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Effects of maternal periconceptional undernutrition in sheep on offspring glucose–insulin axis function into adulthood

Published online by Cambridge University Press:  20 November 2020

Mark H. Oliver
Liggins Institute, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
Frank H. Bloomfield
Liggins Institute, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
Amita Bansal
Liggins Institute, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
Hui Hui Phua
Liggins Institute, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
Eric B. Thorstensen
Liggins Institute, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
Jane E. Harding
Liggins Institute, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
Anne L. Jaquiery*
Liggins Institute, University of Auckland, Private Bag 92019, Auckland, 1142, New Zealand
Address for correspondence: Anne L. Jaquiery, Liggins Institute, University of Auckland, Private Bag 92019, Auckland1142, New Zealand. Email:


Maternal periconceptional undernutrition (PCUN) affected fetal pancreatic maturation in late gestation lambs and impaired glucose tolerance in 10-month-old sheep. To examine the importance of the timing of maternal undernutrition around conception, a further cohort was born to PCUN ewes [undernourished for 61 d before conception (PreC), 30 d after conception (PostC), or 61 d before until 30 d after conception (PrePostC)], or normally fed ewes (Control) (n = 15–20/group). We compared glucose tolerance, insulin secretion, and sensitivity at 36 months of age. We also examined protein expression of insulin signalling proteins in muscle from these animals and in muscle from a fetal cohort (132 d of gestation; n = 7–10/group). Adult PostC and PrePostC sheep had higher glucose area under the curve than Controls (P = 0.07 and P = 0.02, respectively), whereas PreC sheep were similar to Controls (P = 0.97). PostC and PrePostC had reduced first-phase insulin secretion compared with Control (P = 0.03 and P = 0.02, respectively). PreC was similar to Control (P = 0.12). Skeletal muscle SLC2A4 protein expression in PostC and PrePostC was increased 19%–58% in fetuses (P = 0.004), but decreased 39%–43% in adult sheep (P = 0.003) compared with Controls. Consistent with this, protein kinase C zeta (PKCζ) protein expression tended to be increased in fetal (P = 0.09) and reduced in adult (P = 0.07) offspring of all PCUN ewes compared with Controls. Maternal PCUN alters several aspects of offspring glucose homeostasis into adulthood. These findings suggest that maternal periconceptional nutrition has a lasting impact on metabolic homeostasis of the offspring.

Original Article
© The Author(s), 2020. Published by Cambridge University Press in association with International Society for Developmental Origins of Health and Disease

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Current address: ANU Medical School, John Curtin School of Medical Research, ANU College of Health and Medicine, The Australian National University, Canberra, ACT, 2601, Australia.


Morrison, JL, Regnault, TR. Nutrition in pregnancy: optimising maternal diet and fetal adaptations to altered nutrient supply. Nutrients. 2016; 8(6), 342.CrossRefGoogle ScholarPubMed
Rando, OJ, Simmons, RA. I’m eating for two: parental dietary effects on offspring metabolism. Cell. 2015; 161(1), 93105.CrossRefGoogle ScholarPubMed
Schulz, LC. The Dutch Hunger Winter and the developmental origins of health and disease. Proc Natl Acad Sci U S A. 2010; 107(39), 1675716758.CrossRefGoogle Scholar
Roseboom, TJ, van der Meulen, JH, Ravelli, AC, Osmond, C, Barker, DJ, Bleker, OP. Effects of prenatal exposure to the Dutch famine on adult disease in later life: an overview. Mol Cell Endocrinol. 2001; 185(1–2), 9398.CrossRefGoogle ScholarPubMed
Joshi, S, Garole, V, Daware, M, Girigosavi, S, Rao, S. Maternal protein restriction before pregnancy affects vital organs of offspring in Wistar rats. Metabolism. 2003; 52(1), 1318.CrossRefGoogle ScholarPubMed
Edwards, LJ, McMillen, IC. Periconceptional nutrition programs development of the cardiovascular system in the fetal sheep. Am J Physiol Regul Integr Comp Physiol. 2002; 283(3), R669679.CrossRefGoogle ScholarPubMed
Rumball, CW, Harding, JE, Oliver, MH, Bloomfield, FH. Effects of twin pregnancy and periconceptional undernutrition on maternal metabolism, fetal growth and glucose-insulin axis function in ovine pregnancy. J Physiol. 2008; 586(5), 13991411.CrossRefGoogle ScholarPubMed
Rattanatray, L, MacLaughlin, SM, Kleemann, DO, Walker, SK, Muhlhausler, BS, McMillen, IC. Impact of maternal periconceptional overnutrition on fat mass and expression of adipogenic and lipogenic genes in visceral and subcutaneous fat depots in the postnatal lamb. Endocrinology. 2010; 151(11), 51955205.CrossRefGoogle ScholarPubMed
Watkins, AJ, Wilkins, A, Cunningham, C, et al. Low protein diet fed exclusively during mouse oocyte maturation leads to behavioural and cardiovascular abnormalities in offspring. J Physiol. 2008; 586(8), 22312244.CrossRefGoogle ScholarPubMed
Oliver, MH, Hawkins, P, Breier, BH, Van Zijl, PL, Sargison, SA, Harding, JE. Maternal undernutrition during the periconceptual period increases plasma taurine levels and insulin response to glucose but not arginine in the late gestational fetal sheep. Endocrinology. 2001; 142(10), 45764579.CrossRefGoogle Scholar
Rumball, CW, Bloomfield, FH, Oliver, MH, Harding, JE. Different periods of periconceptional undernutrition have different effects on growth, metabolic and endocrine status in fetal sheep. Pediatr Res. 2009; 66(6), 605613.CrossRefGoogle Scholar
Smith, NA, McAuliffe, FM, Quinn, K, Lonergan, P, Evans, AC. The negative effects of a short period of maternal undernutrition at conception on the glucose-insulin system of offspring in sheep. Anim Reprod Sci. 2010; 121(1–2), 94100.CrossRefGoogle Scholar
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), 409413.CrossRefGoogle ScholarPubMed
Kenyon, PR, Maloney, SK, Blache, D. Review of sheep body condition score in relation to production characteristics. NZ J Agric Research. 2014; 57(1), 3864.CrossRefGoogle Scholar
Oliver, MH, Hawkins, P, Harding, JE. Periconceptional undernutrition alters growth trajectory and metabolic and endocrine responses to fasting in late-gestation fetal sheep. Pediatr Res. 2005; 57(4), 591598.CrossRefGoogle Scholar
Jaquiery, AL, Oliver, MH, Bloomfield, FH, Harding, JE. Periconceptional events perturb postnatal growth regulation in sheep. Pediatr Res. 2011; 70(3), 261266.CrossRefGoogle ScholarPubMed
DeFronzo, RA, Tobin, JD, Andres, R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979; 237(3), E214223.Google 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), 37633776.CrossRefGoogle ScholarPubMed
Oliver, MH, Harding, JE, Breier, BH, Evans, PC, Gluckman, PD. Glucose but not a mixed amino acid infusion regulates plasma insulin-like growth factor-I concentrations in fetal sheep. Pediatr Res. 1993; 34(1), 6265.CrossRefGoogle Scholar
Jaquiery, AL, Oliver, MH, Honeyfield-Ross, M, Harding, JE, Bloomfield, FH. Periconceptional undernutrition in sheep affects adult phenotype only in males. J Nutr Metab. 2012; 2012, 123610.CrossRefGoogle ScholarPubMed
Nicholas, LM, Morrison, JL, Rattanatray, L, et al. Differential effects of exposure to maternal obesity or maternal weight loss during the periconceptional period in the sheep on insulin signalling molecules in skeletal muscle of the offspring at 4 months of age. PLoS One. 2013; 8(12), e84594.CrossRefGoogle ScholarPubMed
Taniguchi, CM, Emanuelli, B, Kahn, CR. Critical nodes in signalling pathways: insights into insulin action. Nat Rev Mol Cell Biol. 2006; 7(2), 8596.CrossRefGoogle ScholarPubMed
Klip, A, Paquet, MR. Glucose transport and glucose transporters in muscle and their metabolic regulation. Diabetes Care. 1990; 13(3), 228243.CrossRefGoogle ScholarPubMed
DeFronzo, RA, Tripathy, D. Skeletal muscle insulin resistance is the primary defect in type 2 diabetes. Diabetes Care. 2009; 32 (Suppl 2), S157163.CrossRefGoogle ScholarPubMed
Huang, S, Czech, MP. The GLUT4 glucose transporter. Cell Metab. 2007; 5(4), 237252.CrossRefGoogle ScholarPubMed
Saltiel, AR, Kahn, CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001; 414(6865), 799806.CrossRefGoogle ScholarPubMed
Farese, RV, Sajan, MP, Standaert, ML. Insulin-sensitive protein kinases (atypical protein kinase C and protein kinase B/Akt): actions and defects in obesity and type II diabetes. Exp Biol Med (Maywood). 2005; 230(9), 593605.CrossRefGoogle ScholarPubMed
Limesand, SW, Rozance, PJ, Zerbe, GO, Hutton, JC, Hay, WW Jr. Attenuated insulin release and storage in fetal sheep pancreatic islets with intrauterine growth restriction. Endocrinology. 2006; 147(3), 14881497.CrossRefGoogle ScholarPubMed
Ozanne, SE, Wang, CL, Coleman, N, Smith, GD. Altered muscle insulin sensitivity in the male offspring of protein-malnourished rats. Am J Physiol. 1996; 271(6 Pt 1), E11281134.Google ScholarPubMed
De Blasio, MJ, Gatford, KL, McMillen, IC, Robinson, JS, Owens, JA. Placental restriction of fetal growth increases insulin action, growth, and adiposity in the young lamb. Endocrinology. 2007; 148(3), 13501358.CrossRefGoogle ScholarPubMed
Ozanne, SE, Jensen, CB, Tingey, KJ, Storgaard, H, Madsbad, S, Vaag, AA. Low birthweight is associated with specific changes in muscle insulin-signalling protein expression. Diabetologia. 2005; 48(3), 547552.CrossRefGoogle ScholarPubMed
Bloomfield, FH, Oliver, MH, Hawkins, P, et al. Periconceptional undernutrition in sheep accelerates maturation of the fetal hypothalamic-pituitary-adrenal axis in late gestation. Endocrinology. 2004; 145(9), 42784285.CrossRefGoogle ScholarPubMed
Bloomfield, FH, Oliver, MH, Hawkins, P, et al. A periconceptional nutritional origin for noninfectious preterm birth. Science. 2003; 300(5619), 606.CrossRefGoogle ScholarPubMed
Oliver, MH, Bloomfield, FH, Jaquiery, AL, Todd, SE, Thorstensen, EB, Harding, JE. Periconceptional undernutrition suppresses cortisol response to arginine vasopressin and corticotropin-releasing hormone challenge in adult sheep offspring. J Dev Orig Health Dis. 2012; 3(1), 5258.CrossRefGoogle ScholarPubMed
Donovan, EL, Hernandez, CE, Matthews, LR, et al. Periconceptional undernutrition in sheep leads to decreased locomotor activity in a natural environment. J Dev Orig Health Dis. 2013; 4(4), 296299.CrossRefGoogle Scholar
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