Maternal Diabetes Leads to Adaptation in Embryonic Amino Acid Metabolism during Early Pregnancy

Gürke, Jacqueline; Hirche, Frank; Thieme, René; Haucke, Elisa; Schindler, Maria; Stangl, Gabriele I.; Fischer, Bernd; Santos, Anne Navarrete

doi:10.1371/journal.pone.0127465

Cited by 20 publications

(16 citation statements)

References 61 publications

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“…Yet, few studies have evaluated the impact of PGDM on BCAA alterations in a pregnant population. In rabbit embryos, maternal diabetes during early pregnancy has been shown to significantly elevate BCAAs [ 35 ]. Isoleucine was not significantly altered in the immediate post-partum period in women with PGDM, suggesting that physiological metabolic alterations during pregnancy may disrupt changes in BCAA metabolism normally observed in diabetes.…”

Section: Discussionmentioning

confidence: 99%

Diabetes Leads to Alterations in Normal Metabolic Transitions of Pregnancy as Revealed by Time-Course Metabolomics

et al. 2020

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Women with diabetes during pregnancy are at increased risk of poor maternal and neonatal outcomes. Despite this, the effects of pre-gestational (PGDM) or gestational diabetes (GDM) on metabolism during pregnancy are not well understood. In this study, we utilized metabolomics to identify serum metabolic changes in women with and without diabetes during pregnancy and the cord blood at birth. We observed elevations in tricarboxylic acid (TCA) cycle intermediates, carbohydrates, ketones, and lipids, and a decrease in amino acids across gestation in all individuals. In early gestation, PGDM had elevations in branched-chain amino acids and sugars compared to controls, whereas GDM had increased lipids and decreased amino acids during pregnancy. In both GDM and PGDM, carbohydrate and amino acid pathways were altered, but in PGDM, hemoglobin A1c and isoleucine were significantly increased compared to GDM. Cord blood from GDM and PGDM newborns had similar increases in carbohydrates and choline metabolism compared to controls, and these alterations were not maternal in origin. Our results revealed that PGDM and GDM have distinct metabolic changes during pregnancy. A better understanding of diabetic metabolism during pregnancy can assist in improved management and development of therapeutics and help mitigate poor outcomes in both the mother and newborn.

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Section: Discussionmentioning

confidence: 99%

Diabetes Leads to Alterations in Normal Metabolic Transitions of Pregnancy as Revealed by Time-Course Metabolomics

et al. 2020

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“…Therefore, we can only speculate whether observed changes in BF are due to selective adaptation mechanism in the uterine epithelium or trophoblast cells. Based on our recent work, we could show that in the uterus, especially the endometrium, but also in the trophoblast transporters for glucose, amino acids and lipids, as well as metabolic pathway molecules are affected in a diabetic pregnancy [18,38,59], indicating that on maternal and embryonic side adaptation mechanism are possible.…”

Section: Amino Acid Metabolism Is Differently Regulated In the Maternmentioning

confidence: 99%

“…Changes in BCAAs (valine, leucine, isoleucine) have been associated with the development of diabetes [57,58] and diabetic pregnancy [59,60]. Diabetic increases in BCAA levels activate mTOR-signalling and forces the synthesis of embryonic proteins [59]. Metabolites of the BCAA pathways enter the TCA at different points [61].…”

Section: Amino Acid Metabolism Is Differently Regulated In the Maternmentioning

confidence: 99%

Metabolic Profiling in Blastocoel Fluid and Blood Plasma of Diabetic Rabbits

Schindler

Pendzialek

Grybel

et al. 2020

IJMS

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Metabolic disorders of the mother adversely affect early embryo development, causing changes in maternal metabolism and consequent alterations in the embryo environment in the uterus. The goal of this study was to analyse the biochemical profiles of embryonic fluids and blood plasma of rabbits with and without insulin-dependent diabetes mellitus (DT1), to identify metabolic changes associated with maternal diabetes mellitus in early pregnancy. Insulin-dependent diabetes was induced by alloxan treatment in female rabbits 10 days before mating. On day 6 post-coitum, plasma and blastocoel fluid (BF) were analysed by ultrahigh performance liquid chromatography-tandem mass spectroscopy (UPLC-MS/MS) (Metabolon Inc. Durham, NC, USA). Metabolic datasets comprised a total of 284 and 597 compounds of known identity in BF and plasma, respectively. Diabetes mellitus had profound effects on maternal and embryonic metabolic profiles, with almost half of the metabolites changed. As predicted, we observed an increase in glucose and a decrease in 1,5-anhydroglucitol in diabetic plasma samples. In plasma, fructose, mannose, and sorbitol were elevated in the diabetic group, which may be a way of dealing with excess glucose. In BF, metabolites of the pentose metabolism were especially increased, indicating the need for ribose-based compounds relevant to DNA and RNA metabolism at this very early stage of embryo development. Other changes were more consistent between BF and plasma. Both displayed elevated acylcarnitines, body3-hydroxybutyrate, and multiple compounds within the branched chain amino acid metabolism pathway, suggesting that lipid beta-oxidation is occurring at elevated levels in the diabetic group. This study demonstrates that maternal and embryonic metabolism are closely related. Maternal diabetes mellitus profoundly alters the metabolic profile of the preimplantation embryo with changes in all subclasses of metabolites.

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“…Results suggest that flux through BCAAT is influenced by PYR availability. Decreased RNA amounts of BCAAT and BCKAD in the liver and muscles of rabbits with T1DM induced by alloxan [ 92 ]. …”

Section: Etiopathogenesis Of Increased Bcaa Levels In Starvation mentioning

confidence: 99%

Why Are Branched-Chain Amino Acids Increased in Starvation and Diabetes?

Holeček

2020

Nutrients

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Branched-chain amino acids (BCAAs; valine, leucine, and isoleucine) are increased in starvation and diabetes mellitus. However, the pathogenesis has not been explained. It has been shown that BCAA catabolism occurs mostly in muscles due to high activity of BCAA aminotransferase, which converts BCAA and α-ketoglutarate (α-KG) to branched-chain keto acids (BCKAs) and glutamate. The loss of α-KG from the citric cycle (cataplerosis) is attenuated by glutamate conversion to α-KG in alanine aminotransferase and aspartate aminotransferase reactions, in which glycolysis is the main source of amino group acceptors, pyruvate and oxaloacetate. Irreversible oxidation of BCKA by BCKA dehydrogenase is sensitive to BCKA supply, and ratios of NADH to NAD+ and acyl-CoA to CoA-SH. It is hypothesized that decreased glycolysis and increased fatty acid oxidation, characteristic features of starvation and diabetes, cause in muscles alterations resulting in increased BCAA levels. The main alterations include (i) impaired BCAA transamination due to decreased supply of amino groups acceptors (α-KG, pyruvate, and oxaloacetate) and (ii) inhibitory influence of NADH and acyl-CoAs produced in fatty acid oxidation on citric cycle and BCKA dehydrogenase. The studies supporting the hypothesis and pros and cons of elevated BCAA concentrations are discussed in the article.

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Maternal Diabetes Leads to Adaptation in Embryonic Amino Acid Metabolism during Early Pregnancy

Cited by 20 publications

References 61 publications

Diabetes Leads to Alterations in Normal Metabolic Transitions of Pregnancy as Revealed by Time-Course Metabolomics

Diabetes Leads to Alterations in Normal Metabolic Transitions of Pregnancy as Revealed by Time-Course Metabolomics

Metabolic Profiling in Blastocoel Fluid and Blood Plasma of Diabetic Rabbits

Why Are Branched-Chain Amino Acids Increased in Starvation and Diabetes?

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