Impairment of rat fetal beta-cell development by maternal exposure to dexamethasone during different time-windows.
ABSTRACT Glucocorticoids (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.
Pregnant 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.
Dexamethasone 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.
GCs 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.
Full-textDOI: · Available from: Olivier Dumortier, May 20, 2015
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ABSTRACT: Peroxisome proliferator-activated receptor gamma-coactivator-1α (PGC-1α) has recently been implicated as a crucial factor in the glucocorticoid-suppressed expansion and transdifferentiation of porcine neonatal pancreatic cell clusters (NPCCs). However, the molecular mechanism has not been clarified. We investigated whether the suppression of PGC-1α expression protects against β-cell dysfunction induced by dexamethasone (Dx) treatment in vitro and in vivo and determined the mechanism of action of PGC-1α in porcine NPCCs. The reduction in Pdx-1 gene expression caused by either Dx treatment or PGC-1α overexpression was normalized by siPGC-1α. Nuclear FOXO1 and cytoplasmic Pdx-1 were detected after Dx treatment. However, FOXO1 was observed in the cytoplasm, and Pdx-1 was observed in the nucleus after siPGC-1α. Suppression of PGC-1α by siPGC-1α improved the Dx-induced repression of insulin secretion and insulin content. In vivo studies showed that the glucose level in the Ad-siPGC-1α-infected group was significantly lower than that in the Dx-treated group. Insulin expression in the graft tissue disappeared in the Dx-injected group. However, the siPGC-1α- and Dx-treated group showed increased insulin expression and an increase in graft mass, β-cell mass, and β-cell % in the graft. Conversely, the Dx-induced ductal cystic area was markedly reduced in the siPGC-1α- and Dx-treated group. Our results suggest that the transdifferentiation of porcine NPCCs into β cells is influenced by the duration of the Dx treatment, which might result from the suppression of key pancreatic transcription factors. PGC-1α is an attractive target for modulating the deleterious effects of glucocorticoids on pancreatic stem cells.Transplantation 01/2014; 97(3). DOI:10.1097/01.TP.0000438627.68225.25 · 3.78 Impact Factor
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ABSTRACT: Context: Low birth weight is associated with adverse metabolic outcome in adulthood. Exposure to glucocorticoid excess in utero is associated with decreased birth weight, but the prospective longitudinal relationship between glucocorticoid (GC) metabolism and growth has not been examined. Objective: We have hypothesised that changes in glucocorticoid metabolism leading to increased availability may impair growth. Design: A prospective, longitudinal study with clinical measurements and 24h urinary steroid metabolite analysis at 1, 4, 12, 26 and 52 weeks post delivery in mothers and their babies. Setting: Observations and samples collected in the volunteers' own home. Participants: Healthy mothers and newborn babies / infants Interventions: None Main outcome measures: Urinary steroid metabolite excretion quantified by gas chromatography / mass spectroscopy across the first year of life in relation to change in weight. Results: Total production of the glucocorticoid metabolites quantified increased across the first year of life. Markers of 11β-HSD1 activity increased from the age of 3 months as did those of 5α-reductase activity. After correcting for confounding variables, low markers of 11β-HSD2 activity was associated with reduced absolute weight and decreased weight gain over the first year of life. In the mothers, 5α-reductase activity was low at birth and progressively increased to normal over the the first 6 months post partum. Conclusions: Increased GC exposure as a consequence of reduced 11β-HSD2 activity is likely to be a critical determinant of growth in early life. This not only highlights the central role of GCs and their metabolism, but also emphasises the need for detailed longitudinal analyses.The Journal of Clinical Endocrinology and Metabolism 02/2014; 99(5):jc20133254. DOI:10.1210/jc.2013-3254 · 6.31 Impact Factor
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ABSTRACT: The intrauterine environment of the fetus is a preeminent actor in long-term health. Indeed, mounting evidence shows that maternal malnutrition increases the risk of type 2 diabetes (T2D) in progeny. Although the consequences of disturbed prenatal environment on pancreas development are known, the underlying mechanisms are poorly defined. In rats, gestational protein restriction alters the endocrine pancreas development and favors T2D appearance later in life. Here we evaluate the potential role of perturbed microRNA (miRNA) expression in the decreased β-cell mass and insulin secretion characterizing progeny of pregnant dams fed a low protein (LP) diet. miRNA profiling shows increased expression of several miRNAs in pancreas of LP fetuses including miR-375. Its expression remains augmented in neoformed islets derived from LP fetuses and in islets from adult 3 month-old LP progeny. miR-375 regulates the proliferation and insulin secretion of dissociated islet cells, contributing to the reduced β-cell mass and function of LP progeny. Remarkably, miR-375 normalization in LP derived islet cells restores β-cell proliferation and insulin secretion. Our findings suggest the existence of a developmental memory in islets that registers intrauterine protein restriction. Hence, pancreatic failure after in utero malnutrition could result from transgenerational transmission of microRNA misexpression in β-cells.Diabetes 05/2014; 63(10). DOI:10.2337/db13-1431 · 8.47 Impact Factor