Current progress in metabolomics of gestational diabetes mellitus

Table 2 Selected gestational diabetes mellitus metabolomic studies in recent years

Study design	Study methods	GDM diagnostic guidelines	Sample collection time	Biological samples	Analytical platform (s)	Changes in direction (vs control)	Main differential metabolites	Ref.
Biological samples collected before GDM diagnosis
Prospective study (overweight and obese), n = 82 GDM, n = 275 controls	Targeted NMR-based metabolomics approach	IADPSG	12.8–15.6 wk	Maternal serum (fasting)	NMR	Up	All-sized VLDL particles; medium-sized HDL particles; small-sized HDL particles; glucose; lactate; pyruvate; isoleucine; leucine; alanine; phenylalanine; GlycA	Mokkala et al[44], Finland, 2020
						Down	Very large HDL particles
Nested case-control study, n = 243 GDM, n = 243 controls	Targeted Lysophosphatidylcholines and bile acids	IADPSG	9-11 wk	Maternal plasma (fasting)	LC-MS/MS	Up	LPC egg; LPC 15:0; LPC 17:0; LPC 18:0; LPC 18:1	Liu et al[45], China, 2020
						Down	Deoxycholic acid; glycoursodeoxycholic acid
Case-control study, n = 65 GDM, n = 366 controls	Targeted amino acids	IADPSG	12-16 wk	Maternal serum	UHPLC-MS/MS	Up	Alanine; glutamate; isoleucine; phenylalanine; tyrosine	Jiang et al[46], China, 2020
						Down	None
Case-control study, n = 121 p-GDM, n = 121 control	Targeted metabolomics	multi-step screening	16-19 wk	Maternal serum(randomly)	HILIC-MS/MS	Up	None	Sakurai et al[47], Japan, 2019
						Down	Glutamine; pyrophosphate; octulose-1,8-bisphosphate
Case-controls study, n = 36 p-GDM, n = 31 controls				Maternal urine (randomly)	HILIC-MS/MS	Up	Shikimate-3-phosphate; 1,3-diphosphoglycerate; N-acetyl-L-alanine
						Down	Ethanolamine; methionine
Nested case-control study, n = 131 GDM, n = 138 controls	Nontargeted metabolomics	IADPSG	12 wk	Maternal serum (fasting)	UPLC-QTOFMS, UPLC-TQMS, GC-TOFMS	Up	C14:1(trans-9); C16:1 (cis-7); C17:1 (cis-10); C18:1 (cis-9); C19:1 (cis-10); C20:1 (cis-11); C12:0; C16:0; C17:0; C20:0; C16:2 (cis-9_12); C18:2 (9_11&10_12-cis&trans-conjugated-99%); C18:3 (cis-9_12_15); C22:3 (cis-13_16_19); C18:3 (cis-6_9_12); C18:2 (cis-9_12); C20:4 (cis-5_8_11_14); C20:3 (cis-8_11_14); C20:2 (cis-11_14); C22:5 (cis-7_10_13_16_19); THDCA; LCA; HDCA; isoDCA; 6_7_diketoLCA; leucine; isoleucine; valine; acetylaspartic acid; alanine; glutamic acid; 2-aminobutanoic acid; 2-oxo-4-methylvaleric acid; gamma-aminobutanoic acid; Aminomalonic acid; pyruvic acid; 1-monooleoylglycerol; 2-ethylhexanoic acid; mannose; threitol	Hou et al[48], China, 2018
						Down	CA; dehydro_LCA; cysteine; 2,3,4-trihydroxybutyric acid; maltose; threonic acid
Biological samples collected after or simultaneously with GDM diagnosis
Nested case-control study, n = 23 GDM, n = 77 controls	Targeted polar metabolites and lipids	IADPSG	24-28 wk	Maternal serum (2 h OGTT)	LC-MS	Up	Adenosine; taurolithocholic acid; glycoli thocholic acid; glycochenodeoxycholic acid	Geiaye et al[49], Peru, 2019
						Down	Methionine sulfoxide; C58:10 triacylglycerol; C58:9 triacylglycerol; C8 carnitine; C14:2 carnitine; C14:1 carnitine; C12 carnitine; C4-OH carnitine
Case-control study (overweight), n = 100 GDM, n = 252 controls	Targeted NMR-based metabolomics approach	IADPSG	34.6-35.9 wk	Maternal serum (fasting)	NMR	Up	VLDL particles; glucose; citrate; isoleucine; leucine; phenylalanine; acetoacetate; GlycA	Mokkala et al[50], Finland, 2020
						Down	Small HDL particles
Case-control study (overweight), n = 19 GDM with medication, n = 76 GDM with diet						Up	VLDL particles; lactate; isoleucine; leucine; GlycA
						Down	Small HDL particles
Case-control study, n = 45 GDM, n = 98 controls	Targeted lipids metabolomics approach	IADPSG	At admission, after admission, and up to 24 h after delivery	Maternal plasma (fasting)	LC-IMS-MS	Up	PE(P-20:0_18:1); PE(P-18:0_22:6); PE(P-20:0_22:6); PE(P-18:1_22:6); PC(P-18:0_22:6); PC(17:0_22:6)	Odenkerk et al[51], United States, 2020
						Down	PEBP1; TG(12:0_16:0_18:1); TG(14:0_16:0_18:1); TG(14:0_16:0_18:2); PDIA6; PDIA5;LYAG; EXT1; B4GA1
Case-control study, n = 11 GDM only, n = 11 hyperlipidemia only, n = 12 GDM plus hyperlipidemia, n = 11 controls	Targeted lipids metabolomics approach	IADPSG	27–33 wk	Maternal serum (fasting)	GC-MS/MS	Up	3-Dehydrocarnitine; 6-hexanoyl-D-erythro-sphingosine; arachidoyl ethanolamide; CER; Che; DG; dMePE; eicosanoicacid; FA; hexadecanamide; LdMePE; LPA; LPC; LPEt; LPG; LPI; MG; N-hexadecyl-ethanolamine; OAHFA; octadecanoicacid; PAF; PC; PE; Pet; PG; phSM; PI; PIP,SM; So; TG	Liu et al[52], China, 2019
						Down	None
Case-control study, n = 30 GDM, n = 30 controls	Nontargeted metabolomics	IADPSG	24-28 wk	Maternal serum	LC-MS	Up	TXB2; traumatic acid; PGC2; PGJ2; PGB2; PGA2; pravastatin; PGD2-d4; PGE2-d4; crotonoyl-CoA; methacrylyl-CoA; 2S-hydroxybutanoic acid; D(-)-beta-hydroxy butyric acid; 4-hydroxy-butyric acid; DPA; oleic acid; rumenic acid; linoleic acid; urocortisone; corticosterone; 11-deoxycortisol; tetrahydrocortisol; 2-hydroxyestrone; dehydroepiandrosterone sulfate; tetrahydrocorticosterone; LPA (0:0/16:0); LysoPC (20:4); psychosine	Li et al[53], China, 2019
						Down	PGG2; 6-keto PGE1; 11-dehydro-TXB2; cholesterol; lathosterol; coenzyme Q10; lutein; zeaxanthin
Case-control study, n = 32 GDM, n = 11 controls	Targeted lipidomic profile	WHO—2013 criteria	24-28 wk	Maternal erythrocyte membrane (fasting)	GC-MS	Up	Oleic acid; vaccenic acid; sapienic acid	Bukowiecka-Matusiak et al[54], Poland, 2018
						Down	Myristic, palmitic, and stearic acids
Biological samples collected in longitudinal cohort study
Nested case–control studyBaseline (6–9 wk postpartum), n = 173 future T2D, n = 485 non-T2D	Targeted metabolomics	Carpenter and Coustan criteria	6–9 wk postpartum (baseline);	Maternal plasma (fasting)	FIA-MS/MSLC-MS/MS	Up (baseline)	Hexose; histidine; isoleucine; serine; tyrosine; leucine; methionine; glutamate; lysine; tryptophan; threonine; proline; acylcarnitines AC3; acylcarnitines AC10; acylcarnitines AC16; spermidine; diacyl-glycerophospholipids	Lai et al[55], United States, 2020
						Down (baseline)	Glutamine; kynurenine; sphingomyelins; lysophosphatidylcholines; acyl-alkyl-glycerophospholipids
Follow-up (2~8 yr postbaseline), n = 98 future T2D, n = 239 non-T2D			Up to 2 yr postbaseline (follow-up).			Up (follow-up)	Hexose; glutamate; isoleucine; tyrosine; leucine; valine; alanine; PC; aa C32:1; acylcarnitines AC5
						Down (follow-up)	Glycine; PC aa C38:1; PC aa C38:6; PC ae C36:2; PC ae C40:6; PC ae C34:3; PC ae C34:2; PC ae C36:3; PC ae C38:4; lysoPC a C17:0; lysoPC a C18:1; lysoPC a C20:4; lysoPC a C18:2; lysoPC a C16:0; lysoPC a C18:0; SM(OH)C22:2; SM(OH)C14:1; creatinine
Case-control study, n = 90 GDM, n = 94 controls	Nontargeted metabolomics	IADPSG	1–3 d postpartum	Colostrum	GC-MS	Up	None	Wen et al[3], China, 2019
						Down	Heneicosane; G\glycine, N-(methoxyoxoacetyl)-methyl ester; 3-aminoisobutyric acid; glutamine; oxaloacetic acid; 4-aminobutyric acid
			7-10 d postpartum	Transition milk	GC-MS	Up	Asparagine; malic acid
						Down	D-Proline; glycine, N-(methoxyoxoacetyl)-, methyl ester; hydroxybenzoic acid; malonic acid; 9-heptadecenoic acid
			4 wk postpartum	Mature milk	GC-MS	Up	Heneicosane; cysteine; lignoceric; malic acid
						Down	Nonacosane; glycine; N-ethyl-N-(2-ethoxyethoxycarbonyl)-; 2-methoxyethyl ester; pyroglutamic acid; beta-alanine; 2-oxoadipic acid; 3-methyl- 2-oxovaleric acid; 4-aminobutyric acid; glutamine; oxalic acid; oxaloacetic acid; pimelic acid; 9-heptadecenoic acid; 10-pentadece- noic acid; 2-hydroxyglutaramic acid; nervonic acid
Case-control study, n = 50 Healthy, overweight/obese, n = 45 GDM, n = 67 Healthy, normal weight	Targeted metabolomics	National Diabetes Data Group criteria	At delivery	Maternal plasma	LC–MS/MS	Up	Hexoses; Asn/Asp	Shokry et al[56], Spain, 2019
						Down	Phospholipids (PL); LPC16:0; PCaa38:3; PCaa 38:5; SM32.2
Case-control study, n = 40 Healthy, overweight/obese, n = 27 GDM, n = 49 Healthy, normal weight				Cord plasma of offspring		Up	Hexoses; Asn/Asp; 3-methyl-2-oxobutanoic acid
						Down	PCae38:0; Carn; short-chain AC; acetyl carnitine; NEFA26:1, malic; succinic acids
Case-control study, n = 107 GDM, n = 107 controls	Nontargeted metabolomics	Criteria of the American Diabetes Association	First trimester (12.8 wk median)	Maternal serum	UHPLC-MS	Up	Proline; ornithine; glycerophosphocholine; glutamic acid; taurine; acetylcarnitine; uracil; hypoxanthine; aspartyl-isoleucine; pantothenic acid; lysoPC (14:0); LysoPC [16:1(9Z)]; linoleoyl carnitine; palmitoylcarnitine; LysoPC (16:0); histidine; succinic acid semialdehyde; malic acid; xanthosine	Zhao et al[57], China, 2019
						Down	Threoninyl-phenylalanine; asparaginyl-tryptophan; phenylalanyl-gamma-glut amate; valyl-isoleucine; aspartyl –phenylalanine; phenylalanyl-valine; DL-2-aminooctanoic acid; phenylalanyl-isoleucine; acetylglycine
			Second trimester (26.1 wk median)			Up	Guanidoacetic acid; acetylcarnitine; propionylcarnitine; 2-octenoylcarnitine; LysoPC (14:0); LysoPC [16:1(9Z)]; palmitoylcarnitine; vaccenyl carnitine; LysoPC (16:0); LysoPE [0:0/18:1(11Z)]; LysoPC (17:0)
						Down	Threoninyl-phenylalanine; phenylalanyl-gamma-glut-amate; phenylalanyl-isoleucine
Case-control study, n = 15 GDM, n = 50 controls	Nontargeted metabolomics	IADPSG	6-8 wk	Maternal urine	UPLC-MS/MS	Up	Levoglucosan; polyethylene glycol; 6-hydroxy-5-methoxyindole glucuronide	Liu et al[58], China, 2019
						Down	1'-acetoxyeugenol acetate; 3,4-dimethyl-5-pentyl-2-furanundecanoic acid; 2-hydroxylauroylcarnitine; L-phenylalanyl-L-proline

GDM: Gestational diabetes mellitus; p-GDM: Prior to diagnosis of gestational diabetes mellitus; T2D: Type 2 diabetes; IADPSG: International Association of Diabetes and Pregnancy Study Group; WHO: World Health Organization; OGTT: Oral glucose tolerance test; NMR: Nuclear magnetic resonance spectroscopy; LC-MS/MS: Liquid chromatography-tandem mass spectrometry; UHPLC-MS/MS: Ultra-high-performance liquid chromatography-tandem mass spectrometry; HILIC-MS/MS: Hydrophilic interaction chromatography-tandem mass spectrometry; UPLC-QTOFMS: Ultra performance liquid chromatography-quadrupole-time-of-flight mass spectrometry; UPLC-TQMS: Ultraperformance liquid chromatography-triple triple-quadrupole mass spectrometry; GC-TOFMS: Gas chromatography-time-of-flight mass spectrometry; LC-MS: Liquid chromatography-mass spectrometry; LC-IMS-MS: Liquid chromatography-ion mobility spectrometry and mass spectrometry; GC-MS/MS: Gas chromatography-tandem mass spectrometry; GC-MS: Gas chromatography-mass spectrometry; FIA-MS/MS: Flow injection analysis-tandem mass spectrometry; UPLC-MS/MS: Ultra performance liquid chromatography-tandem mass spectrometry; VLDL: Very low density lipoprotein; HDL: High density lipoproteins; GlycA: Glycoprotein acetylation; LPC: Lysophosphatidylcholine; CA: Cholic acid; LCA: Lithocholic acid; PE: Phosphatidylethanolamine; PC: Phosphatidylcholine; PEBP1: Phosphatidylethanolamine-binding protein 1; TG: Triacylglycerols; PDIA: Protein disulfide-isomerase A; LYAG: Lysosomal alpha-glucosidase; EXT: Exostoses; B4GA1: Beta-1,4-galactosyltransferase 1; CER: Ceramides; Che: Choleterylesters; DG : Diacylglycerols; dMePE: Dimethyl-phosphatidylethanolamine; FA: Fatty acids; LdMePE: Lysodimethylphosphatidylethanolamine; LPA: Lysophosphatidic acid; LPEt: Lysophosphatidylethanol; LPG: Lysophosphatidylglycerol; LPI: Lysophosphatidylinositol; MG: Monoglyceride; OAHFA: Octadecanoicacid; PAF: Platelet-activating factor; Pet: Phosphatidylethanol; PG: Phosphatidylglycerols; PI: Phosphatidylinositol; PIP: Phosphatidylinositol; SM: Sphingomyelins; So: Sphingoshine; TXB2: Thromboxane B2; PG: Prostaglandins; LysoPC: Lysophosphatidlycholine; AC: Acylcarnitine; PCaa: Diacyl-phosphatidylcholines; Asn: Asparagine; Asp: Aspartic acid; PCae: Acyl-alkyl-phosphatidylcholines; Carn: Carnitine; NEFA: Nonestesterified fatty acid; LysoPE: Lysophosphatidylethanolamine.