PMC:3202114 / 32936-36846 JSONTXT

{"project":"MyTest","denotations":[{"id":"22110471-16118061-29905735","span":{"begin":466,"end":468},"obj":"16118061"},{"id":"22110471-16557373-29905736","span":{"begin":470,"end":473},"obj":"16557373"},{"id":"22110471-15860532-29905737","span":{"begin":859,"end":861},"obj":"15860532"},{"id":"22110471-11914745-29905738","span":{"begin":1184,"end":1186},"obj":"11914745"},{"id":"22110471-15860532-29905739","span":{"begin":1188,"end":1190},"obj":"15860532"},{"id":"22110471-16557373-29905740","span":{"begin":1192,"end":1195},"obj":"16557373"},{"id":"22110471-19864158-29905741","span":{"begin":1349,"end":1352},"obj":"19864158"},{"id":"22110471-20005734-29905741","span":{"begin":1349,"end":1352},"obj":"20005734"},{"id":"22110471-17226802-29905742","span":{"begin":1436,"end":1439},"obj":"17226802"},{"id":"22110471-18464933-29905743","span":{"begin":1802,"end":1805},"obj":"18464933"},{"id":"22110471-18326493-29905744","span":{"begin":1807,"end":1810},"obj":"18326493"},{"id":"22110471-17450140-29905745","span":{"begin":1904,"end":1907},"obj":"17450140"},{"id":"22110471-17226802-29905746","span":{"begin":2362,"end":2365},"obj":"17226802"},{"id":"22110471-16118061-29905747","span":{"begin":2452,"end":2454},"obj":"16118061"},{"id":"22110471-16118061-29905748","span":{"begin":2831,"end":2833},"obj":"16118061"},{"id":"22110471-8288046-29905749","span":{"begin":3906,"end":3908},"obj":"8288046"}],"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":"5. Transgenerational Inheritance of Beta-Cell Mass Programming\nWhile a large number of animal studies have shown the effects of undernutrition during foetal/perinatal development on the glucose metabolism of offspring (F1) in adulthood, several studies have shown that glucose metabolism is also altered in the offspring (F2) as well as grand offspring (F3) of fetally malnourished F1 females, even when the F1 and F2 females have been well nourished since weaning [32, 128] (Figure 1, Table 1). With an aim to dissect the relative parental contributions that lead to F2 offspring outcomes in these models of maternal (F0) undernutrition, it was recently reported that F1 males exhibit moderate hyperglycemia and IGT with aging and impaired glucose-stimulated insulin secretion and that all F2 offspring of F1 males or F1 females develop glucose intolerance [99]. Therefore, intergenerational progression of glucose intolerance can derive from both the maternal and paternal lines. This is an experimental proof that transgenerational transmission of IGT may also occur through the paternal lineage, beside the more widely accepted maternal and grandmaternal inheritance of diabetes [94, 99, 128, 129].\nConceptually, transgenerational inheritance of disease risk may be mediated by nongenomic mechanisms, including either (1) epigenetic mechanisms [130–133] or (2) other broader indirect mechanisms associated with parental physiology [134]. First, alterations in nutrition during development can alter epigenetic marks, thus regulating gene expression through DNA methylation and/or histone modifications. Interestingly, such epigenetic modifications may progress with aging during postnatal life, in association with metabolic phenotypes, as recently observed at the Pdx1 and GLUT4 loci in UPI rats [109, 135]. If these epigenetic changes occur in the germ line, they can be inherited through meiosis [136], thus providing a plausible explanation for intergenerational effects, transmitted via either maternal or paternal lines. In addition, other indirect biological processes may influence phenotypes in subsequent generations. For example, physical constraints may alter birth size through the maternal lineage: since uterine size is reduced in girls that are born small and remain short, this may influence fetal growth and reduce weight in their progeny [134]. \nFurthermore, maternal metabolism may also influence cross-generational phenotypes [32]. Maternal undernutrition during pregnancy (F0) increases risk for developing diabetes and obesity in her offspring (F1). When these high-risk adult F1 females become pregnant, the metabolic stress of pregnancy may result in hyperglycemia and/or overt gestational diabetes that may, in turn, contribute to defective beta-cell mass and increased diabetes risk in F2 offspring [32]. By this mechanism gestational diabetes may pass from one generation to the next one. In these last examples, intergenerational transmission of phenotypes would occur exclusively through the maternal lineage, as opposed to the epigenetic mechanisms mentioned above. Such a scenario is relevant to the GK/Par rat (Figure 3), since the GK/Par mothers are mildly hyperglycemic through their gestation and during the suckling period. It offers a rationale to elucidate several clues: (1) the initiation of pancreas programming in the F1 offspring of the first founders (F0), since the GK line is issued from intercrosses between Wistar females and males with borderline IGT but otherwise normal basal blood glucose level [23]; (2) the progression of the IGT phenotype until a stable mild diabetic phenotype was reached among the generations n = 30 [23]; (3) the lack of attenuation of the diabetic GK phenotype overtime (along more than 20 years and 80 generations), since offspring of GK female/W male crosses were more hyperglycemic than those of W female/GK male crosses [89]."}

{"project":"2_test","denotations":[{"id":"22110471-16118061-29905735","span":{"begin":466,"end":468},"obj":"16118061"},{"id":"22110471-16557373-29905736","span":{"begin":470,"end":473},"obj":"16557373"},{"id":"22110471-15860532-29905737","span":{"begin":859,"end":861},"obj":"15860532"},{"id":"22110471-11914745-29905738","span":{"begin":1184,"end":1186},"obj":"11914745"},{"id":"22110471-15860532-29905739","span":{"begin":1188,"end":1190},"obj":"15860532"},{"id":"22110471-16557373-29905740","span":{"begin":1192,"end":1195},"obj":"16557373"},{"id":"22110471-19864158-29905741","span":{"begin":1349,"end":1352},"obj":"19864158"},{"id":"22110471-20005734-29905741","span":{"begin":1349,"end":1352},"obj":"20005734"},{"id":"22110471-17226802-29905742","span":{"begin":1436,"end":1439},"obj":"17226802"},{"id":"22110471-18464933-29905743","span":{"begin":1802,"end":1805},"obj":"18464933"},{"id":"22110471-18326493-29905744","span":{"begin":1807,"end":1810},"obj":"18326493"},{"id":"22110471-17450140-29905745","span":{"begin":1904,"end":1907},"obj":"17450140"},{"id":"22110471-17226802-29905746","span":{"begin":2362,"end":2365},"obj":"17226802"},{"id":"22110471-16118061-29905747","span":{"begin":2452,"end":2454},"obj":"16118061"},{"id":"22110471-16118061-29905748","span":{"begin":2831,"end":2833},"obj":"16118061"},{"id":"22110471-8288046-29905749","span":{"begin":3906,"end":3908},"obj":"8288046"}],"text":"5. Transgenerational Inheritance of Beta-Cell Mass Programming\nWhile a large number of animal studies have shown the effects of undernutrition during foetal/perinatal development on the glucose metabolism of offspring (F1) in adulthood, several studies have shown that glucose metabolism is also altered in the offspring (F2) as well as grand offspring (F3) of fetally malnourished F1 females, even when the F1 and F2 females have been well nourished since weaning [32, 128] (Figure 1, Table 1). With an aim to dissect the relative parental contributions that lead to F2 offspring outcomes in these models of maternal (F0) undernutrition, it was recently reported that F1 males exhibit moderate hyperglycemia and IGT with aging and impaired glucose-stimulated insulin secretion and that all F2 offspring of F1 males or F1 females develop glucose intolerance [99]. Therefore, intergenerational progression of glucose intolerance can derive from both the maternal and paternal lines. This is an experimental proof that transgenerational transmission of IGT may also occur through the paternal lineage, beside the more widely accepted maternal and grandmaternal inheritance of diabetes [94, 99, 128, 129].\nConceptually, transgenerational inheritance of disease risk may be mediated by nongenomic mechanisms, including either (1) epigenetic mechanisms [130–133] or (2) other broader indirect mechanisms associated with parental physiology [134]. First, alterations in nutrition during development can alter epigenetic marks, thus regulating gene expression through DNA methylation and/or histone modifications. Interestingly, such epigenetic modifications may progress with aging during postnatal life, in association with metabolic phenotypes, as recently observed at the Pdx1 and GLUT4 loci in UPI rats [109, 135]. If these epigenetic changes occur in the germ line, they can be inherited through meiosis [136], thus providing a plausible explanation for intergenerational effects, transmitted via either maternal or paternal lines. In addition, other indirect biological processes may influence phenotypes in subsequent generations. For example, physical constraints may alter birth size through the maternal lineage: since uterine size is reduced in girls that are born small and remain short, this may influence fetal growth and reduce weight in their progeny [134]. \nFurthermore, maternal metabolism may also influence cross-generational phenotypes [32]. Maternal undernutrition during pregnancy (F0) increases risk for developing diabetes and obesity in her offspring (F1). When these high-risk adult F1 females become pregnant, the metabolic stress of pregnancy may result in hyperglycemia and/or overt gestational diabetes that may, in turn, contribute to defective beta-cell mass and increased diabetes risk in F2 offspring [32]. By this mechanism gestational diabetes may pass from one generation to the next one. In these last examples, intergenerational transmission of phenotypes would occur exclusively through the maternal lineage, as opposed to the epigenetic mechanisms mentioned above. Such a scenario is relevant to the GK/Par rat (Figure 3), since the GK/Par mothers are mildly hyperglycemic through their gestation and during the suckling period. It offers a rationale to elucidate several clues: (1) the initiation of pancreas programming in the F1 offspring of the first founders (F0), since the GK line is issued from intercrosses between Wistar females and males with borderline IGT but otherwise normal basal blood glucose level [23]; (2) the progression of the IGT phenotype until a stable mild diabetic phenotype was reached among the generations n = 30 [23]; (3) the lack of attenuation of the diabetic GK phenotype overtime (along more than 20 years and 80 generations), since offspring of GK female/W male crosses were more hyperglycemic than those of W female/GK male crosses [89]."}