St. Louis, Dec. 1, 1998 -- A paper in the December issue of Nature Medicine suggests that diabetic women who are trying to get pregnant should be very careful about controlling their blood sugar levels. The study found that high glucose levels make embryonic cells kill themselves even before implantion into the womb. This loss of cells could help explain the higher rates of miscarriage and malformed babies among diabetic women.
"A lot of diabetic women figure they'll go to the doctor once they get pregnant," says lead author Kelle H. Moley, M.D. "But by that time, the damage may be done. So it's very important for them to tell their doctor they want to get pregnant so they can be monitored very closely from that point on."
Moley is a reproductive endocrinologist and instructor in obstetrics and gynecology at Washington University School of Medicine in St. Louis. She performed the study independently while she was a postdoctoral fellow in the laboratory of Mike M. Mueckler, Ph.D., professor of cell biology and physiology.
Diabetic women have up to eight times as many malformed babies as other women, and even if their blood sugar levels are under control by the time a baby's organs form, malformation rates are still two to three times higher than normal. "So I thought that high glucose might be killing embyronic cells very early, even before a woman knew she was pregnant," Moley says. "If that cell death was significant enough, it would cause a miscarriage. If only a few cells died, it would manifest itself later as a malformation, such as a heart and neural tube defect."
The National Institutes of Health does not permit human embryo research, so Moley tested her idea on mice, whose development has much in common with that of humans. Using blastocysts - the stage before implantation - she looked for signs of cell suicide, a process called apoptosis.
First she measured levels of a protein called Bax, which triggers apoptosis. Bax levels in blastocysts from diabetic mice or blastocysts cultured in high concentrations of glucose were five to 10 times higher than in those from nondiabetic mice. But when diabetic mice received insulin before they became pregnant, their blastocysts had normal Bax levels.
"So there seemed to be a link between high glucose levels and apoptosis, both in cultured blastocysts and blastocysts taken from mice," Moley says. She reasoned that embryos without Bax should be spared the harmful effects of glucose. Because male mice that lack both Bax genes are infertile, she mated males that had one copy of the gene with females that lacked both copies. Half of the embryos were resistant to glucose-induced apoptosis, as predicted.
Searching for other evidence that might implicate apoptosis, Moley looked for DNA fragmentation - suicidal cells chop up their DNA before they die. The glucose-exposed blastocysts had cut up about half of their DNA, whereas only about 10 percent of the DNA in the normal embryos or the Bax-deficient embryos was fragmented.
Moley also examined another cell death signal called ceramide. This lipid appeared to play a role in the glucose effect. A protein-chopping enzyme called caspase I also was involved.
"This study is one of the first to suggest that apoptosis before implantion may be responsible for later problems in development," Moley says.
Her findings also may be pertinent to nondiabetic women. "Even if we are not insulin-dependent diabetics, many of us have blood glucose fluctuations," she says. "And pregnancy itself causes a lot of carbohydrate changes very early on. Perhaps even subtle metabolic alterations during this early critical time in development have serious effects on pregnancy outcomes. So if you're thinking of getting pregnant, you might want to pass up the soda and candy bars."
Moley KH, Chi MM-Y, Knudson CM, Korsmeyer SJ, Mueckler MM. Hyperglycemia induces apoptosis in preimplantation embryos via cell death effector pathways. Nature Medicine, Dec. 1998.
Grants from the National Institutes of Health and the Berlex Foundation supported this research.
The full- and part-time faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals. The School of Medicine is one of the leading medical research, teaching and patient care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC Health System.
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Nature Medicine