Teratogenicity of 3-deoxyglucosone and diabetic embryopathy.

Abstract

The increased rate of embryonic dysmorphogenesis in diabetic pregnancy is correlated with the severity and duration of the concurrent hyperglycemia during early gestation. Whole embryo culture was used to investigate a possible association of hyperglycemia-induced disturbances of embryo development with tissue levels of the three alpha-oxoaldehydes: glyoxal, methylglyoxal, and 3-deoxyglucosone (3-DG). Rat embryos exposed to high glucose levels in vitro showed severe dysmorphogenesis and a 17-fold increased concentration of 3-DG compared with control embryos cultured in a low glucose concentration. Exogenous 3-DG (100 micromol/l) added to the medium of control cultures yielded an increased embryonic malformation rate and a 3-DG concentration similar to that of embryos cultured in high glucose. Addition of superoxide dismutase (SOD) to the culture medium decreased the malformation rates of embryos exposed to either high glucose or high 3-DG levels, but it did not decrease the high embryonic 3-DG concentrations caused by either agent. Our results implicate the potent glycating agent 3-DG as a teratogenic factor in diabetic embryopathy. In addition, the anti-teratogenic effect of SOD administration appears to occur downstream of 3-DG formation, suggesting that 3-DG accumulation leads to superoxide-mediated embryopathy.

Maternal Diabetes In Vivo and High Glucose In Vitro Diminish GAPDH Activity in Rat Embryos

“…However, attempts to block dysmorphogenesis by inhibiting aldose reductase have not been particularly successful (52)(53)(54). Evidence in favor of enhanced hexosamine pathway activity has been found in embryos of diabetic mice (55) as well as in the enhanced formation of the reactive glycosylating agent deoxyglucosone (56) in embryos subjected to high glucose concentration. The teratological potential of these pathways is currently under investigation.…”

3,4-Dideoxyglucosone-3-ene Induces Apoptosis in Renal Tubular Epithelial Cells

“…A role for 3,4-DGE in diabetes complications should also be explored. The concentration of several glucose degradation products (e.g., 3-DG) is increased in diabetic individuals (31,32). 3-DG levels are well correlated with plasma glucose and HbA 1c levels (18).…”

Altered gene expression with abnormal patterning of the telencephalon in embryos of diabetic Albino Swiss mice

“…Although several teratogenic factors such as sorbitol accumulation [51], myo-inositol deficiency [19], arachidonic acid deficiency [18], altered prostaglandin metabolism [52] and increased concentration of 3-deoxyglucosone [53] are altered in embryos of diabetic pregnancy, the mechanisms by which these abnormalities lead to dysmorphogenesis have not been determined. Only recently, it has been shown that oxidative stress induced by maternal diabetes could lead to neural tube defects by impairing the expression of genes that control developmental processes [23].…”