Sexually dimorphic changes in the endocrine pancreas and skeletal muscle in young adulthood following intra-amniotic IGF-I treatment of growth-restricted fetal sheep.

Fetal growth restriction (FGR) is associated with decreased insulin secretory capacity and decreased insulin sensitivity in muscle in adulthood. We investigated whether intra-amniotic IGF-I treatment in late gestation mitigated the adverse effects of FGR on the endocrine pancreas and skeletal muscle at 18 mo of age. Singleton-bearing ewes underwent uterine artery embolization between 103 and 107 days of gestational age, followed by 5 once-weekly intra-amniotic injections of 360-&#xb5;g IGF-I (FGRI) or saline (FGRS) and were compared with an unmanipulated control group (CON). We measured offspring pancreatic endocrine cell mass and pancreatic and skeletal muscle mRNA expression at 18 mo of age (<i>n</i> = 7-9/sex/group). Total &#x3b1;-cell mass was increased &#x223c;225% in FGRI males versus CON and FGRS males, whereas &#x3b2;-cell mass was not different between groups of either sex. Pancreatic mitochondria-related mRNA expression was increased in FGRS females versus CON (<i>NRF1</i>, <i>MTATP6</i>, <i>UCP2</i>), and FGRS males versus CON (<i>TFAM</i>, <i>NRF1</i>, <i>UCP2</i>) but was largely unchanged in FGRI males versus CON. In skeletal muscle, mitochondria-related mRNA expression was decreased in FGRS females versus CON (<i>PPARGC1A</i>, TFAM, <i>NRF1</i>, <i>UCP2</i>, <i>MTATP6</i>), FGRS males versus CON (<i>NRF1</i> and <i>UCP2</i>), and FGRI females versus CON (<i>TFAM</i> and <i>UCP2</i>), with only <i>MTATP6</i> expression decreased in FGRI males versus CON. Although the window during which IGF-I treatment was delivered was limited to the final 5 wk of gestation, IGF-I therapy of FGR altered the endocrine pancreas and skeletal muscle in a sex-specific manner in young adulthood.<b>NEW &amp; NOTEWORTHY</b> Fetal growth restriction (FGR) is associated with compromised metabolic function throughout adulthood. Here, we explored the long-term effects of fetal IGF-I therapy on the adult pancreas and skeletal muscle. This is the first study demonstrating that IGF-I therapy of FGR has sex-specific long-term effects at both the tissue and molecular level on metabolically active tissues in adult sheep.