Metabolomics: Uncovering Insights into Obesity and Diabetes
Abstract
1. Introduction
2. Results
2.1. Participants’ Characteristics
2.2. Overall Analysis
2.3. Fold Change, T-Test, and Volcano Plot Relative to Healthy Controls
- (i)
- Obese only
- (ii)
- Obese prediabetes
- (iii)
- Obese diabetes
2.4. PLS-DA All Groups
2.5. OPLS-DA
- (i)
- Obese only
- (ii)
- Obese prediabetes
- (iii)
- Obese diabetes
2.6. Hierarchal Clustering Analysis (HCA)
3. Discussion
3.1. Cluster 1
3.1.1. Glycine
3.1.2. Myo-Inositol
3.1.3. Trimethylamine N-Oxide (TMAO)
3.1.4. Taurine
3.2. Cluster 2
Branched-Chain Amino Acids (BCAAs)
3.3. Cluster 3
3.3.1. 3-Hydroxybutyrate (3HB)
3.3.2. 3-Amino Isobutyrate
3.3.3. Fucose
3.4. Cluster 4
3.4.1. trans-4-Hydroxy-L-proline
3.4.2. Glutamine
3.4.3. Hydroxyacetone
Metabolites | Author | Populations | Platform | Findings |
---|---|---|---|---|
Cluster 1 | ||||
Glycine | Thalacker-Mercer, A.E., et al. [69] | 124 adults (60 African American and 63 European American) | Hyperinsulinemic-euglycemic clamp | Concentration of glycine was correlated to glucose disposal rate (GDR) |
Cheng, S., et al. [70] | Framingham Heart Study (n = 1015); Malmö Diet & Cancer Study (n = 746) | Liquid chromatography-tandem mass spectrometry (LC-MS) | The criteria for metabolic syndrome were met by 45% individuals | |
Floegel, A., et al. [19] | (EPIC)-Potsdam study (2282 individuals of the subcohort and 800 individuals with incident T2D) | Tandem mass spectrometry (FIA-MS/MS) | Glycine levels tend to be lower in individuals with obesity and T2D | |
Takashina, C., et al. [71] | Ninety-four healthy Japanese volunteers aged 20–60 years | HPLC | The 2 h or fasting plasma glucose levels or HOMA-IR were positively correlated with glutamate, valine, and tyrosine levels but negatively correlated with glutamine, citrulline, and glycine levels | |
Tulipani, S., et al. [72] | 64 adults; sex-matched groups for BMI and risk of developing T2D | LC- and flow injection analysis-(electrospray ionization) mass spectrometry (FIA-ESI-MS/MS) | Glycine concentration is negatively associated with fasting insulin and HOMA-IR (R = −0.51, R = −0.49, respectively; both p < 0.0033) | |
Wijayatunga, N.N., et al. [73] | 20 patients undergoing RYGB surgery, pre- and 6 months post-surgery | NMR | Serum glycine was significantly elevated at 6 months post-surgery compared with pre-surgery (n = 8, p < 0.05) | |
1,6-anhydro-D-glucose | Kawaguchi, T., et al. [74] | Five male patients with NAFLD; a randomized, single-blinded controlled interventional study | LC-time-of-flight mass spectrometry (TOFMS) | Isomaltulose improved insulin resistance in NAFLD patients |
myo-inositol | Croze, M.L., et al. [30] | High-fat diet (HFD) was fed to C57BL/6 male mouse for 1 month (n = 10) | HPLC | Inosituria, which is myo-inositol urinary excretion, was correlated with glycosuria in mice (R2 0.915, linear regression) |
Wu, C., et al. [32] | Chinese cohort of 631 obese subjects and 374 normal-weight controls | Shotgun metagenomic sequencing | Identified a Megamonas-dominated, enterotype-like cluster enriched in obese subjects, where Megamonas rupellensis possessed genes for myo-inositol degradation, which is a myo-inositol degrader. This function enhances lipid absorption and obesity | |
Sikes, K.J., et al. [75] | 90 mice | Gas Chromatography Mass Spectrometry (GCMS) | Untargeted metabolomics analysis identifies creatine, myo-inositol, and lipid pathway modulation in a murine model of tendinopathy | |
4-hydroxyphenylacetate | Wang, P., et al. [76] | 24 mice, 16 weeks | GC-MS | 4-HPA was sufficient to reverse obesity and glucose intolerance in HFD-fed mice. Mechanistically, 4-HPA treatment markedly regulates SIRT1 signaling pathways and induces the expression of beige fat and thermogenesis-specific markers in white adipose tissue (WAT) |
Osborn, L.J., et al. [77] | Male C57BL/6 mice | High-performance liquid chromatography tandem mass spectrometry (LC-MS/MS) | a single gut microbial flavonoid catabolite, 4-hydroxyphenylacetic acid (4-HPAA), is sufficient to reduce diet-induced cardiometabolic disease (CMD) burden in mice | |
Chen, W., et al. [78] | 32 male C57BL mice | Urine metabolomic analysis by UHPLC-Q-TOF/MS | Microbial phenolic metabolites 3-(3′,4′-dihydroxyphenyl) propanoic acid and 3′,4′-dihydroxyphenylacetic acid prevent obesity in mice fed with high-fat diet | |
3-hydroxyphenylacetate | Zhang, Y., et al. [56] | 28 of 6-week-old male ICR/KM mice, high-fat diet | 1H-NMR | High-fat diet significantly reduced the 3-hydroxyphenylacetate concentrations in the cecum contents of mice |
Glucose | Li, M., et al. [79] | Virgin Wistar rats, supplemented with taurine | Autoanalyser | Maternal taurine supplementation may ameliorate the adverse effects observed in offspring following a maternal obesogenic diet |
Trimethylamine N-oxid (TMAO) | Zhang, Q., et al. [80] | 28 of 6-week-old male ICR/KM mice, high-fat diet | 1H-NMR | High-fat-diet-induced obese mice supplemented with fibers have lower levels of TMAO, compared to control subjects |
Barrea, L., et al. [34] | 330 adult Caucasians subjects (20–63 years) of both genders | HPLC/MS | TMAO levels increased along with BMI and were positively associated with VAI and FLI, independently | |
Lee, S.J., et al. [81] | 38 obese patients (18 with and 20 without T2D) who underwent bariatric surgery | UPLC/TQ-MS | TMAO increased more than twofold in patients with T2D after surgery, but not in patients without T2D | |
Li, X., et al. [82] | Sixteen M. mulatta (six months old) were fed a control diet or a HFHC diet for 18 months | 1H-NMR | The diet rich in fish affects the concentration of TMAO, also the high-fat and high-calorie diet increases the levels of serum TMAO | |
Cluster 2 | ||||
valine | Ho, J.E., et al. [83] | 2383 Framingham Offspring cohort participants | LC-MS | Valine was associated with 4 metabolic traits: BMI, HOMA-IR, HDL, and triglycerides; circulating branched-chain amino acids, like valine, have emerged as strongly and positively associated with adiposity |
Tai, E.S., et al. [84] | 263 non-obese, Asian-Indian and Chinese men, cross-sectional study in Singapore | Tandem MS (MS/MS) | Insulin resistance (IR) was correlated with increased levels of valine | |
Wang, T.J., et al. [48] | The Framingham Offspring Study, 2422, free of diabetes and cardiovascular disease, underwent routine oral glucose tolerance testing (OGTT), >35 years | LC-MS | 2422 individuals with normal glucose levels followed for 12 years, 201 developed diabetes Valine had highly significant associations with future diabetes | |
2-methylglutarate | Wijayatunga, N.N., et al. [73] | 20 patients undergoing RYGB surgery pre and 6 months post-surgery | 1H-NMR | Serum 2-methylglutarate was significantly reduced, at 6 months post-surgery compared with pre-surgery (n = 8, p < 0.05) |
Leucine | Ozcariz, E., et al. [85] | 1387 individuals from the general population | 1H-NMR | Leucine was found to be significantly different between clusters of metabolic profiles of cardiometabolic risk in patients with obesity |
Isoleucine | Yu, D., et al. [86] | male C57BL/6J mice | Quadrupole-orbitrap mass spectrometer | Reducing isoleucine or valine rapidly restores metabolic health to diet-induced obese mice. A low isoleucine diet reprograms liver and adipose metabolism, increasing hepatic insulin sensitivity |
Trautman M.E. et al., 2024 [87] | C57BL/6J and DBA/2J mice | Quadrupole-orbitrap mass spectrometer | Reducing dietary levels of isoleucine rapidly improves the metabolic health of diet-induced obese male C57BL/6J mice | |
Cluster 3 | ||||
3-hydroxybutyrate (3-OHB) | Zhang, Y., et al. [56] | Four-week-old male C57BL/6 mice | Glucose uptake assay | 3OHB improves glucose tolerance, reduces fasting blood glucose level, and ameliorates insulin resistance in T2D mice through hydroxycarboxylic acid receptor 2 (HCAR2) |
Jung, J., et al. [88] | Mice (db/db) were fed normal chow, high-fat, or ketogenic diets | Determination of Reactive Oxygen Species (ROS) | in vivo and in vitro models show that 3-OHB delays the progression of diabetic nephropathy by augmenting autophagy and inhibiting oxidative stress | |
3-aminoisobutyrate | Yousri, N.A., et al. [89] | 996 individuals in Qatar | ultra-performance liquid chromatography (UPLC), mass spectrometer interfaced with a heated electrospray ionization (HESI-II) source and Orbitrap mass analyzer | 3-aminoisobutyrate was in the T2D top most significant metabolites from the total of 229 metabolites, sorted by pathway |
Kistner, S., et al. [90] | 255 healthy women and men, urine samples | 1H-NMR | 15–30 min following an incremental cycling test, valine derivative 3-aminoisobutyrate increased | |
Cluster 4 | ||||
trans-4-hydroxy-L-proline | Kenéz, Á., et al. [91] | Twenty horses of various breeds, ages, and body weights | LC-MS/MS | Due to trans-4-hydroxy-l-proline, and high concentration of glycine, collagen has been shown to stimulate insulin secretion and stabilize blood sugar levels in individuals with T2D Lower plasma trans-4-hydroxyproline is associated with insulin dysregulation in horses |
Glutamine | Floegel, A., et al. [19] | 27,548 participants from the general population in Germany; 35–65 years of age | FIA-MS/MS | Glutamine improved insulin sensitivity |
Stancáková, A., et al. [92] | 9369 non-diabetic or newly diagnosed T2D men from the population-based study (METSIM Study) (mean ± SD age, 57 ± 7 years; BMI, 27.0 ± 4.0 kg/m2) | 1H-NMR | Elevated fasting and 2 h plasma glucose levels were associated with increasing levels of several amino acids and reduced levels of glutamine | |
Palmer, N.D., et al. [93] | 196 subjects European American, Hispanic, and African American Insulin Resistance Atherosclerosis Study (IRAS) | Mass spectrometry | the glutamine-to-glutamate ratio was found to predict insulin resistance after 5 years in participants | |
Hydroxyacetone | Reichard, G.A., et al. [67] | Patients with diabetes ketoacidosis (DKA) | Gas chromatograph equipped with a flame ionization detector | Acetol (1-hydroxyacetone), a possible metabolite of acetone, was detected in plasma of the patient during diabetic ketoacidosis |
Schumacher, D., et al. [94] | 15 diabetes patients 15 healthy controls | LC-MS/MS | Diabetic patients without complications had the highest content of hydroxyacetone |
4. Materials and Methods
4.1. Study Design
4.2. Individual Inclusion and Exclusion Criteria
- Inclusion Criteria
- Exclusion Criteria
4.3. Blood Biochemical Profile
4.4. Sample Preparation for Metabolomic Analysis
4.5. Spectra Acquisition
4.6. Metabolite Identification
4.7. Data Pretreatment
4.8. Statistical Analysis
4.9. Multivariate Analysis
4.10. Clustering and Visualization
4.11. Study Strengths
4.12. Study Limitations
5. Conclusions
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Healthy Controls n = 26 | Obese Only n = 45 | Obese Prediabetes n = 37 | Obese Diabetes n = 29 | |
---|---|---|---|---|
Age, years † | 25 (8) | 37 (13) | 41 (12) | 38 (10) |
Age group, n (%) | ||||
<40 years | 26 (100) | 32 (71.1) | 14 (37.8) | 18 (62.1) |
≥40 years | 13 (28.9) | 23 (62.2) | 11 (37.9) | |
Sex, n (%) | ||||
Female | 16 (61.5) | 36 (80.0) | 19 (51.4) | 16 (55.2) |
Male | 10 (38.5) | 9 (20.0) | 18 (48.6) | 13 (44.8) |
Weight, kg † | 55.42 (8.40) | 97.91 (23.20) a** | 128.51 (41.55) a**,b** | 120.71 (29.92) a**,b* |
BMI, kg/m2 † | 21.12 (2.02) | 36.92 (7.80) a** | 46.09 (12.60) a**,b** | 43.47 (7.71)a**,b* |
HbA1c, % † | 5.10 (0.58) | 5.40 (0.40) | 6.00 (0.35) a** | 6.90 (1.25) a**,b**,c** |
TC, mmol/L | 5.00 (0.69) | 5.22 (0.92) | 4.94 (0.91) | 5.58 (1.31) |
TG, mmol/L † | 0.78 (0.34) | 0.88 (0.66) | 1.27 (0.69) | 1.59 (0.79) a**,b** |
HDL-C, mmol/L † | 1.73 (0.40) | 1.39 (0.34) a** | 1.25 (0.28) a** | 1.15 (0.19) a**,c* |
LDL-C, mmol/L | 2.91 (0.51) | 3.32 (0.81) | 3.11 (0.84) | 3.53 (1.15) a* |
No | Metabolites | Significance |
---|---|---|
1 | Glycine | 1.63 × 10−13 |
2 | 1,6-Anhydro-β-D-glucose | 1.89 × 10−12 |
3 | Glucose | 1.73 × 10−11 |
4 | Taurine | 1.86 × 10−11 |
5 | 4-Hydroxyphenylacetate | 4.56 × 10−11 |
6 | myo-Inositol | 5.69 × 10−11 |
7 | Putrescine | 6.51 × 10−11 |
8 | π-Methylhistidine | 1.39 × 10−10 |
9 | 3-Hydroxyphenylacetate | 1.75 × 10−10 |
10 | Trimethylamine N-oxide (TMAO) | 1.63 × 10−13 |
Category | HbA1c (%) |
---|---|
Normal | <5.7 |
Prediabetes | 5.7–<6.3 |
Type 2 diabetes (T2D) | ≥6.3 |
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Fazliana, M.; Gee, T.; Lim, S.Y.; Tsen, P.Y.; Nor Hanipah, Z.; Zainal Abidin, N.A.; Zhuan, T.Y.; Mohkiar, F.H.; Ahmad Zamri, L.; Ahmad, H.; et al. Metabolomics: Uncovering Insights into Obesity and Diabetes. Int. J. Mol. Sci. 2025, 26, 6216. https://doi.org/10.3390/ijms26136216
Fazliana M, Gee T, Lim SY, Tsen PY, Nor Hanipah Z, Zainal Abidin NA, Zhuan TY, Mohkiar FH, Ahmad Zamri L, Ahmad H, et al. Metabolomics: Uncovering Insights into Obesity and Diabetes. International Journal of Molecular Sciences. 2025; 26(13):6216. https://doi.org/10.3390/ijms26136216
Chicago/Turabian StyleFazliana, Mansor, Tikfu Gee, Shu Yu Lim, Poh Yue Tsen, Zubaidah Nor Hanipah, Nur Azlin Zainal Abidin, Tan You Zhuan, Farah Huda Mohkiar, Liyana Ahmad Zamri, Haron Ahmad, and et al. 2025. "Metabolomics: Uncovering Insights into Obesity and Diabetes" International Journal of Molecular Sciences 26, no. 13: 6216. https://doi.org/10.3390/ijms26136216
APA StyleFazliana, M., Gee, T., Lim, S. Y., Tsen, P. Y., Nor Hanipah, Z., Zainal Abidin, N. A., Zhuan, T. Y., Mohkiar, F. H., Ahmad Zamri, L., Ahmad, H., Draman, M. S., Yusaini, N. S., & Mohd Nawi, M. N. (2025). Metabolomics: Uncovering Insights into Obesity and Diabetes. International Journal of Molecular Sciences, 26(13), 6216. https://doi.org/10.3390/ijms26136216