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      Pre-Pubertal Children Born Post-Term Have Reduced Insulin Sensitivity and Other Markers of the Metabolic Syndrome

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          Abstract

          Background

          There are no data on the metabolic consequences of post-term birth (≥42 weeks gestation). We hypothesized that post-term birth would adversely affect insulin sensitivity, as well as other metabolic parameters and body composition in childhood.

          Methods

          77 healthy pre-pubertal children, born appropriate-for-gestational-age were studied in Auckland, New Zealand: 36 born post-term (18 boys) and 41 (27 boys) born at term (38–40 weeks gestation). Primary outcome was insulin sensitivity measured using intravenous glucose tolerance tests and Bergman’s minimal model. Other assessments included fasting hormone concentrations and lipid profiles, body composition from whole-body dual-energy X-ray absorptiometry, 24-hour ambulatory blood pressure monitoring, and inflammatory markers.

          Results

          Insulin sensitivity was 34% lower in post-term than in term children (7.7 vs. 11.6 x10 -4·min -1·(mU/l); p<0.0001). There was a compensatory increase in acute insulin response among post-term children (418 vs 304 mU/l; p=0.037), who also displayed lower glucose effectiveness than those born at term (2.25 vs 3.11 x10 -2·min -1; p=0.047). Post-term children not only had more body fat (p=0.014) and less fat-free mass (p=0.014), but also had increased central adiposity with more truncal fat (p=0.017) and greater android to gynoid fat ratio (p=0.007) compared to term controls. Further, post-term children displayed other markers of the metabolic syndrome: lower normal nocturnal systolic blood pressure dipping (p=0.027), lower adiponectin concentrations (p=0.005), as well as higher leptin (p=0.008) and uric acid (p=0.033) concentrations. Post-term boys (but not girls) also displayed a less favourable lipid profile, with higher total cholesterol (p=0.018) and LDL-C (p=0.006) concentrations, and total cholesterol to HDL-C ratio (p=0.048).

          Conclusions

          Post-term children have reduced insulin sensitivity and display a number of early markers of the metabolic syndrome. These findings could have important implications for the management of prolonged pregnancies. Future studies need to examine potential impacts later in life, as well as possible underlying mechanisms.

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          Most cited references28

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          Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia (syndrome X): relation to reduced fetal growth

          Two follow-up studies were carried out to determine whether lower birthweight is related to the occurrence of syndrome X-Type 2 (non-insulin-dependent) diabetes mellitus, hypertension and hyperlipidaemia. The first study included 407 men born in Hertfordshire, England between 1920 and 1930 whose weights at birth and at 1 year of age had been recorded by health visitors. The second study included 266 men and women born in Preston, UK, between 1935 and 1943 whose size at birth had been measured in detail. The prevalence of syndrome X fell progressively in both men and women, from those who had the lowest to those who had the highest birthweights. Of 64-year-old men whose birthweights were 2.95 kg (6.5 pounds) or less, 22% had syndrome X. Their risk of developing syndrome X was more than 10 times greater than that of men whose birthweights were more than 4.31 kg (9.5 pounds). The association between syndrome X and low birthweight was independent of duration of gestation and of possible confounding variables including cigarette smoking, alcohol consumption and social class currently or at birth. In addition to low birthweight, subjects with syndrome X had small head circumference and low ponderal index at birth, and low weight and below-average dental eruption at 1 year of age. It is concluded that Type 2 diabetes and hypertension have a common origin in sub-optimal development in utero, and that syndrome X should perhaps be re-named "the small-baby syndrome".
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            Premature birth and later insulin resistance.

            Term infants who are small for gestational age appear prone to the development of insulin resistance during childhood. We hypothesized that insulin resistance, a marker of type 2 diabetes mellitus, would be prevalent among children who had been born prematurely, irrespective of whether they were appropriate for gestational age or small for gestational age. Seventy-two healthy prepubertal children 4 to 10 years of age were studied: 50 who had been born prematurely (32 weeks' gestation or less), including 38 with a birth weight that was appropriate for gestational age (above the 10th percentile) and 12 with a birth weight that was low (i.e., who were small) for gestational age, and 22 control subjects (at least 37 weeks' gestation, with a birth weight above the 10th percentile). Insulin sensitivity was measured with the use of paired insulin and glucose data obtained by frequent measurements during intravenous glucose-tolerance tests. Children who had been born prematurely, whether their weight was appropriate or low for gestational age, had an isolated reduction in insulin sensitivity as compared with controls (appropriate-for-gestational-age group, 14.2x10(-4) per minute per milliunit per liter [95 percent confidence interval, 11.5 to 16.2]; small-for-gestational-age group, 12.9x10(-4) per minute per milliunit per liter [95 percent confidence interval, 9.7 to 17.4]; and control group, 21.6x10(-4) per minute per milliunit per liter [95 percent confidence interval, 17.1 to 27.4]; P=0.002). There were no significant differences in insulin sensitivity between the two premature groups (P=0.80). As compared with controls, both groups of premature children had a compensatory increase in acute insulin release (appropriate-for-gestational-age group, 2002 pmol per liter [95 percent confidence interval, 1434 to 2432] [corrected]; small-for-gestational-age group, 2253 pmol per liter [95 percent confidence interval, 1622 to 3128]; and control group, 1148 pmol per liter [95 percent confidence interval, 875 to 1500]; P<0.001). Like children who were born at term but who were small for gestational age, children who were born prematurely have an isolated reduction in insulin sensitivity, which may be a risk factor for type 2 diabetes mellitus. Copyright 2004 Massachusetts Medical Society.
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              Standards for children's height at ages 2-9 years allowing for heights of parents.

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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                1 July 2013
                : 8
                : 7
                : e67966
                Affiliations
                [1 ]Liggins Institute, University of Auckland, Auckland, New Zealand
                [2 ]Gravida: National Centre for Growth and Development, Auckland, New Zealand
                [3 ]Department of Obstetrics and Gynaecology, Faculty of Medical and Health Sciences, University of Auckland, Auckland, New Zealand
                [4 ]National Women’s Health, Auckland District Health Board, Auckland, New Zealand
                Virgen Macarena University Hospital, School of Medicine, Spain
                Author notes

                Competing Interests: The authors have no financial or non-financial conflicts of interest to disclose that may be relevant to this work.

                Conceived and designed the experiments: AA WSC PLH PS. Performed the experiments: AA JB. Analyzed the data: JGBD . Wrote the manuscript: AA JGBD WSC . Other: Compiled the data: AA JGBD LS SM.

                Article
                PONE-D-13-14174
                10.1371/journal.pone.0067966
                3698136
                23840881
                f3a313aa-6151-4107-a63c-fc632d474315
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 6 April 2013
                : 24 May 2013
                Funding
                This study was funded by Gravida: National Centre for Growth and Development, the Australasian Paediatric Endocrine Group (APEG), and Maureen Trotter. The funders had any role in study design, data collection and analysis, decision to publish, or preparation of this manuscript.
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