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03-02-2025 | Gestational Diabetes | Original Article

Subcutaneous adipose tissue compensates for the perturbations in circulating one-carbon metabolism in women with gestational diabetes

Authors: Xiaojing Wei, Shuangyu Wei, Miao Chen, Yutian Tan, Zhao Yang, Weijie Feng, Guiying Yang, Zhen Han, Xiao Luo

Published in: Acta Diabetologica

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Abstract

The prevalence of gestational diabetes mellitus (GDM) is rising and poses important health risks for the mother, developing fetus and offspring, even when maternal glycemic control is well managed. This study aimed to identify the differently expressed metabolites (DEMs) in maternal plasma between GDM pregnancies with good glycemic control and healthy pregnancies, along with the DEMs-related metabolism in adipose tissue. Pregnant women with scheduled caesarean sections were recruited. Venous blood samples were collected on the day prior to delivery for targeted metabolomics analysis focusing on the 200 polar metabolites in central carbon metabolism. Subcutaneous and omental white adipose tissue (sWAT and oWAT) were harvested at delivery. A total of 162 metabolites were quantified, revealing 2 up-regulated (D-glucose 6-phosphate (G6P), succinate) and 8 down-regulated DEMs, which exhibited a fold change of ≥ 1.5 or ≤ 0.67, respectively. Among the down-regulated DEMs, 5 metabolites—pyridoxine, glycine, S-methyl-l-cysteine, methionine, and S-carboxymethyl-l-cysteine—are related to one-carbon metabolism (OCM). In response to perturbation in circulating OCM, boosted methionine cycle, NAD + metabolism, and adipogenesis were observed in sWAT of GDM subjects, with no changes detected in oWAT. None of the 10 DEMs correlates with either blood glucose or insulin, but showed significant correlations with TG, TC, LDL-C and HDL-C. The present study indicates that sWAT compensates for the perturbations in circulating OCM associated with GDM and targeting to the OCM may be an effective strategy to control the long-term metabolic risk of GDM offsprings.
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Literature
1.
go back to reference American Diabetes Association Professional Practice (2022) Classification and diagnosis of diabetes: standards of medical care in diabetes-2022. Diabetes Care 45(Suppl 1):S17–S38CrossRef American Diabetes Association Professional Practice (2022) Classification and diagnosis of diabetes: standards of medical care in diabetes-2022. Diabetes Care 45(Suppl 1):S17–S38CrossRef
2.
go back to reference Lowe WL Jr et al (2019) Maternal glucose levels during pregnancy and childhood adiposity in the hyperglycemia and adverse pregnancy outcome follow-up study. Diabetologia 62(4):598–610PubMedPubMedCentralCrossRef Lowe WL Jr et al (2019) Maternal glucose levels during pregnancy and childhood adiposity in the hyperglycemia and adverse pregnancy outcome follow-up study. Diabetologia 62(4):598–610PubMedPubMedCentralCrossRef
3.
go back to reference Kramer CK, Campbell S, Retnakaran R (2019) Gestational diabetes and the risk of cardiovascular disease in women: a systematic review and meta-analysis. Diabetologia 62(6):905–914PubMedCrossRef Kramer CK, Campbell S, Retnakaran R (2019) Gestational diabetes and the risk of cardiovascular disease in women: a systematic review and meta-analysis. Diabetologia 62(6):905–914PubMedCrossRef
6.
go back to reference Xie J, Li L, Xing H (2023) Metabolomics in gestational diabetes mellitus: a review. Clin Chim Acta 539:134–143PubMedCrossRef Xie J, Li L, Xing H (2023) Metabolomics in gestational diabetes mellitus: a review. Clin Chim Acta 539:134–143PubMedCrossRef
7.
go back to reference Dudzik D et al (2017) GC-MS based gestational diabetes mellitus longitudinal study: identification of 2-and 3-hydroxybutyrate as potential prognostic biomarkers. J Pharm Biomed Anal 144:90–98PubMedCrossRef Dudzik D et al (2017) GC-MS based gestational diabetes mellitus longitudinal study: identification of 2-and 3-hydroxybutyrate as potential prognostic biomarkers. J Pharm Biomed Anal 144:90–98PubMedCrossRef
8.
go back to reference Lai M et al (2020) Amino acid and lipid metabolism in post-gestational diabetes and progression to type 2 diabetes: a metabolic profiling study. PLoS Med 17(5):e1003112PubMedPubMedCentralCrossRef Lai M et al (2020) Amino acid and lipid metabolism in post-gestational diabetes and progression to type 2 diabetes: a metabolic profiling study. PLoS Med 17(5):e1003112PubMedPubMedCentralCrossRef
9.
go back to reference Logan KM et al (2016) Development of early adiposity in infants of mothers with gestational diabetes mellitus. Diabetes Care 39(6):1045–1051PubMedCrossRef Logan KM et al (2016) Development of early adiposity in infants of mothers with gestational diabetes mellitus. Diabetes Care 39(6):1045–1051PubMedCrossRef
10.
go back to reference Chorell E et al (2017) Pregnancy to postpartum transition of serum metabolites in women with gestational diabetes. Metabolism 72:27–36PubMedCrossRef Chorell E et al (2017) Pregnancy to postpartum transition of serum metabolites in women with gestational diabetes. Metabolism 72:27–36PubMedCrossRef
12.
go back to reference Cai Y, Zhu ZJ (2019) A high-throughput targeted metabolomics workflow for the detection of 200 polar metabolites in central carbon metabolism. Methods Mol Biol 1859:263–274PubMedCrossRef Cai Y, Zhu ZJ (2019) A high-throughput targeted metabolomics workflow for the detection of 200 polar metabolites in central carbon metabolism. Methods Mol Biol 1859:263–274PubMedCrossRef
13.
go back to reference Saravanan P et al (2021) Association of maternal vitamin B(12) and folate levels in early pregnancy with gestational diabetes: a prospective UK cohort study (PRiDE study). Diabetologia 64(10):2170–2182PubMedPubMedCentralCrossRef Saravanan P et al (2021) Association of maternal vitamin B(12) and folate levels in early pregnancy with gestational diabetes: a prospective UK cohort study (PRiDE study). Diabetologia 64(10):2170–2182PubMedPubMedCentralCrossRef
14.
go back to reference Li S et al (2019) Joint effects of folate and vitamin B(12) imbalance with maternal characteristics on gestational diabetes mellitus. J Diabetes 11(9):744–751PubMedCrossRef Li S et al (2019) Joint effects of folate and vitamin B(12) imbalance with maternal characteristics on gestational diabetes mellitus. J Diabetes 11(9):744–751PubMedCrossRef
15.
go back to reference Seghieri G et al (2003) Serum homocysteine levels are increased in women with gestational diabetes mellitus. Metabolism 52(6):720–723PubMedCrossRef Seghieri G et al (2003) Serum homocysteine levels are increased in women with gestational diabetes mellitus. Metabolism 52(6):720–723PubMedCrossRef
16.
go back to reference Guven MA et al (2006) Elevated second trimester serum homocysteine levels in women with gestational diabetes mellitus. Arch Gynecol Obstet 274(6):333–337PubMedCrossRef Guven MA et al (2006) Elevated second trimester serum homocysteine levels in women with gestational diabetes mellitus. Arch Gynecol Obstet 274(6):333–337PubMedCrossRef
17.
go back to reference Huo X et al (2019) Trimethylamine N-oxide metabolites in early pregnancy and risk of gestational diabetes: a nested case-control study. J Clin Endocrinol Metab 104(11):5529–5539PubMedPubMedCentralCrossRef Huo X et al (2019) Trimethylamine N-oxide metabolites in early pregnancy and risk of gestational diabetes: a nested case-control study. J Clin Endocrinol Metab 104(11):5529–5539PubMedPubMedCentralCrossRef
18.
go back to reference Gong X et al (2021) Maternal plasma betaine in middle pregnancy was associated with decreased risk of GDM in twin pregnancy: a cohort study. Diabetes Metab Syndr Obes 14:2495–2504PubMedPubMedCentralCrossRef Gong X et al (2021) Maternal plasma betaine in middle pregnancy was associated with decreased risk of GDM in twin pregnancy: a cohort study. Diabetes Metab Syndr Obes 14:2495–2504PubMedPubMedCentralCrossRef
19.
go back to reference Trivett C, Lees ZJ, Freeman DJ (2021) Adipose tissue function in healthy pregnancy, gestational diabetes mellitus and pre-eclampsia. Eur J Clin Nutr 75(12):1745–1756PubMedPubMedCentralCrossRef Trivett C, Lees ZJ, Freeman DJ (2021) Adipose tissue function in healthy pregnancy, gestational diabetes mellitus and pre-eclampsia. Eur J Clin Nutr 75(12):1745–1756PubMedPubMedCentralCrossRef
21.
go back to reference Cai YP et al (2015) An integrated targeted metabolomic platform for high-throughput metabolite profiling and automated data processing. Metabolomics 11(6):1575–1586CrossRef Cai YP et al (2015) An integrated targeted metabolomic platform for high-throughput metabolite profiling and automated data processing. Metabolomics 11(6):1575–1586CrossRef
22.
go back to reference Roberti A, Fernandez AF, Fraga MF (2021) Nicotinamide N-methyltransferase: at the crossroads between cellular metabolism and epigenetic regulation. Mol Metab 45:101165PubMedPubMedCentralCrossRef Roberti A, Fernandez AF, Fraga MF (2021) Nicotinamide N-methyltransferase: at the crossroads between cellular metabolism and epigenetic regulation. Mol Metab 45:101165PubMedPubMedCentralCrossRef
24.
go back to reference Heath H et al (2023) Identification of potential biomarkers and metabolic insights for gestational diabetes prevention: a review of evidence contrasting gestational diabetes versus weight loss studies that may direct future nutritional metabolomics studies. Nutrition 107:111898PubMedCrossRef Heath H et al (2023) Identification of potential biomarkers and metabolic insights for gestational diabetes prevention: a review of evidence contrasting gestational diabetes versus weight loss studies that may direct future nutritional metabolomics studies. Nutrition 107:111898PubMedCrossRef
30.
go back to reference Pappa KI et al (2007) Intermediate metabolism in association with the amino acid profile during the third trimester of normal pregnancy and diet-controlled gestational diabetes. Am J Obstet Gynecol 196(1):651 e1-655CrossRef Pappa KI et al (2007) Intermediate metabolism in association with the amino acid profile during the third trimester of normal pregnancy and diet-controlled gestational diabetes. Am J Obstet Gynecol 196(1):651 e1-655CrossRef
31.
go back to reference Lu W et al (2021) Discovery of metabolic biomarkers for gestational diabetes mellitus in a Chinese population. Nutr Metab (Lond) 18(1):79PubMedCrossRef Lu W et al (2021) Discovery of metabolic biomarkers for gestational diabetes mellitus in a Chinese population. Nutr Metab (Lond) 18(1):79PubMedCrossRef
34.
go back to reference Finer S et al (2014) The role of the one-carbon cycle in the developmental origins of Type 2 diabetes and obesity. Diabet Med 31(3):263–272PubMedCrossRef Finer S et al (2014) The role of the one-carbon cycle in the developmental origins of Type 2 diabetes and obesity. Diabet Med 31(3):263–272PubMedCrossRef
35.
go back to reference Diaz SO et al (2011) Metabolic biomarkers of prenatal disorders: an exploratory NMR metabonomics study of second trimester maternal urine and blood plasma. J Proteome Res 10(8):3732–3742PubMedCrossRef Diaz SO et al (2011) Metabolic biomarkers of prenatal disorders: an exploratory NMR metabonomics study of second trimester maternal urine and blood plasma. J Proteome Res 10(8):3732–3742PubMedCrossRef
37.
go back to reference Spellacy WN, Buhi WC, Birk SA (1977) Vitamin B6 treatment of gestational diabetes mellitus: studies of blood glucose and plasma insulin. Am J Obstet Gynecol 127(6):599–602PubMedCrossRef Spellacy WN, Buhi WC, Birk SA (1977) Vitamin B6 treatment of gestational diabetes mellitus: studies of blood glucose and plasma insulin. Am J Obstet Gynecol 127(6):599–602PubMedCrossRef
39.
go back to reference Li N et al (2022) Branched-chain amino acids and their interactions with lipid metabolites for increased risk of gestational diabetes. J Clin Endocrinol Metab 107(7):e3058–e3065PubMedPubMedCentralCrossRef Li N et al (2022) Branched-chain amino acids and their interactions with lipid metabolites for increased risk of gestational diabetes. J Clin Endocrinol Metab 107(7):e3058–e3065PubMedPubMedCentralCrossRef
40.
go back to reference Park S et al (2015) Plasma levels of lysine, tyrosine, and valine during pregnancy are independent risk factors of insulin resistance and gestational diabetes. Metab Syndr Relat Disord 13(2):64–70PubMedCrossRef Park S et al (2015) Plasma levels of lysine, tyrosine, and valine during pregnancy are independent risk factors of insulin resistance and gestational diabetes. Metab Syndr Relat Disord 13(2):64–70PubMedCrossRef
41.
go back to reference Yang J et al (2023) Plasma amino acids in early pregnancy and midpregnancy and their interplay with phospholipid fatty acids in association with the risk of gestational diabetes mellitus: results from a longitudinal prospective cohort. Diabetes Care 46(4):722–732PubMedPubMedCentralCrossRef Yang J et al (2023) Plasma amino acids in early pregnancy and midpregnancy and their interplay with phospholipid fatty acids in association with the risk of gestational diabetes mellitus: results from a longitudinal prospective cohort. Diabetes Care 46(4):722–732PubMedPubMedCentralCrossRef
42.
go back to reference Cetin I et al (2005) Maternal and fetal amino acid concentrations in normal pregnancies and in pregnancies with gestational diabetes mellitus. Am J Obstet Gynecol 192(2):610–617PubMedCrossRef Cetin I et al (2005) Maternal and fetal amino acid concentrations in normal pregnancies and in pregnancies with gestational diabetes mellitus. Am J Obstet Gynecol 192(2):610–617PubMedCrossRef
43.
go back to reference Liu L et al (2021) Differentiation of gestational diabetes mellitus by nuclear magnetic resonance-based metabolic plasma analysis. J Biomed Res 35(5):351–360PubMedPubMedCentralCrossRef Liu L et al (2021) Differentiation of gestational diabetes mellitus by nuclear magnetic resonance-based metabolic plasma analysis. J Biomed Res 35(5):351–360PubMedPubMedCentralCrossRef
44.
go back to reference Menni C et al (2013) Biomarkers for type 2 diabetes and impaired fasting glucose using a nontargeted metabolomics approach. Diabetes 62(12):4270–4276PubMedPubMedCentralCrossRef Menni C et al (2013) Biomarkers for type 2 diabetes and impaired fasting glucose using a nontargeted metabolomics approach. Diabetes 62(12):4270–4276PubMedPubMedCentralCrossRef
45.
go back to reference Herman MA, Kahn BB (2006) Glucose transport and sensing in the maintenance of glucose homeostasis and metabolic harmony. J Clin Invest 116(7):1767–1775PubMedPubMedCentralCrossRef Herman MA, Kahn BB (2006) Glucose transport and sensing in the maintenance of glucose homeostasis and metabolic harmony. J Clin Invest 116(7):1767–1775PubMedPubMedCentralCrossRef
46.
go back to reference Fiehn O et al (2010) Plasma metabolomic profiles reflective of glucose homeostasis in non-diabetic and type 2 diabetic obese African-American women. PLoS ONE 5(12):e15234PubMedPubMedCentralCrossRef Fiehn O et al (2010) Plasma metabolomic profiles reflective of glucose homeostasis in non-diabetic and type 2 diabetic obese African-American women. PLoS ONE 5(12):e15234PubMedPubMedCentralCrossRef
47.
go back to reference Aiston S, Andersen B, Agius L (2003) Glucose 6-phosphate regulates hepatic glycogenolysis through inactivation of phosphorylase. Diabetes 52(6):1333–1339PubMedCrossRef Aiston S, Andersen B, Agius L (2003) Glucose 6-phosphate regulates hepatic glycogenolysis through inactivation of phosphorylase. Diabetes 52(6):1333–1339PubMedCrossRef
48.
go back to reference Mills E, O’Neill LA (2014) Succinate: a metabolic signal in inflammation. Trends Cell Biol 24(5):313–320PubMedCrossRef Mills E, O’Neill LA (2014) Succinate: a metabolic signal in inflammation. Trends Cell Biol 24(5):313–320PubMedCrossRef
51.
go back to reference Lappas M (2014) Effect of pre-existing maternal obesity, gestational diabetes and adipokines on the expression of genes involved in lipid metabolism in adipose tissue. Metabolism 63(2):250–262PubMedCrossRef Lappas M (2014) Effect of pre-existing maternal obesity, gestational diabetes and adipokines on the expression of genes involved in lipid metabolism in adipose tissue. Metabolism 63(2):250–262PubMedCrossRef
52.
go back to reference Gao Y, She R, Sha W (2017) Gestational diabetes mellitus is associated with decreased adipose and placenta peroxisome proliferator-activator receptor gamma expression in a Chinese population. Oncotarget 8(69):113928–113937PubMedPubMedCentralCrossRef Gao Y, She R, Sha W (2017) Gestational diabetes mellitus is associated with decreased adipose and placenta peroxisome proliferator-activator receptor gamma expression in a Chinese population. Oncotarget 8(69):113928–113937PubMedPubMedCentralCrossRef
53.
go back to reference Catalano PM et al (2002) Downregulated IRS-1 and PPARgamma in obese women with gestational diabetes: relationship to FFA during pregnancy. Am J Physiol Endocrinol Metab 282(3):E522–E533PubMedCrossRef Catalano PM et al (2002) Downregulated IRS-1 and PPARgamma in obese women with gestational diabetes: relationship to FFA during pregnancy. Am J Physiol Endocrinol Metab 282(3):E522–E533PubMedCrossRef
54.
go back to reference Okabe K et al (2020) NAD+ metabolism regulates preadipocyte differentiation by enhancing alpha-ketoglutarate-mediated histone H3K9 demethylation at the PPARgamma promoter. Front Cell Dev Biol 8:586179PubMedPubMedCentralCrossRef Okabe K et al (2020) NAD+ metabolism regulates preadipocyte differentiation by enhancing alpha-ketoglutarate-mediated histone H3K9 demethylation at the PPARgamma promoter. Front Cell Dev Biol 8:586179PubMedPubMedCentralCrossRef
55.
go back to reference Ryu KW et al (2018) Metabolic regulation of transcription through compartmentalized NAD (+) biosynthesis. Science 360:6389CrossRef Ryu KW et al (2018) Metabolic regulation of transcription through compartmentalized NAD (+) biosynthesis. Science 360:6389CrossRef
56.
go back to reference Mazaki-Tovi S et al (2015) Characterization of visceral and subcutaneous adipose tissue transcriptome and biological pathways in pregnant and non-pregnant women: evidence for pregnancy-related regional-specific differences in adipose tissue. PLoS ONE 10(12):e0143779PubMedPubMedCentralCrossRef Mazaki-Tovi S et al (2015) Characterization of visceral and subcutaneous adipose tissue transcriptome and biological pathways in pregnant and non-pregnant women: evidence for pregnancy-related regional-specific differences in adipose tissue. PLoS ONE 10(12):e0143779PubMedPubMedCentralCrossRef
Metadata
Title
Subcutaneous adipose tissue compensates for the perturbations in circulating one-carbon metabolism in women with gestational diabetes
Authors
Xiaojing Wei
Shuangyu Wei
Miao Chen
Yutian Tan
Zhao Yang
Weijie Feng
Guiying Yang
Zhen Han
Xiao Luo
Publication date
03-02-2025
Publisher
Springer Milan
Published in
Acta Diabetologica
Print ISSN: 0940-5429
Electronic ISSN: 1432-5233
DOI
https://doi.org/10.1007/s00592-025-02452-z

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