Liu Hong, Schultz Christopher G, De Blasio Miles J, Peura Anita M, Heinemann Gary K, Harryanto Himawan, Hunter Damien S, Wooldridge Amy L, Kind Karen L, Giles Lynne C, Simmons Rebecca A, Owens Julie A, Gatford Kathryn L
Robinson Research Institute and School of Paediatrics and Reproductive Health.
Department of Nuclear Medicine, PET and Bone Densitometry, Royal Adelaide Hospital, Adelaide, South Australia, Australia; and.
Am J Physiol Endocrinol Metab. 2015 Sep 15;309(6):E589-600. doi: 10.1152/ajpendo.00487.2014. Epub 2015 Jul 28.
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.
宫内生长受限（IUGR）会增加成年后患2型糖尿病（T2D）和肥胖症的风险。新生大鼠注射艾塞那肽-4可预防IUGR大鼠患糖尿病，但在出生时胰腺更成熟的物种中是否有效尚不清楚。因此，我们评估了在实验性限制胎盘和胎儿生长后，新生羊注射艾塞那肽-4对其生长及成年后代谢结局的影响。对单胎出生的成年羊进行了身体成分、葡萄糖耐量、胰岛素分泌和敏感性评估，这些羊来自对照组（CON；6只雌性和4只雄性）、胎盘受限妊娠组（PR；13只雌性和7只雄性）以及PR妊娠组中新生期接受艾塞那肽-4治疗的羊（每天皮下注射1 nmol/kg艾塞那肽-4；PR + 艾塞那肽-4；11只雌性和7只雄性）。胎盘受限会降低出生体重（降低29%），并损害成年羊的葡萄糖耐量，但不影响成年羊的肥胖程度、胰岛素分泌或胰岛素敏感性。新生期注射艾塞那肽-4在治疗期间会抑制生长，随后出现生长追赶延迟，成年羊肥胖程度不变。新生期注射艾塞那肽-4可部分恢复PR后代的葡萄糖耐量，但不影响胰岛素分泌或敏感性。尽管对葡萄糖耐量的影响很有前景，但对成年羊身体成分、胰岛素分泌和胰岛素敏感性缺乏影响表明，在出生时比啮齿动物更成熟的物种中，新生期可能为时已晚，无法完全重新编程IUGR的代谢后果。
