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Table 1 Characteristics of the data included in the meta-analysis of type 2 diabetes mellitus

From: Metabolite biomarkers of type 2 diabetes mellitus and pre-diabetes: a systematic review and meta-analysis

Author-year-Journal

Study design

Population

Cases N

Control N

Biological sample

Detection method

Analytical method

Covariates

Metabolites

Zhu et al., 2011, Talanta [10]

Case-control study

Chinese

30

30

plasma

NPLC-TOF/MS

PCA, PLS-DA and ANOVA

Sex

(↑) LPC (16:0), LPC (18:2), LPC (18:0)

Liu et al., 2016, Sci Rep [11]

Case-control study

Chinese

15

15

plasma

1H NMR spectroscopy

PCA, PLS-DA, HCA and ROC curve analysis

Gender, age, BMI, SBP, DBP, total cholesterol, BUN and serum creatinine

(↑) Glucose, glycine

(↓) Valine, leucine, alanine, isoleucine, arginine, proline, glutamine, threonine, tyrosine, creatine

Wang-sattler et al., 2017, Mol Syst Biol [22]

KORA S4 cross-sectional study

Augsburg and the surrounding towns and villages

KORA S4: 91

EPIC: 133

Prospective: 91

KORA S4: 866

EPIC: 1253

Prospective: 91

serum

LC-FIA-MS

Multivariate logistic regression and linear regression

Age, sex, BMI, PA, alcohol intake, smoking, SBP and HDL

(↓) Glycine, LPC (18:2)

Ha et al., 2012, Clin Endocrinol [23]

Case-control study

South Korean (men)

26

27

serum

UPLC/Q-TOF-MS

PLS-DA and ROC curve analysis

Age and BMI

(↑) Myristic acid (14:0)

(−) Palmitic acid (16:0), stearic acid (18:0), arachidonic acid (20:4 ω6)

Menni et al., 2013, Diabetes [24]

Case-control study

British

115

1897

plasma

NA

Random intercept logistic regressions analysis

Age, BMI, batch effect and family relatedness

(↑) Valine, leucine, isoleucine, proline, mannose, glucose,2-hydroxybutyrate, lactate

(↓) Citrulline, myristate (14:0),1,5-anhydroglucitol

Kujala et al., 2016, Front Med [25]

Case-control study

Older Finnish men

126

214

serum

NMR platform

Mann-Whitney U-test or Kruskal-Wallis test

Age

(↑) Valine, isoleucine, leucine

Peddinti et al., 2017, Diabetologia [26]

Botnia Prospective Study

Finland

146

397

serum

UHPLC-MS/MS and GC-MS

Multivariate logistic regression analysis

Age, sex, BMI, fasting insulin level and family history

(↑) Valine, isoleucine, glutamate, mannose, glucose

(↓) Histidine, glutamine

Okekunle et al., 2017, Diabetes Res Clin Pract [27]

Case-control study

Chinese (Harbin)

50

50

serum

UPLC-TQ-MS

ANOVA and covariance analysis

Age, sex, BMI and insulin resistance

(↑) Glutamic acid, ornithine

(↓) Serine, asparagine, glycine, threonine

(−) Valine, leucine, isoleucine, tyrosine, phenylalanine, lysine, alanine, histidine, proline, citrulline, arginine, ethionine, glutamine

Abu Bakar et al., 2017, Mol Biosyst [28]

Nested-case control study

Malaysian

37

32

plasma

LC-MS and HPLC

The Kruskal-Wallis test, PLS-DA and ROC curve analysis

Age, gender, BMI and SBP

(↑) Valine, leucine, tyrosine, soleucine, phenylalanine, glutamine, glutamate, lysine, proline, palmitic acid, arachidonic acid, myristic acid

(↓) Alanine, stearic acid

Andersson-Hall et al., 2018, J Diabetes Res [29]

6-years follow-up study

Women in Gothenburg

44

139

serum

NMR Spectroscopy

ANOVA and ANCOVA

BMI

(↑) Valine, leucine, tyrosine, isoleucine, glucose, mannose, acetoacetate, glycerol, 3-hydroxy-isobutyrate

(↓) Glycine

(−) Phenylalanine

Lee et al., 2016, Metabolomics [30]

KARE cohort (prospective) study

South Korean

517

924

serum

LC/MS/MS and LC-FIA-MS

Multivariable logistic regression and linear regression

Age, sex, BMI and HDL

(↓) Glycine, LPC a (18:2)

Floegel et al., 2013, Diabetes [31]

EPIC-Potsdam case-cohort study

The area of Potsdam in eastern Germany

800

2282

serum

FIA-MS/MS

Cox proportional hazards regression and PCA

Age, sex, alcohol intake, smoking, education, coffee intake, BMI and waist circumference

(↑) Phenylalanine

(↓) Glycine, LPC a (18:2)

Gogna et al., 2015, Mol Biosyst [32]

Case-control study

South Indian Asians

165

128

serum

COSY, HSQC, HMQC, CPMG NMR spectra

PCA and PLS-DA

Age, sex and BMI

(↑) Valine, leucine, isoleucine, lysine, glutamine, phenylalanine, proline, threonine, histidine, glucose, lactate, glycerol

Lu et al., 2016, Diabetologia [33]

Prospective cohort study

Chinese

197

197

serum

LC-MS and GC-MS

OPLS-DA, ROC and conditional logistic regression analysis

Age, sex, BMI, smoking, status and history of hypertension

(↑) Valine, leucine, glycine, isoleucine, threonine, palmitic acid (16:0), stearic acid (18:0)

(↓) Ornithine, proline, serine, glycerol

Palmer et al., 2015, J Clin Endocrinol Metab [34]

5-year follow-up study

European American, Hispanic and African American

76

70

plasma

MS/MS

Logistic regression analysis

Age, sex, ethnicity, recruitment site and BMI

(↑) Valine, leucine, isoleucine, tyrosine, phenylalanine, glutamine and glutamate

(↓) Glycine, alanine

(−) Serine, proline, histidine, methionine, ornithine, citrulline, arginine

Ng et al., 2012, Diabetologia [35]

Singapore Diabetes Cohort Study (SDCS)

Singaporean

44

46

urine

GC/MS and LC/MS

OPLS-DA, PCA and LASSO

Multiple hypotheses testing by controlling for FDR

(↑) L-serine, creatinine

Liu et al., 2017, Metabolomics [36]

14-years follow-up study

Southwest of the Netherlands

137

1434

plasma

LC-MS, NMR-COMP and NMR-LIPO

LASSO and ROC curve analysis

Age, sex, family history and BMI

(↑) Isoleucine, methionine, tyrosine, 1,5-anhydroglucitol, 2-hydroxybutyrate, lactate, glycerol

Merino et al., 2018, Diabetologia [37]

Prospective study

Framingham

95

1055

plasma

LC-MS/MS

LASSO and ROC curve analysis

Age, sex, BMI, fasting glucose and triacylglycerols

(↑) Phenylalanine

(↓) Glycine

Li et al., 2017, Mol Biosyst [38]

Case-control study

Chinese

25

20

urine

GC-TOF-MS

PCA, OPLS-DA and ROC curve analysis

Age

(↓) Glycine

(−) Serine, stearic acid, palmitic acid, 1,5-anhydroglucitol

Chou et al., 2018, J Chromatogr B [39]

Case-control study

Chinese (Harbin)

47

48

serum

GC-MS

ANOVA, ROC, PCA and PLS-DA analysis

Age, sex, smoking and alcohol consumption

(↑) Lactate

(−) α-hydroxybutyrate

Wolak-Dinsmore et al., 2018, Clin Biochem [40]

Cross-sectional study

Groningen cohort-white

67

56

serum

LC-MS/MS and NMR spectroscopy

Multivariable linear regression analyses

Age and sex

(↑) Valine, leucine, isoleucine

Lu et al., 2019, Metabolites [41]

Prospective study

Chinese

144

144

serum

LC-MS

t-test, chi-square test and logistic regression

BMI, history of hypertension, smoking status, HDL-cholesterol and triglycerides

(↑) Valine, leucine, Isoleucine, phenylalanine, lysine, methionine, alanine

(−) Threonine, histidine, glutamine, glycine, tyrosine, serine, proline

Lu et al., 2018, J Clin Endocrinol Metab [42]

Follow-up study

Singapore Chinese

144

144

serum

HPLC-QQQ-MS/GC

ROC and conditional logistic regression analysis

BMI, history of hypertension, smoking, physical activity, fasting status, triglycerides and HDL cholesterol

(↑) Myristic acid (14:0), palmitic acid (16:0), stearic acid (18:0), arachidonic acid (20:4n-6)

Friedrich et al., 2015, Metabolomics [43]

Longitudinal cohort study

North-east area of Germany

Men (87), Women (50)

Men (1266), Women (1306)

urine

NMR spectroscopy

Logistic regression and ROC curve analysis

Age and waist circumference

Women: (↑) alanine, glycine, glucose, lactate

(↓) Creatinine

Men: (↑) valine, glucose, lactate

(−) Glycine

  1. (↑), positive association; (↓), negative association; (−), no significant changes
  2. Abbreviations: GC gas chromatography, MS mass spectrometry, LC liquid chromatography, NMR nuclear magnetic resonance spectroscopy, UPLC-TQ-MS ultra-high performance liquid chromatography tandem quadruple mass spectrometry, FIA-MS/MS flow injection analysis tandem mass spectrometry, FIA-ESI-MS/MS flow injection electrospray ionization tandem mass spectrometry, UHPLC-MS/MS high performance liquid chromatography tandem mass spectrometry, KORA Cooperative Health Research in the Region of Augsburg, UPLC-QTOF-MS ultra-high-performance liquid chromatography-quadrupole time-of-flight mass spectrometry, LC-FIA-MS liquid chromatography-flow injection analysis-mass spectrometry, COSY correlation spectroscopy, CPMG Car-Purcell-Meiboom-Gill, HSQC and HMQC heteronuclear and homonuclear single quantum coherence spectroscopy, NMR-COMP small molecular compounds window based NMR spectroscopy, GC-TOF-MS gas chromatography-time-of-flight mass spectrometry, NPLC-TOF/MS normal phase liquid chromatography coupled with time of flight mass spectrometry, HPLC-QQQ-MS/GC HPLC coupled triple quadrupole mass spectrometry, GC-LC-FIA-MS/MS gas chromatography-liquid chromatography-flow injection analysis mass spectrometry/mass spectrometry, LASSO least absolute shrinkage and selection operator, OPLS-DA orthogonal partial least squares-discriminant analysis, ROC receiver operating characteristic, PCA principal component analysis, ANOVA analysis of variance, ANCOVA analysis of covariance, HCA hierarchical cluster analysis, FDR false discovery rate, BMI body mass index, SBP systolic blood pressure, DBP diastolic blood pressure, BUN blood urea nitrogen, HDL high density lipoprotein, LPC lysophosphatidylcholine, a acyl