Beta-cell mass and proliferation following late fetal and early postnatal malnutrition in the rat

Garofano, A.; Czernichow, P; Bréant, Bernadette

doi:10.1007/s001250051038

Cited by 201 publications

(142 citation statements)

References 36 publications

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“…Pancreatic tissue area and insulin-positive cell area were determined by computerassisted measurements using a Leica DMRB microscope equipped with a colour video camera coupled to a Q500IW computer (screen magnification ×24), as previously described [27]. Morphometrical analysis was performed on ten transversal and 240-μm-spaced sections from wild-type and GR +/null E18 digestive blocks (n=5).…”

Section: Beta Cell Fraction Measurementsmentioning

confidence: 99%

“…The analysis of mice in which the GR has been genetically modified, GR hypo/hypo (also designated GR −/− [6,23] and GR null/null [6,24,25]), has provided evidence for a role of the GR in the development or function of several tissues, including fetal lung, adrenal and erythroblasts, and this modification is associated with neonatal death. 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].…”

Section: Introductionmentioning

confidence: 98%

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Glucocorticoid signalling affects pancreatic development through both direct and indirect effects

et al. 2006

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Aims/hypothesis Beta cell development is sensitive to glucocorticoid levels. Although direct effects of glucocorticoids on pancreatic precursors have been shown to control beta cell mass expansion, indirect effects of these hormones on pancreatic development remain unexplored. This issue was addressed in mice lacking the glucocorticoid receptor (GR) in the whole organism. Materials and Methods The pancreatic phenotype of GR null/null mice was studied at fetal ages (embryonic day [E]) E15.5 and E18 by immunohistochemistry and beta cell fraction measurements. To distinguish between direct and indirect effects, mutant E15.5 fetal pancreata were grafted under the kidney capsule of immunodeficient mice and analysed after 1 week. Results E18 GR null/null fetuses had smaller digestive tracts and tiny pancreata. Massive pancreatic disorganisation and apoptosis were observed despite the presence of all cell types. E15.5 GR null/null mutants were indistinguishable from wild-type regarding pancreatic size, tissue structure and organisation, beta cell fraction and production of exocrine transcription factor Ptf1a, neurogenin 3 and Pdx-1. Grafting E15.5 GR null/null pancreata into a GR-expressing environment rescued the increased apoptosis and mature islets were observed, suggesting that GR null/null pancreatic cell death can be attributed to indirect effects of glucocorticoids on this tissue. Heterozygous GR +/null mutants with reduced GR numbers showed no apoptosis but increased beta cell fraction at E18 and the adult age, strengthening the importance of an accurate GR dosage on beta cell mass expansion. Conclusions/interpretation Our results provide evidence for GR involvement in pancreatic tissue organisation and survival through indirect effects. GR does not appear necessary for early phases, but its accurate dosage is critical to modulate beta cell mass expansion at later fetal stages, presumably through direct effects.

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Section: Beta Cell Fraction Measurementsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Glucocorticoid signalling affects pancreatic development through both direct and indirect effects

et al. 2006

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“…Human beta cells could be more resistant to the toxic action of streptozotocin and alloxan either because they express the GLUT2 glucose transporter only to a very low extent [7,8] (1-2% of the level expression in rat beta cells), or, alternatively, because streptozotocin and alloxan, in contrast to the rat GLUT2 glucose transporter isoform, are not taken up through the human GLUT2 glucose transporter isoform into the intracellular compartment where the toxins exert their cell-death action.…”

Section: Mechanism Underlying Resistance Of Human Pancreatic Beta Celmentioning

confidence: 99%

“…These observations show that prolonging the lactation period in DP-BB rats influences diabetes development later in life. Malnutrition in the neonatal and prepubertal period of rats can reduce beta-cell function later in life [7,8]. The fact that the rats weaned at 40 days showed a reduction in body weight and growth rate compared to their littermates, weaned at 21 days (Fig.…”

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confidence: 96%

The diabetes prone BB rat model of IDDM shows duration of breastfeeding to influence Type 1 diabetes development later in life

et al. 2003

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Besides genetic background, environmental factors such as food ingredients and viral infections have been indicated as important and possibly decisive elements for the induction of insulin-dependent diabetes mellitus (IDDM). Our data show that diabetes development in diabetes-prone (DP)-BB rats can be delayed and prevented by prolonging the nursing period of these rats. These results provide experimental evidence strengthening human epidemiological data that the duration of exclusive breastfeeding influences diabetes development later in life.Most human epidemiological data suggest that a short, as opposed to a long, duration of exclusive breastfeeding is related with an increased risk for IDDM development [1,2,3,4,5]. The introduction of cow's milk and wheat proteins at a young age has been suggested as potential diabetogenic risk factors for infants at risk of developing diabetes [1,2,3,4,5]. The importance of food ingredients in IDDM is further illustrated by the fact that the development of diabetes is reduced in DP-BB rats receiving a special diet in which hydrolysed casein is the sole source of protein [6]. Since, in epidemiological studies the period of nursing is established using questionnaires, the exact duration of breastfeeding remains unclear and duration of breastfeeding varies considerably between the siblings [1,2,3,4,5]. DP-BB rats normally spontaneously develop diabetes between 60 and 160 days of age and are used as an animal model for the study of Type 1 diabetes. In the DP-BB rat model for the study of diabetes, the period of suckling can be established precisely. To investigate whether a relation exists between the duration of exclusive breastfeeding and the onset of diabetes

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“…A recent review study suggested that inadequate maternal nutrition might disturb the development of the fetus, which must adopt strategies to ensure survival that will programme its future health [3]. In experimental animal models, alteration of the intrauterine environment induced, for example, by gestational diabetes [4], placental insufficiency [5,6] or poor maternal nutrition [7][8][9][10][11] compromise the development of endocrine pancreas in the progeny and impact on its future health even in the subsequent generation [4,6,12]. Reduction of food intake by 50% in rats during gestation reduced the beta cell mass in offspring at birth by 30% [9].…”

Section: Introductionmentioning

confidence: 99%

The intrauterine metabolic environment modulates the gene expression pattern in fetal rat islets: prevention by maternal taurine supplementation

et al. 2008

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Aims/hypothesis Events during fetal life may in critical time windows programme tissue development leading to organ dysfunction with potentially harmful consequences in adulthood such as diabetes. In rats, the beta cell mass of progeny from dams fed with a low-protein (LP) diet during gestation is decreased at birth and metabolic perturbation lasts through adulthood even though a normal diet is given after birth or after weaning. Maternal and fetal plasma taurine levels are suboptimal. Maternal taurine supplementation prevents these induced abnormalities. In this study, we aimed to reveal changes in gene expression in fetal islets affected by the LP diet and how taurine may prevent these changes. Methods Pregnant Wistar rats were fed an LP diet (8% [wt/wt] protein) supplemented or not with taurine in the drinking water or a control diet (20% [wt/wt] protein). At 21.5 days of gestation, fetal pancreases were removed, digested and cultured for 7 days. Neoformed islets were collected and transcriptome analysis was performed. Results Maternal LP diet significantly changed the expression of more than 10% of the genes. Tricarboxylic acid cycle and ATP production were highly targeted, but so too were cell proliferation and defence. Maternal taurine supplementation normalised the expression of all altered genes. Conclusions/interpretation Development of the beta cells and particularly their respiration is modulated by the intrauterine environment, which may epigenetically modify expression of the genome and programme the beta cell towards a pre-diabetic phenotype. This mis-programming by maternal LP diet was prevented by early taurine intervention.Keywords Diabetes . Early programming . Fetal islets . Maternal low-protein diet . Rats . Taurine . Transcriptome Abbreviations EST expressed sequence tag LP low protein LPT low-protein diet supplemented with taurine SAM significance analysis of microarrays TCA tricarboxylic acid Diabetologia (2008) 51:836-845

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Beta-cell mass and proliferation following late fetal and early postnatal malnutrition in the rat

Cited by 201 publications

References 36 publications

Glucocorticoid signalling affects pancreatic development through both direct and indirect effects

Glucocorticoid signalling affects pancreatic development through both direct and indirect effects

The diabetes prone BB rat model of IDDM shows duration of breastfeeding to influence Type 1 diabetes development later in life

The intrauterine metabolic environment modulates the gene expression pattern in fetal rat islets: prevention by maternal taurine supplementation

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