gestation in the rat increases both maternal and fetal glucocorticoid levels, which further causes decreased fetal pancreatic beta cell mass [26,27]. In addition, in normally nourished rat fetuses increased beta cell mass was associated with low corticosterone levels, while decreased beta cell mass was observed under conditions of fetal overexposure to these hormones [28]. Beta cell development is thus sensitive to glucocorticoids.…”

Fetal programming of glucose–insulin metabolism

“…Maternal calorie restriction in the rat to 50% ad libitum during pregnancy leads to low birth weight, beta cell dysfunction and to an age dependent loss of glucose tolerance (32). Severe calorie restriction in the pregnant rat to 30% ad libitum has been shown to lead to severe growth retardation of the fetus, along with Excessive dexamethasone exposure in rodents in utero also leads to low birth weight and permanent hypertension and hyperglycaemia in adult offspring (reviewed by Nyirenda and Seckl) (54), as well as having a negative effect on fetal beta cell development (55). Low birth weight is not seen in the offspring of dams fed a high fat diet, which is another example of where low birth weight can be a somewhat crude method of measuring fetal nutritional status.…”

Combined xenotransplantation as a method of prolonging the viability and function of the graft in the treatment of various forms of hypocorticism

“…×åðåç 13-15 òèaeí³â ï³ñëÿ êîìá³íîâàíî¿ òðàíñïëàíòàö³¿ âè-ÿâëåíî ³íòàêòí³ ôîë³êóëè, â³äçíà÷åíî çðîñòàííÿ ê³ëüêîñò³ ôîë³êóë³â ³ çá³ëüøåííÿ âì³ñòó êîëî¿äó [100]. Âîäíî÷àñ òðàíñïëàíòàö³ÿ ñ³ì'ÿíèê³â ³ç ã³-ïîô³çîì íå ñïðàâëÿëà âèðàaeåíîãî âïëèâó íà ñïåðìàòîãåíåç [101].…”