In vivo evidence for the existence of a threshold for hyperglycemia-induced major fetal malformations: relevance to the etiology of diabetic teratogenesis.

The present study was carried out to evaluate whether hyperglycemia-induced major fetal anomalies are thresholded phenomena. Streptozotocin (STZ)-treated female ICR mice were examined on day 19 of pregnancy by methods routinely used in Segment II teratological studies. Simultaneously, the glucose and hemoglobin A1c (HbA1c) levels in maternal-blood were measured and mice with glucose levels > 9.5 mmol/l (mean + 3 SD) were considered to be diabetic. The occurrence of litters with fetuses having gross structural anomalies was clearly associated with glucose levels > 27.8 mmol/l. A wide range of HbA1c levels (between 6 and 18 SD above the mean) were observed, within which only single malformed fetuses were found in the litters of diabetic females. A decreased pregnancy rate in diabetic ICR mice was associated with glucose levels > 16.7 mmol/l and with HBA1c levels > 6 SD above the mean. The results of this study suggest that there is a threshold glucose level associated with a clear increase of the number of litters with severely malformed fetuses in diabetic ICR mice. Results of this study also suggest the existence of HbA1c-associated factors determining, along with glucose, the teratogenic response of ICR mice to diabetes. The interpretation of results obtained in terms of the multifactorial/threshold model leads to the hypothesis that the teratogenic potential of diabetes may consist of two components; one associated with 'direct' teratogens perturbing developmental processes in embryos at a 'critical moment' in organogenesis, and a second component, associated with a direct or indirect influence of the diabetic environment on developmental processes in the preimplantation embryos.