ABSTRACT
The heterozygous C57BLKS-Leprdb/ mouse is a genetic model of spontaneous GDM with features closely resembling those found in the human GDM. Beginning in late pregnancy, db/ mice develop impaired glucose tolerance (IGT) associated with hyperinsulinemia and extreme insulin resistance compared to wild-type / mothers. After delivery, IGT recovers and plasma glucose and insulin levels return to normal. The newborn fetuses from db/ mothers have higher insulin, normal to low glucose, increased birth and placental weight, and greater susceptibility to dietary-induced obesity compared to offspring from wild-type / mothers. This occurs in both / and db/ offsprings, suggesting that fetal imprinting of metabolism occurs in utero as a consequence of the maternal diabetic environment. Maternal insulin resistance in GDM is due to a novel mechanism for resistance including: (1) defects in tyrosine phosphorylation of insulin receptor without change of insulin receptor protein level, (2) low level of IRS-1 protein and increased serine phosphorylation, (3) increased expression and abnormal distribution of PI 3-kinase, Akt, and p70S6 kinase in skeletal muscle. These changes are unique to pregnancy, and are implicated as a mechanism for increased serine phosphorylation of IRS-1 and its degradation. Studies also show that improving maternal insulin resistance by overexpressing maternal GLUT4 in skeletal muscle reduces nutrient flux to fetus and improves fetal development. Reducing excess energy intake in db/ mice during pregnancy also prevents spontaneous GDM and fetal macrosomia. However, leptin administration during gestation suggests that there are other factors beside maternal glucose concentration that determine the growth of the fetus. Thus, the db/ mouse model of spontaneous GDM is a useful model for understanding factors that trigger excess insulin resistance in pregnancy, promote fetal overgrowth, and lead to imprinting of fetal and adult metabolism.
