title: Effect of placental restriction and neonatal exendin-4 treatment on postnatal growth, adult body composition, and in vivo glucose metabolism in the sheep.
abstract: Intrauterine growth restriction (IUGR) increases the risk of adult type 2 diabetes (T2D) and obesity. Neonatal exendin-4 treatment can prevent diabetes in the IUGR rat, but whether this will be effective in a species where the pancreas is more mature at birth is unknown. Therefore, we evaluated the effects of neonatal exendin-4 administration after experimental restriction of placental and fetal growth on growth and adult metabolic outcomes in sheep. Body composition, glucose tolerance, and insulin secretion and sensitivity were assessed in singleton-born adult sheep from control (CON; n = 6 females and 4 males) and placentally restricted pregnancies (PR; n = 13 females and 7 males) and in sheep from PR pregnancies that were treated with exendin-4 as neonates (daily sc injections of 1 nmol/kg exendin-4; PR + exendin-4; n = 11 females and 7 males). Placental restriction reduced birth weight (by 29%) and impaired glucose tolerance in the adult but did not affect adult adiposity, insulin secretion, or insulin sensitivity. Neonatal exendin-4 suppressed growth during treatment, followed by delayed catchup growth and unchanged adult adiposity. Neonatal exendin-4 partially restored glucose tolerance in PR progeny but did not affect insulin secretion or sensitivity. Although the effects on glucose tolerance are promising, the lack of effects on adult body composition, insulin secretion, and insulin sensitivity suggest that the neonatal period may be too late to fully reprogram the metabolic consequences of IUGR in species that are more mature at birth than rodents.
authors.affiliation: Robinson Research Institute and School of Paediatrics and Reproductive Health.
authors.forename: Hong
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Nuclear Medicine, PET and Bone Densitometry, Royal Adelaide Hospital, Adelaide, South Australia, Australia; and.
authors.forename: Christopher G
authors.initials: CG
authors.lastname: Schultz
authors.affiliation: Robinson Research Institute and School of Paediatrics and Reproductive Health.
authors.forename: Miles J
authors.initials: MJ
authors.lastname: De Blasio
authors.affiliation: Robinson Research Institute and School of Paediatrics and Reproductive Health.
authors.forename: Anita M
authors.initials: AM
authors.lastname: Peura
authors.affiliation: Robinson Research Institute and School of Paediatrics and Reproductive Health.
authors.forename: Gary K
authors.initials: GK
authors.lastname: Heinemann
authors.affiliation: Robinson Research Institute and School of Paediatrics and Reproductive Health.
authors.forename: Himawan
authors.initials: H
authors.lastname: Harryanto
authors.affiliation: Robinson Research Institute and School of Paediatrics and Reproductive Health, School of Animal and Veterinary Sciences, and.
authors.forename: Damien S
authors.initials: DS
authors.lastname: Hunter
authors.affiliation: Robinson Research Institute and School of Paediatrics and Reproductive Health.
authors.forename: Amy L
authors.initials: AL
authors.lastname: Wooldridge
authors.affiliation: Robinson Research Institute and School of Animal and Veterinary Sciences, and.
authors.forename: Karen L
authors.initials: KL
authors.lastname: Kind
authors.affiliation: School of Population Health, University of Adelaide, Adelaide, South Australia, Australia;
authors.forename: Lynne C
authors.initials: LC
authors.lastname: Giles
authors.affiliation: University of Pennsylvania Medical School, Philadelphia, Pennsylvania.
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Simmons
authors.affiliation: Robinson Research Institute and School of Paediatrics and Reproductive Health.
authors.forename: Julie A
authors.initials: JA
authors.lastname: Owens
authors.affiliation: Robinson Research Institute and School of Paediatrics and Reproductive Health, kathy.gatford@adelaide.edu.au.
authors.forename: Kathryn L
authors.identifier: http://orcid.org/0000-0002-2823-3004
authors.initials: KL
authors.lastname: Gatford
mesh_terms: D050154:Adiposity / Q000187:drug effects*; D000818:Animals; D000831:Animals, Newborn; D001786:Blood Glucose / Q000187:drug effects* / Q000378:metabolism; D001823:Body Composition / Q000187:drug effects; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism* / Q000517:prevention & control; D004195:Disease Models, Animal; D004717:Endometrium / Q000601:surgery; D000077270:Exenatide; D005260:Female; D005317:Fetal Growth Retardation / Q000378:metabolism*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D000078790:Insulin Secretion; D010455:Peptides / Q000494:pharmacology*; D011247:Pregnancy; D011897:Random Allocation; D012756:Sheep; D014688:Venoms / Q000494:pharmacology*
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D010455:Peptides; D014688:Venoms; D000077270:Exenatide
keywords: body composition; exendin-4; glucose tolerance; insulin action; intrauterine growth restriction