Intrauterine growth restriction (IUGR) increases the risk of developing type 2 diabetes, in part through insulin resistance, which emerges after enhanced insulin sensitivity early in life. Why this occurs is unknown and we hypothesized that IUGR alters expression and actions of microRNA. MicroRNA is a small non-coding RNA that can co-ordinately regulate many molecules and pathways, in insulin sensitive tissues of offspring.
Placental restriction (PR) and IUGR was induced in rats by bilateral uterine vessel ligation, at day 18 of pregnancy to restrict fetal growth. Insulin secretion and sensitivity assessed in vivo in adult offspring (at 3 and 6 months of age). Expression of selected insulin signalling and related molecules in liver, skeletal muscle and omental fat in older offspring was analysed by qRT-PCR. MicroRNA expression was analysed by Exiqon miRCURY arrays v11 and qRT-PCR. Predicted targets were identified by miRecords database then subjected to Ingenuity Pathway Analysis.
PR induces insulin deficiency in young adult male offspring, which persists, with later onset in females. PR increases insulin sensitivity in young adult female offspring which also persists, with no effect in males. In older offspring, PR reduces hepatic expression of insr, p110b and Slc2a2 and skeletal muscle expression of insr and p110b in males; and reduces hepatic expression of p110β but increases that of p85a in females, with no changes in skeletal muscle.
PR increased microRNA expression in insulin sensitive tissues in older offspring only (liver: miR-126, miR-199b; skeletal muscle: rno-451) and in fat of males only (miR-16, 18a, 19b, 20b, 21, 106a, 142-3p). Their predicted targets include insulin signallers and other molecules regulating metabolism, and functions including lipid metabolism, molecular transport and small molecule biochemistry.
PR alters expression of microRNAs in insulin sensitive tissues in older offspring, which may contribute to changes in insulin signalling, impaired lipid and metabolic control.