Diabetologisk disputation

ACTA UNIVERSITATIS UPSALIENSIS
Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine 704
Distributor: Uppsala University Library, Uppsala, Sweden

C. Martin Simán

Congenital Malformations in Experimental Diabetic Pregnancy
Aetiology and Antioxidative Treatment

Dissertation in Medical Cell Biology to be publicly examined in the lecture hall B21, Biomedical Centre, Uppsala University, on September 19, 1997, at 9.15 a.m., for the Degree of Doctor of Medical Science. The examination will be conducted in English.

ABSTRACT
Simán, C.M. 1997. Congenital malformations in experimental diabetic pregnancy. Aetiology and antioxidative treatment. Acta Universitatis Upsaliensis. 704. 55 pp. Uppsala. ISBN 91-554-4023-1.

Diabetes mellitus in pregnancy causes congenital malformations in the offspring. The aim of this work was to characterize biochemical and morphologic anomalies in the conceptus of an animal model of diabetic pregnancy. In addition, a preventive treatment against diabetes-induced dysmorphogenesis was developed.
Congenital cataract was often found in the offspring of diabetic rats. The fetal lenses had increased water accumulation, sorbitol concentration and aldose reductase activity compared to control lenses. The results suggest that the cataracts form via osmotic attraction of water due to sorbitol accumulation in the fetal lens.
Another set of malformations, with possible neural crest cell origin, occurred frequently in offspring of diabetic rats. These included low set ears, micrognathia, hypoplasia of the thymus, thyroid and parathyroid glands, as well as anomalies of the heart and great vessels. Furthermore, diabetes caused intrauterine death and resorptions more frequently in the late part of gestation.
When the pregnant diabetic rats were treated with the antioxidants butylated hydroxytoluene, vitamin E or vitamin C, the occurrence of gross malformations was reduced from approximately 25% to less than 8%, and late resorptions from 17% to 7%. This suggests that an abnormal handling of reactive oxygen species (ROS) is involved in diabetes-induced dysmorpho-genesis in vivo. Indeed, an increased concentration of lipid peroxides, indicating damage caused by ROS, was found in fetuses of diabetes rats. In addition, embryos of diabetic rats had low concentrations of the antioxidant vitamin E compared to control embryos. These biochemical alterations were normalized by vitamin E treatment of the pregnant diabetic rats.
The antioxidants are likely to have prevented ROS injury in the em-bryos of the diabetic rats, in particular in the neural crest cells, thereby normal-izing embryonic development. These results provide a rationale for develop-ing new anti-teratogenic treatments for pregnant women with diabetes mellitus.

Key words: Diabetes, pregnancy, teratology, malformations, embryo, fetus, cataract, sorbitol, antioxidants, butylated hydroxytoluene, vitamin E, vitamin C, TBARS, neural crest cells.

C. Martin Simán, Department of Medical Cell Biology, Uppsala University, P.O. Box 571, S-751 23 Uppsala, Sweden