PMC:3202114 / 18534-23169 JSONTXT

{"project":"MyTest","denotations":[{"id":"22110471-10976051-29905689","span":{"begin":1368,"end":1371},"obj":"10976051"},{"id":"22110471-8866548-29905690","span":{"begin":2359,"end":2362},"obj":"8866548"},{"id":"22110471-9428419-29905691","span":{"begin":2364,"end":2367},"obj":"9428419"},{"id":"22110471-8187648-29905692","span":{"begin":2501,"end":2504},"obj":"8187648"},{"id":"22110471-9584126-29905693","span":{"begin":2506,"end":2509},"obj":"9584126"},{"id":"22110471-17882398-29905694","span":{"begin":3020,"end":3022},"obj":"17882398"},{"id":"22110471-17882398-29905695","span":{"begin":3709,"end":3711},"obj":"17882398"},{"id":"22110471-21047942-29905696","span":{"begin":4047,"end":4049},"obj":"21047942"},{"id":"22110471-21047942-29905697","span":{"begin":4309,"end":4311},"obj":"21047942"},{"id":"22110471-11698417-29905698","span":{"begin":4438,"end":4441},"obj":"11698417"}],"namespaces":[{"prefix":"_base","uri":"https://www.uniprot.org/uniprot/testbase"},{"prefix":"UniProtKB","uri":"https://www.uniprot.org/uniprot/"},{"prefix":"uniprot","uri":"https://www.uniprot.org/uniprotkb/"}],"text":"3.1. Critical Windows for Adaptive Response to Early-Life Stressors\nThe development of the endocrine pancreas starts from a pool of common precursor cells that become progressively committed to the endocrine lineage under the control of a hierarchical network of transcription factors. During late fetal and early postnatal life, the beta-cell mass is determined by the recruitment of undifferentiated precursors, as well as the replication and apoptosis rates of the beta cells. Obviously, any disturbance of the environment of the endocrine cells at a specific developmental time-point, as it occurs in a perturbed intrauterine milieu, may modify the balance of controlling factors, thereby contributing to an adaptive beta-cell growth response which is metabolically appropriate on the short term. However, this adaptive response may turn to be detrimental if maintained on the long term, as it may foster beta-cell failure and diabetes later in life. We are largely ignorant of when programming may be initiated during development.\nPreimplantatio\nAn early onset for programming was indicated, as maternal low-protein diet during only the preimplantation period of rat development (0–4 days after mating), before return to control diet for the remainder of the gestation, induced blastocyst abnormalities, and programming of postnatal growth rate and hypertension [102]. More specifically it was shown that preimplantation embryos collected from dams after 0–4 days of maternal low-protein diet displayed significantly reduced cell numbers, within the inner cell mass and trophectoderm lineages, apparently induced by a slower rate of cellular proliferation. The low-protein diet significantly reduced insulin and essential amino acid levels and increased glucose levels within maternal serum by day 4 of development. These data indicate that the mildly hyperglycemic and amino-acid-depleted maternal environment generated by undernutrition may act as an early mechanism of programming and initiate conditions of “metabolic stress,” restricting early embryonic proliferation and the generation of appropriately sized stem-cell lineages. In chemically or genetically obtained rat diabetes models in which maternal serum insulin depletion and hyperglycemia are induced, proliferation of inner cell mass or total cell numbers within blastocysts is inhibited [103, 104]. Therefore, the preimplantation embryo is particularly sensitive to metabolic modifications that may have programming consequences [105, 106], and one possibility is that it is the preimplantation embryo itself that is programmed. \nPostimplantation\nEmbryo transfer experiments may also help to dissociate the impact of the maternal environment in early (preimplantation) versus late gestation (postimplantation). We recently found that embryos (blastocysts) from a nondiabetic Wistar strain placed into a diabetic GK/Par uterus develop a reduced beta-cell mass which remains low on the long term [42]. Data with rat models of prenatal undernutrition [95] also illustrate that low-energy and low-protein diets that reduce the development of the beta-cell mass in both cases act at different critical time windows. The beta-cell mass is deficient in the low-energy pancreas because this diet reduces neogenesis, probably because of high glucocorticoid levels, rather than by impairing vascularisation and proliferation. Early gestation is thus a very sensitive period in this model. By contrast, pancreatic alterations take place at a later fetal stage in the low-protein model, and the beta-cell mass is deficient in this case because this diet reduces beta-cell vascularisation and proliferation without altering beta-cell differentiation [95]. \nPostnatal versus Prenata\nFurther support for the crucial impact of prenatal nutritional environment is the recent report that prenatal nutrient restriction in both male and female rats led to an inappropriate postnatal beta-cell mass formation attributed to a decrease in the rate of beta-cell replication and beta-cell neogenesis [93]. In contrast, male and female rats exposed to postnatal nutrient restriction alone (with normal prenatal nutrient exposure) were characterized by decreased pancreatic and body weights, but a weight-adjusted beta-cell mass higher compared to control animals [93]. Another illustration is offered by observations in normal rat pups reared artificially on a high-carbohydrate milk formula [107]: such alteration of nutrition, during the suckling period only, induced persistent adaptation of energy metabolism in adulthood (obesity, glucose intolerance, and impaired insulin secretion).\n"}

{"project":"2_test","denotations":[{"id":"22110471-10976051-29905689","span":{"begin":1368,"end":1371},"obj":"10976051"},{"id":"22110471-8866548-29905690","span":{"begin":2359,"end":2362},"obj":"8866548"},{"id":"22110471-9428419-29905691","span":{"begin":2364,"end":2367},"obj":"9428419"},{"id":"22110471-8187648-29905692","span":{"begin":2501,"end":2504},"obj":"8187648"},{"id":"22110471-9584126-29905693","span":{"begin":2506,"end":2509},"obj":"9584126"},{"id":"22110471-17882398-29905694","span":{"begin":3020,"end":3022},"obj":"17882398"},{"id":"22110471-17882398-29905695","span":{"begin":3709,"end":3711},"obj":"17882398"},{"id":"22110471-21047942-29905696","span":{"begin":4047,"end":4049},"obj":"21047942"},{"id":"22110471-21047942-29905697","span":{"begin":4309,"end":4311},"obj":"21047942"},{"id":"22110471-11698417-29905698","span":{"begin":4438,"end":4441},"obj":"11698417"}],"text":"3.1. Critical Windows for Adaptive Response to Early-Life Stressors\nThe development of the endocrine pancreas starts from a pool of common precursor cells that become progressively committed to the endocrine lineage under the control of a hierarchical network of transcription factors. During late fetal and early postnatal life, the beta-cell mass is determined by the recruitment of undifferentiated precursors, as well as the replication and apoptosis rates of the beta cells. Obviously, any disturbance of the environment of the endocrine cells at a specific developmental time-point, as it occurs in a perturbed intrauterine milieu, may modify the balance of controlling factors, thereby contributing to an adaptive beta-cell growth response which is metabolically appropriate on the short term. However, this adaptive response may turn to be detrimental if maintained on the long term, as it may foster beta-cell failure and diabetes later in life. We are largely ignorant of when programming may be initiated during development.\nPreimplantatio\nAn early onset for programming was indicated, as maternal low-protein diet during only the preimplantation period of rat development (0–4 days after mating), before return to control diet for the remainder of the gestation, induced blastocyst abnormalities, and programming of postnatal growth rate and hypertension [102]. More specifically it was shown that preimplantation embryos collected from dams after 0–4 days of maternal low-protein diet displayed significantly reduced cell numbers, within the inner cell mass and trophectoderm lineages, apparently induced by a slower rate of cellular proliferation. The low-protein diet significantly reduced insulin and essential amino acid levels and increased glucose levels within maternal serum by day 4 of development. These data indicate that the mildly hyperglycemic and amino-acid-depleted maternal environment generated by undernutrition may act as an early mechanism of programming and initiate conditions of “metabolic stress,” restricting early embryonic proliferation and the generation of appropriately sized stem-cell lineages. In chemically or genetically obtained rat diabetes models in which maternal serum insulin depletion and hyperglycemia are induced, proliferation of inner cell mass or total cell numbers within blastocysts is inhibited [103, 104]. Therefore, the preimplantation embryo is particularly sensitive to metabolic modifications that may have programming consequences [105, 106], and one possibility is that it is the preimplantation embryo itself that is programmed. \nPostimplantation\nEmbryo transfer experiments may also help to dissociate the impact of the maternal environment in early (preimplantation) versus late gestation (postimplantation). We recently found that embryos (blastocysts) from a nondiabetic Wistar strain placed into a diabetic GK/Par uterus develop a reduced beta-cell mass which remains low on the long term [42]. Data with rat models of prenatal undernutrition [95] also illustrate that low-energy and low-protein diets that reduce the development of the beta-cell mass in both cases act at different critical time windows. The beta-cell mass is deficient in the low-energy pancreas because this diet reduces neogenesis, probably because of high glucocorticoid levels, rather than by impairing vascularisation and proliferation. Early gestation is thus a very sensitive period in this model. By contrast, pancreatic alterations take place at a later fetal stage in the low-protein model, and the beta-cell mass is deficient in this case because this diet reduces beta-cell vascularisation and proliferation without altering beta-cell differentiation [95]. \nPostnatal versus Prenata\nFurther support for the crucial impact of prenatal nutritional environment is the recent report that prenatal nutrient restriction in both male and female rats led to an inappropriate postnatal beta-cell mass formation attributed to a decrease in the rate of beta-cell replication and beta-cell neogenesis [93]. In contrast, male and female rats exposed to postnatal nutrient restriction alone (with normal prenatal nutrient exposure) were characterized by decreased pancreatic and body weights, but a weight-adjusted beta-cell mass higher compared to control animals [93]. Another illustration is offered by observations in normal rat pups reared artificially on a high-carbohydrate milk formula [107]: such alteration of nutrition, during the suckling period only, induced persistent adaptation of energy metabolism in adulthood (obesity, glucose intolerance, and impaired insulin secretion).\n"}