Diabetes, Vol 48, Issue 5 1138-1144, Copyright © 1999 by American Diabetes Association

ARTICLES

Significance of glutathione-dependent antioxidant system in diabetes-induced embryonic malformations

H Sakamaki, S Akazawa, M Ishibashi, K Izumino, H Takino, H Yamasaki, Y Yamaguchi, S Goto, Y Urata, T Kondo and S Nagataki
First Department of Internal Medicine, Atomic Disease Institute, Nagasaki University School of Medicine, Japan.

Hyperglycemia-induced embryonic malformations may be due to an increase in radical formation and depletion of intracellular glutathione (GSH) in embryonic tissues. In the past, we have investigated the role of the glutathione-dependent antioxidant system and GSH on diabetes-related embryonic malformations. Embryos from streptozotocin-induced diabetic rats on gestational day 11 showed a significantly higher frequency of embryonic malformations (neural lesions 21.5 vs. 2.8%, P<0.001; nonneural lesions 47.4 vs. 6.4%, P<0.001) and growth retardation than those of normal mothers. The formation of intracellular reactive oxygen species (ROS), estimated by flow cytometry, was increased in isolated embryonic cells of diabetic rats on gestational day 11. The concentration of intracellular GSH in embryonic tissues of diabetic pregnant rats on day 11 was significantly lower than that of normal rats. The activity of y-glutamylcysteine synthetase (gamma-GCS), the rate-limiting GSH synthesizing enzyme, in embryos of diabetic rats was significantly low, associated with reduced expression of gamma-GCS mRNA. Administration of buthionine sulfoxamine (BSO), a specific inhibitor of gamma-GCS, to diabetic rats during the period of maximal teratogenic susceptibility (days 6-11 of gestation) reduced GSH by 46.7% and increased the frequency of neural lesions (62.1 vs. 21.5%, P<0.01) and nonneural lesions (79.3 vs. 47.4%, P<0.01). Administration of GSH ester to diabetic rats restored GSH concentration in the embryos and reduced the formation of ROS, leading to normalization of neural lesions (1.9 vs. 21.5%) and improvement in nonneural lesions (26.7 vs. 47.4%) and growth retardation. Administration of insulin in another group of pregnant rats during the same period resulted in complete normalization of neural lesions (4.3 vs. 21.5%), nonneural lesions (4.3 vs. 47.4%), and growth retardation with the restoration of GSH contents. Our results indicate that GSH depletion and impaired responsiveness of GSH-synthesizing enzyme to oxidative stress during organogenesis may have important roles in the development of embryonic malformations in diabetes.
CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. R. Loeken Advances in Understanding the Molecular Causes of Diabetes-Induced Birth Defects Reproductive Sciences, January 1, 2006; 13(1): 2 - 10. [Abstract] [PDF]

				Z. Zhao and E. A. Reece Experimental Mechanisms of Diabetic Embryopathy and Strategies for Developing Therapeutic Interventions Reproductive Sciences, December 1, 2005; 12(8): 549 - 557. [Abstract] [PDF]

				C. A Hobbs, M. A Cleves, W. Zhao, S. Melnyk, and S J. James Congenital heart defects and maternal biomarkers of oxidative stress Am. J. Clinical Nutrition, September 1, 2005; 82(3): 598 - 604. [Abstract] [Full Text] [PDF]

				P. Wentzel, A. Ejdesjo, and U. J. Eriksson Maternal Diabetes In Vivo and High Glucose In Vitro Diminish GAPDH Activity in Rat Embryos Diabetes, May 1, 2003; 52(5): 1222 - 1228. [Abstract] [Full Text] [PDF]

				J. M. Burlingame, N. Esfandiari, R. K. Sharma, E. Mascha, and T. Falcone Total Antioxidant Capacity and Reactive Oxygen Species in Amniotic Fluid Obstet. Gynecol., April 1, 2003; 101(4): 756 - 761. [Abstract] [Full Text] [PDF]

				L. Pani, M. Horal, and M. R. Loeken Polymorphic Susceptibility to the Molecular Causes of Neural Tube Defects During Diabetic Embryopathy Diabetes, September 1, 2002; 51(9): 2871 - 2874. [Abstract] [Full Text] [PDF]

				A. F. Machado, E. F. Zimmerman, D. N. Hovland Jr., R. Weiss, and M. D. Collins Diabetic Embryopathy in C57BL/6J Mice: Altered Fetal Sex Ratio and Impact of the Splotch Allele Diabetes, May 1, 2001; 50(5): 1193 - 1199. [Abstract] [Full Text]