Maternal Diabetes Induces Increased Expression of Extracellular Matrix Components in Rat Embryos

Abstract

The mechanisms responsible for the increased incidence of congenital malformations in offspring of diabetic mothers are poorly understood. Because the abnormal metabolic milieu of diabetes induces in the adult organism increased synthesis of basement membrane components, and these molecules play a prominent role in morphogenesis, we investigated whether maternal diabetes or high glucose levels disturb extracellular matrix synthesis in rat embryos. In gestational day 11 embryos, maternal diabetes induced a small but significant increase in laminin B1 (127 ± 40% of control, mean ± SD, P < 0.02) but not in fibronectin mRNA (101 ± 26% of control). Day 12 embryos from diabetic mothers showed a larger increment in laminin B1 (179 ± 91% of control, P < 0.02) and also an increase in fibronectin mRNA (172 ± 73% of control, P < 0.02). A similar increase in the expression of fibronectin was observed in the kidneys and hearts of day 20 fetuses dissected from diabetic rats. High glucose levels mimicked in vitro the effects of maternal diabetes. Day 9 embryos cultured for 48 h in 50 mM D-glucose showed, akin to the day 11 embryos in vivo, an increase in laminin B1 mRNA (129 ± 47% of control) and no changes in fibronectin mRNA (106 ± 35% of control). The finding that maternal diabetes induces increased expression of extracellular matrix components in developing embryos establishes a link with the abnormalities occurring in the chronic complications of diabetes and proposes a new path of investigation for the mechanism of teratogenicity of the diabetic milieu.