Neonatal Exendin-4 Prevents the Development of Diabetes in the Intrauterine Growth Retarded Rat

Stoffers, Doris A.; Desai, Biva M.; León, Diva D. De; Simmons, Rebecca A.

doi:10.2337/diabetes.52.3.734

Cited by 248 publications

(229 citation statements)

References 54 publications

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“…This is not specific to pancreas, since hepatocytes from offspring of LP-fed animals showed a reduced rate of proliferation, a lower expression of IGF-I, and an increased synthesis of IGF-binding proteins (El-Kattabi et al 2003). The relevance of impaired growth factor presence or action to the reduction in islet mass has been demonstrated by its reversal following the administration of the glucagonlike polypeptide-1 analog, exendin 4, to growth retarded, neonatal offspring from mothers subjected to uterine vessel occlusion (Stoffers et al 2003).…”

Section: Discussionmentioning

confidence: 95%

Altered pancreatic morphology in the offspring of pregnant rats given reduced dietary protein is time and gender specific

Chamson-Reig¹,

Thyssen²,

Arany³

et al. 2006

Journal of Endocrinology

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Restriction of dietary protein during gestation and lactation in the rat results in a reduction in b cell mass, insulin content and release in the offspring, and glucose intolerance when the offspring reach adulthood. The present study was designed to identify if a particular developmental window existed during prenatal development when endocrine pancreatic development was most susceptible to nutritional insult. Pregnant rats received a low-protein (8%, LP), but isocalorific diet from conception to parturition, during the first 2 weeks of gestation (LP (1-2)), the second week only (LP (2)), or the third week (LP (3)). At other times, they received a 20% protein (C) diet, while control animals received this diet continuously. When the offspring were examined at 130 days age, animals that had received LP diet had a significantly impaired glucose tolerance compared with control-fed animals. Pancreatic morphology was examined in the offspring on postnatal days 1 and 21. The LP diet resulted in a significant decrease in the numbers of large (more than 10 000 mm 2 ) and medium (between 5000 and 10 000 mm 2 ) sized islets present at postnatal day 1 for all LP treatments. Consequently, mean islet area and the mean number of b cells were reduced. The impact of LP diet was most pronounced in LP (2) for females and in LP (3) for males, and this was greater than for continuous LP exposure. Insulin and Glut-2 mRNA expression were impacted negatively by LP in early and late gestation, but increased following administration in midgestation. Total pancreatic insulin content was not altered by LP treatment. Pdx-1, a transcription factor associated with both b cell development and insulin gene transcription, was decreased in female offspring following LP (1-2) and LP (3), but not in males. Pancreatic expression of nestin mRNA, and the abundance of nestin-immunoreactive cells within islets, was decreased by all LP treatments. By postnatal day 21, the mean islet area and number of b cells had largely recovered. However, insulin and Glut-2 mRNAs were elevated in offspring exposed to LP diet, particularly in females. The studies show that LP dietary insult in early, middle, or late gestation, all result in a relative deficiency of b cells following birth, due to a failure to develop larger islets, but that females were particularly susceptible in mid-gestation and males in late gestation.

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Section: Discussionmentioning

confidence: 95%

Altered pancreatic morphology in the offspring of pregnant rats given reduced dietary protein is time and gender specific

Chamson-Reig¹,

Thyssen²,

Arany³

et al. 2006

Journal of Endocrinology

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“…Other strategies for reversal may also be possible. 63,64 It is the mismatch between the developmental trajectory chosen in response to the early-life signals and the later adipogenic environment that creates the added risk of obesity. It is interesting to note the broad nature of the induced phenotype, including altered food preference and appetite, alterations in intermediary metabolism including insulin resistance, and sarcopenia.…”

Section: The 'Mismatch' or 'Thrifty' Pathwaymentioning

confidence: 99%

Developmental and epigenetic pathways to obesity: an evolutionary-developmental perspective

2008

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Although variation in individual lifestyle and genotype are important factors in explaining individual variation in the risk of developing obesity in an obesogenic environment, there is growing evidence that developmentally plastic processes also contribute. These effects are mediated at least in part through epigenetic processes. These developmental pathways do not directly cause obesity but rather alter the risk of an individual developing obesity later in life. At least two classes of developmental pathway are involved. The mismatch pathway involves the evolved adaptive responses of the developing organism to anticipated future adverse environments, which have maladaptive consequences if the environment is mismatched to that predicted. This pathway can be cued by prenatal undernutrition or stresses that lead the organism to forecast an adverse future environment and change its developmental trajectory accordingly. As a result, individuals develop with central and peripheral changes that increase their sensitivity to an obesogenic environment. It provides a model for how obesity emerges in populations in rapid transition, but also operates in developed countries. There is growing experimental evidence that this pathway can be manipulated by, for example, postnatal leptin exposure. Secondly, maternal diabetes, maternal obesity and infant overfeeding are associated with a greater risk of later obesity. Early life offers a potential point for preventative intervention.

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“…This decrease correlates with reduced beta cell mass by 80% in IUGR animals at 3 months. Treatment of the IUGR animals with exendin-4 (Ex-4) in the early postnatal period completely rescues Pdx1 expression, as well as rescuing beta cell mass (64). In late gestation the beta cell population roughly doubles on a daily basis (65) which coincides with islet vascularisation (66).…”

Section: The Role Of the Pancreatic Beta Cell In Glucose/insulin Metamentioning

confidence: 99%

Fetal programming of glucose–insulin metabolism

Jones

Ozanne

2009

Molecular and Cellular Endocrinology

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Epidemiological studies have shown a link between poor fetal growth and increased risk of developing type 2 diabetes. These observations are highly reproducible in many populations worldwide although the mechanisms behind them remain elusive.The 'Thrifty Phenotype Hypothesis' was proposed to explain the underlying causes of these relationships. Animal models of poor intrauterine nutrition have been utilised to help to define the causal factors and identify the molecular mechanisms. Programmed changes in beta cell function and insulin action have been a common feature of animal models of poor intrauterine nutrition. Fundamental underlying mechanisms are starting to emerge, including changes in the epigenotype and mitochondrial function.

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Neonatal Exendin-4 Prevents the Development of Diabetes in the Intrauterine Growth Retarded Rat

Cited by 248 publications

References 54 publications

Altered pancreatic morphology in the offspring of pregnant rats given reduced dietary protein is time and gender specific

Altered pancreatic morphology in the offspring of pregnant rats given reduced dietary protein is time and gender specific

Developmental and epigenetic pathways to obesity: an evolutionary-developmental perspective

Fetal programming of glucose–insulin metabolism

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