Effect of placental restriction and neonatal exendin-4 treatment on postnatal growth, adult body composition and in vivo glucose metabolism in the sheep

Intrauterine growth restriction (IUGR) increases risks 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. We therefore 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 F, 4 M) and placentally restricted pregnancies (PR; n = 13 F, 7 M), and in sheep from PR pregnancies that were treated with exendin-4 as neonates (daily s.c. injections of 1 nmol.kg(-1) exendin-4; PR+EX-4; n = 11 F, 7 M). 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 catch-up 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.Hong Liu, Christopher G Schultz, Miles J De Blasio, Anita M Peura, Gary K Heinemann, Himawan Harryanto, Damien S Hunter, Amy L Wooldridge, Karen L Kind, Lynne C. Giles, Rebecca A Simmons, Julie A Owens, Kathryn L Gatfor