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Maternal diabetes in vivo and high glucose concentration in vitro increases apoptosis in rat embryos
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. (Teratolog)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. (Teratolog)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. (Teratolog)
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology. (Teratolog)
2007 (English)In: Reproductive Toxicology, ISSN 0890-6238, E-ISSN 1873-1708, Vol. 23, no 1, 63-74 p.Article in journal (Refereed) Published
Abstract [en]

Apoptosis may be involved in diabetes-induced embryonic dysmorphogenesis. We estimated the occurrence of apoptosis in embryos of a rat model for diabetic pregnancy. We found decreased Bcl-2, increased Bax and cleaved Caspase 3 proteins in embryos from diabetic rats. Moreover, we found increased activation of Caspase 3 in cells from embryos previously exposed to a diabetes-like environment (in vivo, in vitro) compared to cells from control embryos, which was normalized by supplementation of N-acetylcysteine or apoptosis inhibitor. We detected increased propidium iodide uptake in embryonic cells exposed to maternal diabetes, a finding confirmed by vital staining. Additionally, we found increased dysmorphogenesis in embryos exposed to a diabetic environment in vivo and in vitro. Exposure to a diabetic milieu during organogenesis increases apoptosis in embryonic cells and dysmorphogenesis in embryos. Enhanced apoptotic rate may have a role in diabetic embryopathy by inducing disturbed embryonic maturation, increased rates of resorptions and congenital malformations.

Place, publisher, year, edition, pages
2007. Vol. 23, no 1, 63-74 p.
Keyword [en]
Apoptosis, Bax, Bcl-2, Caspase 3, Diabetes in pregnancy, Embryopathy, Rat
National Category
Medical and Health Sciences
Identifiers
URN: urn:nbn:se:uu:diva-95025DOI: 10.1016/j.reprotox.2006.08.009ISI: 000243772800007PubMedID: 17034987OAI: oai:DiVA.org:uu-95025DiVA: diva2:169078
Available from: 2006-11-02 Created: 2006-11-02 Last updated: 2011-02-15Bibliographically approved
In thesis
1. Teratogenicity Involved in Experimental Diabetic Pregnancy
Open this publication in new window or tab >>Teratogenicity Involved in Experimental Diabetic Pregnancy
2006 (English)Doctoral thesis, comprehensive summary (Other academic)
Abstract [en]

Maternal diabetes is associated with increased risk of growth disturbances and congenital malformations. The malformations rate in the offspring of diabetic mothers is 2-3 fold higher compared to infants of nondiabetic mothers. In this thesis we have investigated the role of the protein kinase C (PKC) pathway and the apoptotic machinery in embryopathy.

We investigated the involvement of PKC isoforms in the embryopathy of diabetic rat pregnancy. Embryos of diabetic rats showed altered activity and protein distribution of several PKC isoforms compared with embryos of normal rats. Using whole embryo culture we found increased activity of PKC-delta and PKC-zeta after 24h of culture and increased rate of malformations and growth retardation in embryos cultured in high glucose concentration compared to embryos cultured in low glucose concentration. Addition of α-cyano-4-cinnamic acid and N-acetylcysteine to the culture medium normalized malformations and growth retardations whereas specific PKC-inhibitors abolished malformations and partly restored the growth retardations. All treatment normalized glucose-induced increase of PKC activity.

Estimated occurrence of apoptosis in embryos of diabetic rats and in embryonic cells exposed to high glucose concentration showed increased rate of pro-apoptotic markers. The increased apoptosis in the high glucose exposed embryonic cells was normalized by supplementation of N-acetylcysteine or apoptosis inhibitor. Treatment with vitamin E and folic acid to diabetic pregnant rats decreased diabetes-induced malformations and resorptions, concomitant with normalization of apoptotic protein levels.

These results suggest that oxidative stress is augmented in embryos of diabetic rats and that it also plays a role in the activation of PKC and apoptosis. We used antioxidative treatment with beneficial effect although we could not completely abolish the embryonic demise; this may indicate that other mechanisms are involved in diabetic embryopathy. Further studies are needed to develop multi-nutrient dietary supplement to eliminate embryonic abnormalities induced by maternal diabetes.

Place, publisher, year, edition, pages
Uppsala: Acta Universitatis Upsaliensis, 2006. 57 p.
Series
Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Medicine, ISSN 1651-6206 ; 187
Keyword
Cell biology, Diabetes, Pregnancy, PKC, Apoptosis, Rat, Embryopathy, Vitamin E, Folic acid, CHC, NAC, Cellbiologi
Identifiers
urn:nbn:se:uu:diva-7203 (URN)91-554-6690-7 (ISBN)
Public defence
2006-11-25, B21, Biomedicinskt centrum, Uppsala, 10:15 (English)
Opponent
Supervisors
Available from: 2006-11-02 Created: 2006-11-02 Last updated: 2009-10-14Bibliographically approved

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