Mechanisms and Pathophysiological Significance of Insulin Resistance in Offspring With Intrauterine Growth Restriction Mediated by Hepatic GR/miR-1224 Programming.

Insulin resistance (IR) has fetal origin and gender preference. Here we traced glucose-insulin phenotypical changes of intrauterine growth restriction (IUGR) female offspring at different ages and explore the mechanism. The IUGR model was established by prenatal caffeine exposure (PCE): dams were orally administered caffeine [(30, 120 mg(kg.d)] from gestational day 9 to 20. PCE offspring presented decreased basal serum glucose, insulin, and insulin resistance index, accompanied by improved glucose tolerance and insulin sensitivity. However, after postnatal week (PW) 36, all these changes were gradually reversed in age-dependent manner and finally developed glucose intolerance and IR. Meanwhile, hepatic insulin signaling and glucose uptake were also gone from enhancement to inhibition. Mechanistically, a negative regulation of blood glucocorticoid on hepatic insulin signaling and glucose uptake via glucocorticoid receptor (GR)/miR-1224 signaling in the PCE offspring was programmed in utero. Postnatally, the persistent decreased blood glucocorticoid and consequent elevated hepatic glucose uptake caused over-accumulation of advanced glycation end products (AGEs). AGEs promoted inflammation by interacting with its receptor and conversely repressed hepatic insulin signaling and glucose uptake after PW36. Conclusively, PCE-induced IUGR offspring exhibited a shift from insulin sensitization to IR, which may be related to hepatic insulin signaling changes via GR/miR-1224 programming.