Abstract
AimGlucocorticoids (GCs) take part in the direct control of cell lineage during the late phase of pancreas development when endocrine and exocrine cell differentiation occurs. However, other tissues such as the vasculature exert a critical role before that phase. This study aims to investigate the consequences of overexposure to exogenous glucocorticoids during different time-windows of gestation for the development of the fetal endocrine pancreas.MethodsPregnant Wistar rats received dexamethasone acetate in their drinking water (1 µg/ml) during the last week or throughout gestation. Fetuses and their pancreases were analyzed at day 15 and 21 of gestation. Morphometrical analysis was performed on pancreatic sections after immunohistochemistry techniques and insulin secretion was evaluated on fetal islets collected in vitro.ResultsDexamethasone given the last week or throughout gestation reduced the beta-cell mass in 21-day-old fetuses by respectively 18% or 62%. This was accompanied by a defect in insulin secretion. The alpha-cell mass was reduced similarly. Neither islet vascularization nor beta-cell proliferation was affected when dexamethasone was administered during the last week, which was however the case when given throughout gestation. When given from the beginning of gestation, dexamethasone reduced the number of cells expressing the early marker of endocrine lineage neurogenin-3 when analyzed at 15 days of fetal age.ConclusionsGCs reduce the beta- and alpha-cell mass by different mechanisms according to the stage of development during which the treatment was applied. In fetuses exposed to glucocorticoids the last week of gestation only, beta-cell mass is reduced due to impairment of beta-cell commitment, whereas in fetuses exposed throughout gestation, islet vascularization and lower beta-cell proliferation are involved as well, amplifying the reduction of the endocrine mass.
Highlights
Epidemiological studies performed in distinct populations throughout the world have clearly reported that individuals who had a low birth weight or were thin at birth feature a higher prevalence of glucose intolerance and type 2 diabetes (T2D) during adult life [1,2,3,4]
In such low birth weight offspring, one may wonder whether the beta cell alteration observed later in life has been already acquired in utero or is a consequence of an adaption to the disturbed insulin sensitivity of target tissues
We demonstrate that in addition to compromising the beta and alpha cell differentiation, glucocorticoids given from the beginning of gestation inhibit the beta-cell proliferation as well as function and reduce the islet vascularization which presumably may contribute to amplify the reduction of the endocrine mass
Summary
Epidemiological studies performed in distinct populations throughout the world have clearly reported that individuals who had a low birth weight or were thin at birth feature a higher prevalence of glucose intolerance and type 2 diabetes (T2D) during adult life [1,2,3,4]. Maternal use of glucocorticoids during pregnancy in human and experimental animal may cause low birth weight and intrauterine growth retardation (IUGR) and later may lead to chronic diseases such as hypertension and type 2 diabetes [8,9,10,11]. In growthretarded animals or humans, functional disruption in multiple tissues including muscle, adipose tissue, liver, and pancreas is observed in adults. In such low birth weight offspring, one may wonder whether the beta cell alteration observed later in life has been already acquired in utero or is a consequence of an adaption to the disturbed insulin sensitivity of target tissues
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