Hyperglycemia induces apoptosis in pre-implantation embryos through cell death effector pathways

Abstract

Although perinatal mortality rates have improved for pregnant diabetic women because of insulin therapy and tight metabolic control, infants of diabetics still experience significantly higher rates of congenital malformations and spontaneous miscarriages compared with those of non-diabetic women. Our results here indicate that hyperglycemic conditions, either in vivo or in vitro, modulate the expression of an apoptosis regulatory gene as early as the pre-implantation blastocyst stage in the mouse. Apoptosis in the mammalian pre-implantation blastocyst is a normal process, thought to protect the early embryo by eliminating abnormal cells. Here we demonstrate that expression of Bax, a Bcl-2-like protein, is increased at the blastocyst stage in the presence of high concentrations of glucose, and that these changes correlate morphologically with increased DNA fragmentation. Expression of Bax and caspase are necessary for this in vitro glucose-induced apoptotic event, and ceramide is involved in mediating this embryotoxic effect of glucose. We also show that these apoptotic cellular changes can be prevented in vivo by treating hyperglycemic mice with insulin before and immediately after conception. These findings emphasize the importance of tight glycemic control in diabetic women at the earliest stages after conception.

The facilitative glucose transporter GLUT3: 20 years of distinction

“…They proposed that, if this threshold was crossed, an apoptotic pathway was triggered leading to loss of key cells required for optimal survival (88,89). These findings all point to GLUT3 being a critical transporter protein required for this stage of development.…”

“…These findings were consistent with those of Pantaleon et al (99), in which downregulation with antisense oligoneucletides induced a similar decrease in glucose uptake. In addition, Moley et al demonstrated increased apoptosis and an abnormal metabolic profile (25,88). In vitro culture in high glucose concentrations induced the same decrease in GLUT3 expression and when transferred into recipient mice, these embryos displayed intrauterine growth retardation and a high incidence of fetal resorptions (133).…”

The impact of obesity on egg quality

“…Hyperglycemic conditions either in-vivo or in-vitro cause downregulation of glucose transporters, decreased glucose transport into cells, abnormal metabolism, and increased apoptosis in cells of preimplantation embryos [91][92][93]. This hyperglycemia-induced apoptosis of progenitor cells in the embryo can affect differentiation of the remaining cells, manifesting later as malformations or miscarriages.…”

Transgenic mice overproducing human thioredoxin-1, an antioxidative and anti-apoptotic protein, prevents diabetic embryopathy

“…Furthermore, enhanced production of ROS is reportedly an important stimulus in the induction of mitochondrial transition, caspase activation and apoptosis [23,24]. Moreover, hyperglycaemia induces apoptosis in early organogenesis in pre-and post-implantation rodent embryos through cell-death effector pathways [25][26][27][28][29]. Also, neural tube defects (NTDs) are associated with apoptosis in the offspring of diabetic mice [30,31].…”