Effects of Interrupted Insulin Treatment on Fetal Outcome of Pregnant Diabetic Rats

Streptozocin-induced diabetic female rats became normoglycemic after subcutaneous insertion of insulin-releasing osmotic minipumps. These female rats were mated with normal males from the same Sprague-Dawley substrain. In this substrain, the offspring of diabetic rats show a markedly increased congenital malformation rate compared with fetuses of nondiabetic rats. The pregnant diabetic rats were subjected to removal and insertion of pumps at defined gestational days that marked the beginning or end of a 2- or 4-day period of insulin withdrawal. Evaluation of the offspring on day 20 of pregnancy included fetal/placental weights, estimated number of implants, resorptions, and morphological assessment of congenital malformations. Resorptions occurred in all interruption groups, but malformations were found only in animals with insulin withdrawal on gestational days 4–8, 6–8, 6–10, 8–10, and 8–12. The highest resorption (42%) and malformation (17%) rates were found in the rats subjected to insulin withdrawal during gestational days 6–10. Because manifestly diabetic rats with no insulin treatment showed similar resorption (39%) and malformation (17%) rates, this study suggests that a teratogenic period in diabetic rat pregnancy occurs during gestational days 6–10, a period corresponding to postconceptional wk 2–4 in human pregnancy. Interruption of insulin treatment induced similar maternal weight loss and similar maternal serum concentrations of D-glucose, cholesterol, urea, and creatinine in rats with and without malformed offspring. Although the teratogenic agents of diabetic pregnancy in this animal model remain to be identified, the simultaneously high levels of serum β-hydroxybutyrate and triglycerides in the rats with the highest malformation rate suggest that the teratogenic environment may include a severe disturbance in maternal lipid metabolism in addition to glucose dysregulation.