Hostname: page-component-848d4c4894-hfldf Total loading time: 0 Render date: 2024-05-05T20:13:23.664Z Has data issue: false hasContentIssue false
  • English
  • Français

Effects of preterm birth induced with or without exogenous glucocorticoids on the ovine glucose–insulin axis

Published online by Cambridge University Press:  15 January 2020

Amita Bansal Open the ORCID record for Amita Bansal [Opens in a new window] ,
Jane M. Alsweiler ,
Mark H. Oliver ,
Anne Jaquiery ,
Hui Hui Phua ,
Mike Dragunow ,
Rob de Matteo ,
Jane E. Harding  and
Frank H. Bloomfield
Amita Bansal
Affiliation:
College of Health and Medicine, ANU Medical School, The Australian National University, Canberra, ACT 2601, Australia
Jane M. Alsweiler
Affiliation:
Department of Paediatrics, Child and Youth Health, Faculty of Medical and Health Sciences, University of Auckland, Auckland1023, New Zealand
Mark H. Oliver
Affiliation:
College of Health and Medicine, ANU Medical School, The Australian National University, Canberra, ACT 2601, Australia
Anne Jaquiery
Affiliation:
College of Health and Medicine, ANU Medical School, The Australian National University, Canberra, ACT 2601, Australia
Hui Hui Phua
Affiliation:
College of Health and Medicine, ANU Medical School, The Australian National University, Canberra, ACT 2601, Australia
Mike Dragunow
Affiliation:
Centre of Brain Research, Faculty of Medical and Health Sciences, University of Auckland, Auckland1023, New Zealand
Rob de Matteo
Affiliation:
Department of Anatomy and Developmental Biology, Monash University, Melbourne, Australia
Jane E. Harding
Affiliation:
College of Health and Medicine, ANU Medical School, The Australian National University, Canberra, ACT 2601, Australia
Frank H. Bloomfield*
Affiliation:
College of Health and Medicine, ANU Medical School, The Australian National University, Canberra, ACT 2601, Australia
*
Address for correspondence: Frank H. Bloomfield, Liggins Institute, University of Auckland, Private Bag 92019, Auckland1142, New Zealand. Email: f.bloomfield@auckland.ac.nz
Get access Rights & Permissions [Opens in a new window]

Abstract

Antenatal exogenous glucocorticoids (ANG) are standard management for women at risk of preterm birth but are reputed to impair glucose tolerance in preterm offspring. We compared lambs born preterm (137 days gestation) following labour induced with exogenous glucocorticoids (G-Prem, glucocorticoid-induced preterm group), or with a progesterone synthesis inhibitor (NG-Prem, non-glucocorticoid-induced preterm group), with term-born lambs (Term; 149 days). We assessed glucose tolerance, insulin secretion and sensitivity at 4 and 10 months n = 11–14/group) and pancreatic and hepatic gene and protein expression at 4 weeks post-term (4 weeks; n = 6/group) and 12 months (12 months; n = 12–13/group). NG-Prem had higher plasma glucose concentrations than G-Prem, but not Term, at 4 months (Mean[SEM] mM: NG-Prem = 4.1[0.1]; G-Prem = 3.4[0.1]; Term = 3.7[0.1]; p = 0.003) and 10 months (NG-Prem = 3.9[0.1]; G-Prem = 3.5[0.1]; Term = 3.7[0.1]; p = 0.01). Insulin sensitivity decreased from 4 to 10 months, in NG-Prem but not in Term (Mean[SEM] µmol·ml−1·kg−1·min−1·ng−1, 4 vs. 10 months: NG-Prem = 18.7[2.5] vs. 9.5[1.5], p < 0.01; Term: 12.1[2.8] vs. 10.4[1.5], p = 0.44). At 12 months, β-cell mass in NG-Prem was reduced by 30% vs. G-Prem (p < 0.01) and 75% vs. Term (p < 0.01) and was accompanied by an increased β-cell apoptosis: proliferation ratio at 12 months. At 12 months, pancreatic glucokinase, igf2 and insulin mRNA levels were reduced 21%–71% in NG-Prem vs. G-Prem and 42%–80% vs. Term. Hepatic glut2 mRNA levels in NG-Prem were 250% of those in G-Prem and Term. Thus, induction of preterm birth without exogenous glucocorticoids more adversely affected pancreas and liver than induction with exogenous glucocorticoids. These findings do not support that ANG lead to long-term adverse metabolic effects, but support an effect of preterm birth itself.

Keywords

Preterm birthsteroidsinsulin secretioninsulin sensitivityβ-cells
Type
Original Article
Information
Journal of Developmental Origins of Health and Disease , Volume 12 , Issue 1 , February 2021 , pp. 58 - 70
Check for updates
Copyright
© Cambridge University Press and the International Society for Developmental Origins of Health and Disease 2020

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

Footnotes

†

Current address: Center for Research on Reproduction and Women’s Health, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA

References

Roberts, D, Brown, J, Medley, N, Dalziel, SR. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2017; 3, CD004454. doi: 10.1002/14651858.CD14004454.pub14651853Google ScholarPubMed
Kemp, MW, Newnham, JP, Challis, JG, Jobe, AH, Stock, SJ. The clinical use of corticosteroids in pregnancy. Hum Reprod Update. 2016; 22(2), 240–259.Google ScholarPubMed
Vogel, JP, Oladapo, OT, Pileggi-Castro, C, et al. Antenatal corticosteroids for women at risk of imminent preterm birth in low-resource countries: the case for equipoise and the need for efficacy trials. BMJ Glob Health. 2017; 2(3), e000398.CrossRefGoogle ScholarPubMed
Gesina, E, Blondeau, B, Milet, A, et al. Glucocorticoid signalling affects pancreatic development through both direct and indirect effects. Diabetologia. 2006; 49(12), 2939–2947.CrossRefGoogle ScholarPubMed
Blondeau, B, Lesage, J, Czernichow, P, Dupouy, JP, Breant, B. Glucocorticoids impair fetal beta-cell development in rats. Am J Physiol Endocrinol Metab. 2001; 281(3), E592–E599.CrossRefGoogle ScholarPubMed
De Blasio, MJ, Dodic, M, Jefferies, AJ, Moritz, KM, Wintour, EM, Owens, JA. Maternal exposure to dexamethasone or cortisol in early pregnancy differentially alters insulin secretion and glucose homeostasis in adult male sheep offspring. Am J Physiol Endocrinol Metab. 2007; 293(1), E75–E82.CrossRefGoogle ScholarPubMed
Nyirenda, MJ, Lindsay, RS, Kenyon, CJ, Burchell, A, Seckl, JR. Glucocorticoid exposure in late gestation permanently programs rat hepatic phosphoenolpyruvate carboxykinase and glucocorticoid receptor expression and causes glucose intolerance in adult offspring. J Clin Invest. 1998; 101(10), 2174–2181.CrossRefGoogle ScholarPubMed
Moss, TJ, Sloboda, DM, Gurrin, LC, Harding, R, Challis, JR, Newnham, JP. Programming effects in sheep of prenatal growth restriction and glucocorticoid exposure. Am J Physiol Regul Integr Comp Physiol. 2001; 281(3), R960–R970.CrossRefGoogle ScholarPubMed
Sloboda, DM, Moss, TJ, Li, S, et al. Hepatic glucose regulation and metabolism in adult sheep: effects of prenatal betamethasone. Am J Physiol Endocrinol Metab. 2005; 289(4), E721–E728.CrossRefGoogle ScholarPubMed
Hofman, PL, Regan, F, Jackson, WE, et al. Premature birth and later insulin resistance. N Engl J Med. 2004; 351(21), 2179–2186.CrossRefGoogle ScholarPubMed
Crump, C, Winkleby, MA, Sundquist, K, Sundquist, J. Risk of diabetes among young adults born preterm in Sweden. Diabetes Care. 2011; 34(5), 1109–1113. doi: 1110.2337/dc1110-2108. Epub 2011 Mar 1116.CrossRefGoogle ScholarPubMed
Dalziel, SR, Walker, NK, Parag, V, et al. Cardiovascular risk factors after antenatal exposure to betamethasone: 30-year follow-up of a randomised controlled trial. Lancet. 2005; 365(9474), 1856–1862.CrossRefGoogle ScholarPubMed
Bansal, A, Bloomfield, FH, Connor, KL, et al. Glucocorticoid-induced preterm birth and neonatal hyperglycemia alter ovine beta-cell development. Endocrinology. 2015; 156(10), 3763–3776.CrossRefGoogle ScholarPubMed
Challis, JRG. Mechanism of parturition and preterm labor. Obstet Gynecol Surv. 2000; 55(10), 650–660.CrossRefGoogle ScholarPubMed
Jenkin, G, Thorburn, GD. Inhibition of progesterone secretion by a 3 beta-hydroxysteroid dehydrogenase inhibitor in late pregnant sheep. Can J Physiol Pharmacol. 1985; 63(2), 136–142.CrossRefGoogle ScholarPubMed
Silver, M. Effects on maternal and fetal steroid concentrations of induction of parturition in the sheep by inhibition of 3 beta-hydroxysteroid dehydrogenase. J Reprod Fertil. 1988; 82(2), 457–465.CrossRefGoogle ScholarPubMed
De Matteo, R, Blasch, N, Stokes, V, Davis, P, Harding, R. Induced preterm birth in sheep: a suitable model for studying the developmental effects of moderately preterm birth. Reprod Sci. 2010; 17(8), 724–733.CrossRefGoogle ScholarPubMed
Todd, SE, Oliver, MH, Jaquiery, AL, Bloomfield, FH, Harding, JE. Periconceptional undernutrition of ewes impairs glucose tolerance in their adult offspring. Pediatr Res. 2009; 65(4), 409–413. doi: 10.1203/PDR.1200b1013e3181975efa CrossRefGoogle ScholarPubMed
Dragunow, M. High-content analysis in neuroscience. Nat Rev Neurosci. 2008; 9(10), 779–788.CrossRefGoogle ScholarPubMed
Davis, SR, Gluckman, PD, Hart, IC, Henderson, HV. Effects of injecting growth hormone or thyroxine on milk production and blood plasma concentrations of insulin-like growth factors I and II in dairy cows. J Endocrinol. 1987; 114(1), 17–24.CrossRefGoogle ScholarPubMed
Pfaffl, MW. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 2001; 29(9), e45.CrossRefGoogle ScholarPubMed
Pfaffl, MW, Tichopad, A, Prgomet, C, Neuvians, TP. Determination of stable housekeeping genes, differentially regulated target genes and sample integrity: BestKeeper – Excel-based tool using pair-wise correlations. Biotechnol Lett. 2004; 26(6), 509–515.CrossRefGoogle ScholarPubMed
Patel, AL, Engstrom, JL, Meier, PP, Kimura, RE. Accuracy of methods for calculating postnatal growth velocity for extremely low birth weight infants. Pediatrics. 2005; 116(6), 1466–1473.CrossRefGoogle ScholarPubMed
Alsweiler, JM, Harding, JE, Bloomfield, FH. Neonatal hyperglycaemia increases mortality and morbidity in preterm lambs. Neonatology. 2013; 103(2), 83–90.CrossRefGoogle ScholarPubMed
Holtkamp, HC, Verhoef, NJ, Leijnse, B. The difference between the glucose concentrations in plasma and whole blood. Clin Chim Acta. 1975; 59(1), 41–49.CrossRefGoogle ScholarPubMed
Dodic, M, Wintour, EM, Whitworth, JA, Coghlan, JP. Effect of steroid hormones on blood pressure. Clin Exp Pharmacol Physiol. 1999; 26(7), 550–552.CrossRefGoogle ScholarPubMed
Edwards, LJ, Coulter, CL, Symonds, ME, McMillen, IC. Prenatal undernutrition, glucocorticoids and the programming of adult hypertension. Clin Exp Pharmacol Physiol. 2001; 28(11), 938–941.CrossRefGoogle ScholarPubMed
Clark, PM. Programming of the hypothalamo-pituitary-adrenal axis and the fetal origins of adult disease hypothesis. Eur J Pediatr. 1998 157(1), S7–S10.CrossRefGoogle ScholarPubMed
Seckl, JR. Glucocorticoid programming of the fetus; adult phenotypes and molecular mechanisms. Mol Cell Endocrinol. 2001; 185(1–2), 61–71.CrossRefGoogle ScholarPubMed
Brownfoot, FC, Gagliardi, DI, Bain, E, Middleton, P, Crowther, CA. Different corticosteroids and regimens for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2013; (8), CD006764. doi: 10.1002/14651858.CD006764.pub3 Google Scholar
Roberts, D, Dalziel, S. Antenatal corticosteroids for accelerating fetal lung maturation for women at risk of preterm birth. Cochrane Database Syst Rev. 2006; (3), CD004454. doi: 004410.001002/14651858.CD14004454.pub14651852 Google Scholar
Dalziel, SR, Lim, VK, Lambert, A, et al. Antenatal exposure to betamethasone: psychological functioning and health related quality of life 31 years after inclusion in randomised controlled trial. BMJ. 2005; 331(7518), 665.Google ScholarPubMed
McKinlay, CJ, Cutfield, WS, Battin, MR, Dalziel, SR, Crowther, CA, Harding, JE. Cardiovascular risk factors in children after repeat doses of antenatal glucocorticoids: an RCT. Pediatrics. 2015; 135(2), e405–e415. doi: 10.1542/peds.2014-2408. Epub 2015 Jan 1519CrossRefGoogle Scholar
Crowther, CA, Anderson, PJ, McKinlay, CJ, et al. Mid-childhood outcomes of repeat antenatal corticosteroids: a randomized controlled trial. Pediatrics. 2016; 138(4), pii: e20160947.CrossRefGoogle ScholarPubMed
Agudo, J, Ayuso, E, Jimenez, V, et al. IGF-I mediates regeneration of endocrine pancreas by increasing beta cell replication through cell cycle protein modulation in mice. Diabetologia. 2008; 51(10), 1862–1872.CrossRefGoogle ScholarPubMed
Smith, FE, Rosen, KM, Villa-Komaroff, L, Weir, GC, Bonner-Weir, S. Enhanced insulin-like growth factor I gene expression in regenerating rat pancreas. Proc Natl Acad Sci U S A. 1991; 88(14), 6152–6156.CrossRefGoogle ScholarPubMed
Gatford, KL, Mohammad, SN, Harland, ML, et al. Impaired beta-cell function and inadequate compensatory increases in beta-cell mass after intrauterine growth restriction in sheep. Endocrinology. 2008; 149(10), 5118–5127.CrossRefGoogle Scholar
Mallol, C, Casana, E, Jimenez, V, et al. AAV-mediated pancreatic overexpression of Igf1 counteracts progression to autoimmune diabetes in mice. Mol Metab. 2017; 6(7), 664–680. doi: 10.1016/j.molmet.2017.1005.1007. eCollection 2017 JulCrossRefGoogle ScholarPubMed
Tinnion, R Gillone, J Cheetham, T Embleton, N. Preterm birth and subsequent insulin sensitivity: a systematic review. Arch Dis Child. 2013; 99(4), 362–368.CrossRefGoogle ScholarPubMed
Mears, K, McAuliffe, F, Grimes, H, Morrison, JJ. Fetal cortisol in relation to labour, intrapartum events and mode of delivery. J Obstet Gynaecol. 2004; 24(2), 129–132.CrossRefGoogle ScholarPubMed
Faxelius, G, Hägnevik, K, Lagercrantz, H, Lundell, B, Irestedt, L. Catecholamine surge and lung function after delivery. Arch Dis Child. 1983; 58(4), 262–266.CrossRefGoogle ScholarPubMed
Creange, JE, Anzalone, AJ, Potts, GO, Schane, HP. Win 32,729, a new, potent interceptive agent in rats and rhesus monkeys. Contraception. 1981; 24(3), 289–299.Google ScholarPubMed
Pattison, NS, Webster, MA, Phipps, SL, Anderson, AB, Gillmer, MD. Inhibition of 3 beta-hydroxysteroid dehydrogenase (3 beta-HSD) activity in first- and second-trimester human pregnancy and the luteal phase using epostane. Fertil Steril. 1984; 42(6), 875–881.CrossRefGoogle ScholarPubMed
Muhlhausler, BS, Bloomfield, FH, Gillman, MW. Whole animal experiments should be more like human randomized controlled trials. PLoS Biol. 2013; 11(2), e1001481.CrossRefGoogle ScholarPubMed
Supplementary material: PDF

Bansal et al. supplementary material

Figures S1-S2 and Table S1

Download Bansal et al. supplementary material(PDF)
PDF 73.4 KB