Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1

Park, Jun H.; Stoffers, Doris A.; Nicholls, Robert D.; Simmons, Rebecca A.

doi:10.1172/jci33655

Cited by 408 publications

(534 citation statements)

References 56 publications

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“…The pancreas is a plastic organ, and early life events may play a role in determining the capacity for adult pancreatic plasticity. Several animal models have demonstrated altered pancreatic development following in utero deprivation [67][68][69][70]. A group of imprinted genes including Igf2, Rasgrf, Grb10, Neuronatin and Zac1 play key roles in pancreatic development and maturation and may be involved in the pathogenesis of these defects, although direct evidence of this remains scanty.…”

Section: Imprinted Genes and The Pancreatic Consequences Of In Uteromentioning

confidence: 99%

“…However, interpretation of these data in the context of the whole pancreatic transcriptome is required to determine whether imprinted genes as a group are uniquely susceptible in the pancreas to environmental perturbation. Convincing evidence for the role of progressive reductions in pancreatic expression of the key transcription factors Hnf4a and Pdx1 following compromised early life conditions suggest that this may be unlikely [69,70].…”

Section: Imprinted Genes and The Pancreatic Consequences Of In Uteromentioning

confidence: 99%

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Genomic imprinting as an adaptative model of developmental plasticity

2011

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Developmental plasticity can be defined as the ability of one genotype to produce a range of phenotypes in response to environmental conditions. Such plasticity can be manifest at the level of individual cells, an organ, or a whole organism. Imprinted genes are a group of approximately 100 genes with functionally monoallelic, parental‐origin specific expression. As imprinted genes are critical for prenatal growth and metabolic axis development and function, modulation of imprinted gene dosage has been proposed to play a key role in the plastic development of the unborn foetus in response to environmental conditions. Evidence is accumulating that imprinted dosage may also be involved in controlling the plastic potential of individual cells or stem cell populations. Imprinted gene dosage can be modulated through canonical, transcription factor mediated mechanisms, or through the relaxation of imprinting itself, reactivating the normally silent allele.

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Section: Imprinted Genes and The Pancreatic Consequences Of In Uteromentioning

confidence: 99%

Section: Imprinted Genes and The Pancreatic Consequences Of In Uteromentioning

confidence: 99%

Genomic imprinting as an adaptative model of developmental plasticity

2011

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“…A number of studies suggest that uteroplacental insufficiency, a common cause of IUGR, induces epigenetic modifications in offspring (97)(98)(99)(100) . Epigenetic modifications affecting processes important to glucose regulation and insulin secretion, characteristics essential to the pathophysiology of T2D have been described in the IUGR liver, pancreatic b-cells and muscle (97)(98)(99)(100) .…”

Section: Epigenetic Regulation Of Gene Expression In Fetal Growth Retmentioning

confidence: 99%

“…Epigenetic modifications affecting processes important to glucose regulation and insulin secretion, characteristics essential to the pathophysiology of T2D have been described in the IUGR liver, pancreatic b-cells and muscle (97)(98)(99)(100) .…”

Section: Epigenetic Regulation Of Gene Expression In Fetal Growth Retmentioning

confidence: 99%

Epigenetics and maternal nutrition: nature v. nurture

Simmons

2010

Proc. Nutr. Soc.

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Under- and over-nutrition during pregnancy has been linked to the later development of diseases such as diabetes and obesity. Epigenetic modifications may be one mechanism by which exposure to an altered intrauterine milieu or metabolic perturbation may influence the phenotype of the organism much later in life. Epigenetic modifications of the genome provide a mechanism that allows the stable propagation of gene expression from one generation of cells to the next. This review highlights our current knowledge of epigenetic gene regulation and the evidence that chromatin remodelling and histone modifications play key roles in adipogenesis and the development of obesity. Epigenetic modifications affecting processes important to glucose regulation and insulin secretion have been described in the pancreatic β-cells and muscle of the intrauterine growth-retarded offspring, characteristics essential to the pathophysiology of type-2 diabetes. Epigenetic regulation of gene expression contributes to both adipocyte determination and differentiation in in vitro models. The contributions of histone acetylation, histone methylation and DNA methylation to the process of adipogenesis in vivo remain to be evaluated.

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“…As adults these growth-manipulated offspring exhibit type 2 diabetes that is associated with progressive epigenetic silencing of the homeobox 1 transcription factor Pdx1 (60) , which is critical for pancreatic b-cell function and development (60) . Nevertheless, during the neonatal period the reduction in Pdx1 expression could be reversed in vitro by inhibition of histone deacetylase action.…”

Section: Nutritional Programming and Epigenetic Adaptations: Responsementioning

confidence: 99%

Nutrition and its contribution to obesity and diabetes: a life-course approach to disease prevention?

Symonds

2008

Proc. Nutr. Soc.

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Whilst previously type 2 diabetes occurred in older adults, its incidence, together with obesity, has increased rapidly in children. An improved understanding of this disease pathway from a developmental view point is critical. It is likely that subtle changes in dietary patterns over an extended period of time contribute to diabetes, although this type of rationale is largely ignored in animal studies aimed at determining the mechanisms involved. Small-animal studies in which large, and often extreme, changes in the diet are imposed at different stages of the life cycle can have substantial effects on fat mass and/or pancreatic functions. These responses are not representative of the much more gradual changes seen in the human population. An increasing number of studies indicate that it is growth rate per se, rather than the type of dietary intervention that determines pancreatic function during development. Epigenetic mechanisms that regulate insulin secretion by the pancreas can be re-set by more extreme changes in dietary supply in early life. The extent to which these changes may contribute to more subtle modulations in glucose homeostasis that can accompany excess fat growth in childhood remains to be established. For human subjects there is much less information as to whether specific dietary components determine disease onset. Indeed, it is highly likely that genotype has a major influence, although recent data relating early diet to physical activity and the FTO gene indicate the difficulty of establishing the relative contribution of diet and changes in body mass to diabetes. Adipose tissue: Carbohydrates: Epigenetics: GrowthA major and dramatic change in the health of children in the UK and many other developed countries has occurred over the past 10-20 years. As a consequence, primarily because of excess weight gain during early life, type 2 diabetes is now being seen in an alarming number of children (1) . This situation is not only of concern in its own right but will substantially add to the health burden of these individuals as they approach adulthood. As a result of the increased concern relating to early disease in children it has even been proposed that they are routinely placed on, for example, statins (2) . These individuals should then remain on prescription for the majority of their lives in order to ensure they do not have raised cholesterol (3) . This approach has been suggested without knowing the adverse developmental consequences statins could cause on growing children and adolescents. The present review will focus on some of the more recent findings that suggest potential pathways responsible for excess adiposity in early life and how this information may lead ultimately to sustainable strategies aimed at overcoming this health challenge. Adiposity in early lifeThe recent finding that obese individuals possess approximately 30 % more fat cells than lean counterparts indicates that it is not only the accumulation of excess lipid within existing adipocytes that contributes to obesity (...

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Development of type 2 diabetes following intrauterine growth retardation in rats is associated with progressive epigenetic silencing of Pdx1

Cited by 408 publications

References 56 publications

Genomic imprinting as an adaptative model of developmental plasticity

Genomic imprinting as an adaptative model of developmental plasticity

Epigenetics and maternal nutrition: nature v. nurture

Nutrition and its contribution to obesity and diabetes: a life-course approach to disease prevention?

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