Impairment of Rat Fetal Beta-Cell Development by Maternal Exposure to Dexamethasone during Different Time-Windows

Flinders University, Australia
PLoS ONE (Impact Factor: 3.23). 10/2011; 6(10):e25576. DOI: 10.1371/journal.pone.0025576
Source: PubMed

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.

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Available from: Olivier Dumortier, Sep 29, 2015
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    • "We have developed an animal model in which an isocaloric lowprotein diet (8 vs. 20% protein) given to dams during gestation led to offspring with lower birth weight and altered endocrine pancreas. In the neonates of lowprotein mothers, the beta-cell mass, pancreatic insulin content, insulin secretion and islet vascularization were reduced (Snoeck et al. 1990, Dahri et al. 1991, Cherif et al. 2001, Boujendar et al. 2002, Dumortier et al. 2011). The beta-cell proliferative capacity was diminished (Snoeck et al. 1990, Petrik et al. 1999), while apoptosis was increased (Petrik et al. 1999). "
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    ABSTRACT: Epidemiological studies related poor maternal nutrition and subsequent growth retardation in the progeny to the development of diabetes later in life. Low protein diet during gestation altered the beta-cell development of the rat progeny, by decreasing beta-cells proliferation, and increasing their sensitivity to nitric oxide and cytokines in the foetus. This disturbed maternal environment had lasting consequences since the higher beta-cell vulnerability was maintained at adulthood. AIM: The aim was to determine whether early malnutrition influences the vulnerability and the regeneration capacity of beta-cells after streptozotocin (STZ) damage at adulthood. METHODS: Gestating rats were fed either a control or a low protein diet until weaning. Adult female offspring received weekly during five weeks, injections of Freund's adjuvant followed 24h later by STZ. Half of the cohort was killed at d34 whereas the other half was maintained until d48 to analyse the regeneration capacity of the beta-cells. RESULTS: Although control and low protein rats had equivalent pancreatic insulin content and beta-cell volume density at d34, hyperglycaemia appeared earlier and was more dramatic in low protein than in control rats. STZ treatment increased beta-cell proliferation similarly in both groups. At d48, apoptotic rate was higher in the low protein group. Regeneration appeared in control but not in the low protein rats, where beta-cell aggregates/surface area and Reg1-positive area were decreased compared to control. CONCLUSION: Maternal malnutrition programs a more vulnerable endocrine pancreas in the progeny which is unable to regenerate after injury therefore predisposing it to develop glucose intolerance and diabetes later in life. This article is protected by copyright. All rights reserved.
    Acta Physiologica 05/2013; 210(1). DOI:10.1111/apha.12121 · 4.38 Impact Factor
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    • "Thus, GR signaling was observed to play a critical role in the programming of beta-cell dysfunction. Other studies have also demonstrated the important role of corticosteroids on beta-cell development and proliferation (Blondeau et al. 2001; Gesina et al. 2004; Dumortier et al. 2011). Evidence has emerged supporting the fact that the effects of GR expression on development are likely to be influenced at least partially by epigenetic modifications (Thomassin et al. 2001; Stevens et al. 2010; Begum et al. 2012). "
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    ABSTRACT: Adverse events in utero can be critical in determining quality of life and overall health. It is estimated that up to 50 % of metabolic syndrome diseases can be linked to an adverse fetal environment. However, the mechanisms linking impaired fetal development to these adult diseases remain elusive. This review uncovers some of the molecular mechanisms underlying how normal physiology may be impaired in fetal and postnatal life due to maternal insults in pregnancy. By understanding the mechanisms, which include epigenetic, transcriptional, endoplasmic reticulum (ER) stress, and reactive oxygen species (ROS), we also highlight how intervention in fetal and neonatal life may be able to prevent these diseases long-term.
    Journal of Cell Communication and Signaling 05/2012; 6(3):139-53. DOI:10.1007/s12079-012-0165-3
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    ABSTRACT: Epidemiological evidence suggests that exposure to an adverse environment in early life is associated with an increased risk of cardio-metabolic and behavioral disorders in adulthood, a phenomenon termed 'early life programming'. One major hypothesis for early life programming is fetal glucocorticoid overexposure. In animal studies, prenatal glucocorticoid excess as a consequence of maternal stress or through exogenous administration to the mother or fetus is associated with programming effects on cardiovascular and metabolic systems and on the brain. These effects can be transmitted to subsequent generations. Studies in humans provide some evidence that prenatal glucocorticoid exposure may exert similar programming effects on glucose/insulin homeostasis, blood pressure and neurodevelopment. The mechanisms by which glucocorticoids mediate these effects are unclear but may include a role for epigenetic modifications. This review discusses the evidence for glucocorticoid programming in animal models and in humans.
    Best Practice & Research: Clinical Endocrinology & Metabolism 10/2012; 26(5):689-700. DOI:10.1016/j.beem.2012.03.007 · 4.60 Impact Factor
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