PMC:3202114 / 39992-43602 JSONTXT

{"project":"MyTest","denotations":[{"id":"22110471-15111519-29905761","span":{"begin":593,"end":596},"obj":"15111519"},{"id":"22110471-16167951-29905762","span":{"begin":794,"end":797},"obj":"16167951"},{"id":"22110471-12915626-29905763","span":{"begin":907,"end":910},"obj":"12915626"},{"id":"22110471-19759171-29905764","span":{"begin":912,"end":915},"obj":"19759171"},{"id":"22110471-15930441-29905765","span":{"begin":1988,"end":1990},"obj":"15930441"},{"id":"22110471-18626486-29905766","span":{"begin":2118,"end":2121},"obj":"18626486"},{"id":"22110471-16020474-29905767","span":{"begin":2296,"end":2299},"obj":"16020474"},{"id":"22110471-18464933-29905768","span":{"begin":2483,"end":2486},"obj":"18464933"},{"id":"22110471-12606515-29905769","span":{"begin":2767,"end":2769},"obj":"12606515"},{"id":"22110471-11978641-29905770","span":{"begin":2938,"end":2940},"obj":"11978641"},{"id":"22110471-19279000-29905771","span":{"begin":3293,"end":3296},"obj":"19279000"}],"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":"7. Implications for Public Health\nAlthough the focus of most studies in the metabolic programming field has been on delineating the effects of reduced maternal nutrition, there is now a growing interest in the role of maternal overnutrition in the programming of diabetes risk. The worldwide prevalence of obesity continues to increase, in association with an increase in the risk of metabolic T2D. Indeed, a recent study estimated that the number of people worldwide with diabetes would increase from 171 million in 2000 to 366 million by 2030 if the prevalence of obesity remained constant [141], which has major implications for public health strategies worldwide [142]. This global trend to increasing obesity is reflected in the increasing numbers of women who are obese during pregnancy [143]. Given that the offspring of obese mothers have an increased risk of developing obesity and T2D themselves [144, 145], the potential impact of the intergenerational consequences of maternal obesity is of great concern for public health policy makers. \nMoreover, maternal hyperglycemia per se increases the probability of adolescent obesity and future T2D. To what extent maternal hyperglycemia is fuelling the global rise in obesity and T2D is unknown, but its contribution is highly significant. The exact degree of hyperglycemia that has this effect and the exact timing in pregnancy that hyperglycemia is impressionable on fetal programming is unknown. The need to identify and treat all women with gestational diabetes is very much dependent on us knowing this. Meanwhile, achieving rigorous glycemic control in women with diabetic pregnancy has to remain a major therapeutic goal.\nSeveral interventions (dietary or pharmacological) to reduce the long-term sequelae of early-life programming effects have been used in animal models. For example, the administration of folic acid with a low-protein diet during pregnancy prevents the altered phenotype and epigenotype in rat offspring [97], and administration of a diet rich in methyl donors prevents the transgenerational increase in obesity in agouti yellow mice [146]. Importantly, the timing of such interventions can be crucial. Examples include neonatal leptin treatment which reverses the programming effects of prenatal undernutrition [147]. In the UPI rat model, epigenetic silencing of the Pdx1 gene can be reversed during a critical developmental window in the neonatal period, using trichostatin A which inhibit HDACs [109]. In the same model, exposure to exendin-4 in the neonatal period reversed the detrimental fetal programming of the beta-cell mass and prevented the development of diabetes in adulthood: this was closely related to restoration of pdx1 expression and beta-cell proliferation rate [69]. A GLP-1 or exendin-4 treatment limited to the neonatal prediabetic period was also shown to delay the installation and limit the severity of T2D in the GK/Par model [88]. In such context, it is important to note that GLP1-derived drugs that are currently used to treat patients with T2D may target chromatin remodelling. Treating beta cells from the INS1 cell line or dispersed mouse islet cells with GLP-1 increased global acetylation of histone H3 and increased its phosphorylation in a concentration-dependent manner [148]. Such histone modifications increased association with the transcription factor phospho-CREB and with cAMP-response CREB coactivator 2. Taken as a whole, these data may provoke optimism—that there may be a window for potential postnatal therapeutic interventions to prevent/modify the “programmed” diabetes risk."}

{"project":"2_test","denotations":[{"id":"22110471-15111519-29905761","span":{"begin":593,"end":596},"obj":"15111519"},{"id":"22110471-16167951-29905762","span":{"begin":794,"end":797},"obj":"16167951"},{"id":"22110471-12915626-29905763","span":{"begin":907,"end":910},"obj":"12915626"},{"id":"22110471-19759171-29905764","span":{"begin":912,"end":915},"obj":"19759171"},{"id":"22110471-15930441-29905765","span":{"begin":1988,"end":1990},"obj":"15930441"},{"id":"22110471-18626486-29905766","span":{"begin":2118,"end":2121},"obj":"18626486"},{"id":"22110471-16020474-29905767","span":{"begin":2296,"end":2299},"obj":"16020474"},{"id":"22110471-18464933-29905768","span":{"begin":2483,"end":2486},"obj":"18464933"},{"id":"22110471-12606515-29905769","span":{"begin":2767,"end":2769},"obj":"12606515"},{"id":"22110471-11978641-29905770","span":{"begin":2938,"end":2940},"obj":"11978641"},{"id":"22110471-19279000-29905771","span":{"begin":3293,"end":3296},"obj":"19279000"}],"text":"7. Implications for Public Health\nAlthough the focus of most studies in the metabolic programming field has been on delineating the effects of reduced maternal nutrition, there is now a growing interest in the role of maternal overnutrition in the programming of diabetes risk. The worldwide prevalence of obesity continues to increase, in association with an increase in the risk of metabolic T2D. Indeed, a recent study estimated that the number of people worldwide with diabetes would increase from 171 million in 2000 to 366 million by 2030 if the prevalence of obesity remained constant [141], which has major implications for public health strategies worldwide [142]. This global trend to increasing obesity is reflected in the increasing numbers of women who are obese during pregnancy [143]. Given that the offspring of obese mothers have an increased risk of developing obesity and T2D themselves [144, 145], the potential impact of the intergenerational consequences of maternal obesity is of great concern for public health policy makers. \nMoreover, maternal hyperglycemia per se increases the probability of adolescent obesity and future T2D. To what extent maternal hyperglycemia is fuelling the global rise in obesity and T2D is unknown, but its contribution is highly significant. The exact degree of hyperglycemia that has this effect and the exact timing in pregnancy that hyperglycemia is impressionable on fetal programming is unknown. The need to identify and treat all women with gestational diabetes is very much dependent on us knowing this. Meanwhile, achieving rigorous glycemic control in women with diabetic pregnancy has to remain a major therapeutic goal.\nSeveral interventions (dietary or pharmacological) to reduce the long-term sequelae of early-life programming effects have been used in animal models. For example, the administration of folic acid with a low-protein diet during pregnancy prevents the altered phenotype and epigenotype in rat offspring [97], and administration of a diet rich in methyl donors prevents the transgenerational increase in obesity in agouti yellow mice [146]. Importantly, the timing of such interventions can be crucial. Examples include neonatal leptin treatment which reverses the programming effects of prenatal undernutrition [147]. In the UPI rat model, epigenetic silencing of the Pdx1 gene can be reversed during a critical developmental window in the neonatal period, using trichostatin A which inhibit HDACs [109]. In the same model, exposure to exendin-4 in the neonatal period reversed the detrimental fetal programming of the beta-cell mass and prevented the development of diabetes in adulthood: this was closely related to restoration of pdx1 expression and beta-cell proliferation rate [69]. A GLP-1 or exendin-4 treatment limited to the neonatal prediabetic period was also shown to delay the installation and limit the severity of T2D in the GK/Par model [88]. In such context, it is important to note that GLP1-derived drugs that are currently used to treat patients with T2D may target chromatin remodelling. Treating beta cells from the INS1 cell line or dispersed mouse islet cells with GLP-1 increased global acetylation of histone H3 and increased its phosphorylation in a concentration-dependent manner [148]. Such histone modifications increased association with the transcription factor phospho-CREB and with cAMP-response CREB coactivator 2. Taken as a whole, these data may provoke optimism—that there may be a window for potential postnatal therapeutic interventions to prevent/modify the “programmed” diabetes risk."}