Maternal Diabetes Leads to Unphysiological High Lipid Accumulation in Rabbit Preimplantation Embryos

Schindler, Maria; Pendzialek, Mareike; Plösch, Torsten; Seyring, Stefanie; Gürke, Jacqueline; Haucke, Elisa; Knelangen, Julia M.; Fischer, Bernd; Santos, Anne Navarrete

doi:10.1210/en.2013-1760

Cited by 19 publications

(25 citation statements)

References 96 publications

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“…Thus, combined results lead to the suggestion that p62 and S6K1 have antagonistic functions in pathways controlling adipogenesis and obesity. The massive lipid accumulation in blastocysts developed under diabetic conditions with a simultaneously increased ratio of nuclear vs cytoplasmatic SREBP1 shown in a previous study (Schindler et al 2013) could therefore arise from higher mTORC1 signalling and decreased p62 levels in these blastocysts.…”

Section: Enhanced Mtorc1 Signalling In Diabetic Pregnancymentioning

confidence: 74%

Maternal diabetes promotes mTORC1 downstream signalling in rabbit preimplantation embryos

Gürke¹,

Schindler²,

Pendzialek³

et al. 2016

Reproduction

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The mammalian target of rapamycin complex 1 (mTORC1) is known to be a central cellular nutrient sensor and master regulator of protein metabolism; therefore, it is indispensable for normal embryonic development. We showed previously in a diabetic pregnancy that embryonic mTORC1 phosphorylation is increased in case of maternal hyperglycaemia and hypoinsulinaemia. Further, the preimplantation embryo is exposed to increased L-leucine levels during a diabetic pregnancy. To understand how mTOR signalling is regulated in preimplantation embryos, we examined consequences of L-leucine and glucose stimulation on mTORC1 signalling and downstream targets in in vitro cultured preimplantation rabbit blastocysts and in vivo. High levels of L-leucine and glucose lead to higher phosphorylation of mTORC1 and its downstream target ribosomal S6 kinase 1 (S6K1) in these embryos. Further, L-leucine supplementation resulted in higher embryonic expression of genes involved in cell cycle (cyclin D1; CCND1), translation initiation (eukaryotic translation initiation factor 4E; EIF4E), amino acid transport (large neutral amino acid transporter 2; Lat2: gene SLC7A8) and proliferation (proliferating cell nuclear antigen; PCNA) in a mTORC1-dependent manner. Phosphorylation of S6K1 and expression patterns of CCND1 and EIF4E were increased in embryos from diabetic rabbits, while the expression of proliferation marker PCNA was decreased. In these embryos, protein synthesis was increased and autophagic activity was decreased. We conclude that mammalian preimplantation embryos sense changes in nutrient supply via mTORC1 signalling. Therefore, mTORC1 may be a decisive mediator of metabolic programming in a diabetic pregnancy.

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Section: Enhanced Mtorc1 Signalling In Diabetic Pregnancymentioning

confidence: 74%

Maternal diabetes promotes mTORC1 downstream signalling in rabbit preimplantation embryos

Gürke¹,

Schindler²,

Pendzialek³

et al. 2016

Reproduction

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“…We have new evidence that the lipid metabolism is altered in the rabbit blastocyst in case of a maternal DM. Besides noticeable lipid accumulations, the transport protein for fatty acids and other lipophilic substances, fatty acid-binding protein, is upregulated (Schindler et al 2014). The two pathways -altered fatty acid metabolism and AGE formation -may interact and contribute to specific aspects of maternal subfertility in DM.…”

Section: Discussionmentioning

confidence: 99%

“…The immunohistochemical analysis was performed with single blastocysts as described previously (Schindler et al 2014). Embryonic discs were incubated with mouse MABs against CML, argpyrimidine, and pentosidine (1:100, Biologo).…”

Section: Immunohistochemical Localization Of Ages In Blastocystsmentioning

confidence: 99%

Accumulation of advanced glycation end products in the rabbit blastocyst under maternal diabetes

Haucke¹,

Simm²,

Henning³

et al. 2014

Reproduction

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Diabetes mellitus (DM) during pregnancy is one of the leading causes of perinatal morbidity and birth defects. The mechanism by which maternal hyperglycemia, the major teratogenic factor, induces embryonic malformations remains unclear. Advanced glycation end products (AGEs) are known to accumulate during the course of DM and contribute to the development of diabetic complications. Employing a diabetic rabbit model, we investigated the influence of maternal hyperglycemia during the preimplantation period on AGE formation (pentosidine, argpyrimidine, and N 3 -carboxymethyllysine (CML)) in the reproductive tract and the embryo itself. As a consequence of type 1 DM, the AGE levels in blood plasma increased up to 50%, correlating closely with an AGE accumulation in the endometrium of diabetic females. Embryos from diabetic mothers had increased protein-bound CML levels and showed enhanced fluorescent signals for AGE-specific fluorescence in the blastocyst cavity fluid (BCF). The quantification of CML by HPLC-mass spectrometry (MS/MS) showed a higher amount of soluble CML in the BCF of blastocysts from diabetic rabbits (0.26G0.05 mmol/l) compared with controls (0.18G0.02 mmol/l). The high amount of AGEs in blastocysts from diabetic mothers correlates positively with an increased AGER (receptor for AGE (RAGE)) mRNA expression. Our study gives alarming insights into the consequences of poorly controlled maternal diabetes for AGE formation in the embryo. Maternal hyperglycemia during the preimplantation period is correlated with an increase in AGE formation in the uterine environment and the embryo itself. This may influence the development of the embryo through increased AGE-mediated cellular stress by RAGEs.

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“…Already in early pregnancy, a maternal insulin‐dependent diabetes mellitus (IDD) affects the uterine milieu and development of the embryo. IDD leads to hyperglycaemia and impairs lipid (Schindler et al., ) and amino acid metabolism (Gürke et al., ) in both mother and the embryo. Higher glucose levels go along with an increase in highly reactive glucose metabolites, such as methylglyoxal (MGO) and glyoxal (GO) (McLellan, Thornalley, Benn, & Sonksen, ; Thornalley et al., ).…”

Section: Introductionmentioning

confidence: 99%

“…Already in early pregnancy, a maternal insulin-dependent diabetes mellitus (IDD) affects the uterine milieu and development of the embryo. IDD leads to hyperglycaemia and impairs lipid (Schindler et al, 2014) and amino acid metabolism (Gürke et al, 2015) in both mother…”

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confidence: 99%

Glyoxalase 1 expression is downregulated in preimplantation blastocysts of diabetic rabbits

Seeling

Haucke

Grybel

et al. 2019

Reprod Domestic Animals

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In a diabetic pregnancy, an altered maternal metabolism led to increased formation of reactive α‐dicarbonyls such as glyoxal (GO) and methylglyoxal (MGO) in the reproductive organs and embryos. The enzyme glyoxalase (GLO) 1 detoxifies reactive α‐dicarbonyls thus protecting cells against malfunction or modifications of proteins by advanced glycated end products (AGEs). The aim of this study was to analyse the influence of a maternal insulin‐dependent diabetes mellitus (IDD) on GLO1 expression and activity in preimplantation embryos in vivo and human trophoblast cells (Ac‐1M88) in vitro. Maternal diabetes was induced in female rabbits by alloxan before conception and maintained during the preimplantation period. GLO1 expression and activity were investigated in 6‐day‐old blastocysts from healthy and diabetic rabbits. Furthermore, blastocysts and human trophoblast cells were exposed in vitro to hyperglycaemia, GO and MGO and analysed for GLO1 expression and activity. During gastrulation, GLO1 was expressed in all compartments of the rabbit blastocyst. Maternal diabetes decreased embryonic GLO1 protein amount by approx. 30 per cent whereas the enzymatic activity remained unchanged, indicating that the specific GLO1 activity increases along with metabolic changes. In in vitro cultured embryos, neither hyperglycaemia nor MGO and GO had an effect on GLO1 protein amount. In human trophoblast cells, a stimulating effect on the GLO1 expression was shown in the highest GO concentration, only. Our data show that maternal diabetes mellitus affects the specific activity of GLO1, indicating that GLO1 was post‐translationally modified due to changes in metabolic processes in the preimplantation embryos.

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Maternal Diabetes Leads to Unphysiological High Lipid Accumulation in Rabbit Preimplantation Embryos

Cited by 19 publications

References 96 publications

Maternal diabetes promotes mTORC1 downstream signalling in rabbit preimplantation embryos

Maternal diabetes promotes mTORC1 downstream signalling in rabbit preimplantation embryos

Accumulation of advanced glycation end products in the rabbit blastocyst under maternal diabetes

Glyoxalase 1 expression is downregulated in preimplantation blastocysts of diabetic rabbits

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