Pharmacometabolomic Approach to Investigate the Response to Metformin in Patients with Type 2 Diabetes: A Cross-Sectional Study
Abstract
:1. Introduction
2. Materials and Methods
2.1. Data Source and Study Participants
2.2. Metabolomics
2.3. Statistical Analysis
3. Results
3.1. General Characteristics of Participants
3.2. Multivariate Analysis of Metabolites Differentiating Poor and Good Metformin Responders
3.3. Univariate Analysis of Metabolites Differentiating Poor and Good Metformin Responders
3.4. Functional Enrichment Analysis
4. Discussion
4.1. Glycolysis, Gluconeogenesis, and Pyruvate Metabolism
4.2. Gut Microbiome Metabolites
4.3. Sphingomyelins
4.4. Glutamine Metabolism
4.5. Choline Metabolism
4.6. Other Metabolites
5. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
References
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Test | Variable | Total (N = 119) | Poor Responders (N = 70) | Good Responders (N = 49) | p Value |
---|---|---|---|---|---|
Vital signs | Gender (M/F) | 58/61 | 34/36 | 24/25 | 0.56 |
Age | 55.0 (8.2) | 55.3 (8.2) | 54.6 (8.3) | 0.67 | |
BMI (kg/m2) | 31.2 (27.2–35.2) | 31.0 (26.8–36.7) | 31.5 (27.9–33.9) | 0.93 | |
Systolic blood pressure (mmHg) | 126.6 (14.4) | 127.9 (14.7) | 124.9 (14.1) | 0.27 | |
Diastolic blood pressure (mmHg) | 74.0 (10.8) | 73.1 (11.0) | 75.4 (10.4) | 0.25 | |
Pulse rate | 73.2 (11.9) | 76.9 (11.4) | 67.9 (10.5) | <0.001 | |
Blood sugar | Fasting blood glucose (mmol/L) | 8.6 (6.6–11.2) | 10.8 (9.1–15.0) | 6.4 (5.7–7.8) | <0.001 |
HbA1C (%) | 7.5 (6.7–9.0) | 8.5 (8.0–9.3) | 6.5 (6.1–6.8) | <0.001 | |
Insulin (uU/mL) | 15.0 (10–26.4) | 18.7 (12.0–35.6) | 12.0 (8.7–16.5) | <0.001 | |
HOMA-IR | 6.5 (3.3–12.9) | 8.6 (5.7–17.2) | 3.3 (2.4–5.80) | <0.001 | |
C-peptide (ng/mL) | 3.0 (2.0–3.9) | 3.2 (2.0–4.0) | 2.5 (2.0–3.7) | 0.21 | |
Lipid profile | Total cholesterol (mmol/L) | 4.50 (3.9–5.0) | 4.63 (3.80–5.30) | 4.40 (3.89–4.98) | 0.45 |
HDL-cholesterol (mmol/L) | 1.12 (1.00–1.33) | 1.12 (0.98–1.30) | 1.14 (1.03–1.34) | 0.34 | |
LDL-cholesterol (mmol/L) | 2.56 (2.00–3.00) | 2.56 (2.00–3.20) | 2.65 (2.00–3.00) | 0.85 | |
Triglyceride (mmol/L) | 1.60 (1.20–2.20) | 1.60 (1.36–2.36) | 1.24 (1.09–1.80) | 0.002 | |
Kidney function | Creatinine (µmol/L) | 66.0 (55.0–77.0) | 67.0 (53.0–77.0) | 65.0 (54.0–79.5) | 0.85 |
Urea (mmol/L) | 4.5 (3.9–5.5) | 4.6 (4.0–5.6) | 4.4 (3.6–5.1) | 0.12 | |
Lactate (mmol/L) | 0.9 (0.7–1.3) | 0.9 (0.7–1.2) | 0.9 (0.7–1.3) | 0.84 | |
Bicarbonate (mmol/L) | 26.6 (2.3) | 26.2 (2.2) | 27.1 (2.4) | 0.029 | |
Total protein (g/L) | 72.3 (3.5) | 72.8 (3.7) | 71.6 (3.1) | 0.056 | |
Uric acid (µmol/L) | 285 (239–336) | 282 (239–309) | 296 (238–392) | 0.084 | |
Liver function | Albumin (g/L) | 44 (43–46) | 44 (43–46) | 45 (42–45) | 0.78 |
ALT (U/L) | 20 (15–30) | 21 (16–30) | 19 (14–29.5) | 0.19 | |
AST (U/L) | 17 (14–21) | 17 (14–22) | 16 (13.5–21) | 0.37 | |
GGT (U/L) | 23 (15–33) | 29 (21–34) | 17 (12–27) | 0.023 | |
Hormones | TSH (mIU/L) | 1.43 (0.97–2.13) | 1.52 (0.95–2.20) | 1.41 (1.02–2.02) | 0.80 |
Free thyroxine (pmol/L) | 13.2 (12.3–14.2) | 13.2 (12.2–14.1) | 12.9 (12.3–14.4) | 0.90 | |
Free triiodothyronine (pmol/L) | 4.22 (0.59) | 4.22 (0.56) | 4.21 (0.63) | 0.89 |
Metabolite | Super-Pathway | Subpathway | Estimate | SE | p-Value | FDR |
---|---|---|---|---|---|---|
1,5-anhydroglucitol (1,5-AG) | Carbohydrate | Glycolysis, Gluconeogenesis, and Pyruvate Metabolism | 1.164 | 0.160 | 5.89 × 10−11 | 5.16 × 10−8 |
Mannose | Carbohydrate | Fructose, Mannose, and Galactose Metabolism | −0.942 | 0.159 | 3.73 × 10−8 | 1.63 × 10−5 |
Pyroglutamine * | Amino Acid | Glutamate Metabolism | 0.898 | 0.154 | 6.92 × 10−8 | 2.02 × 10−5 |
Glucose | Carbohydrate | Glycolysis, Gluconeogenesis, and Pyruvate Metabolism | −0.758 | 0.145 | 8.87 × 10−7 | 0.000194 |
Linoleoylcholine * | Lipid | Fatty Acid Metabolism (Acyl Choline) | 0.862 | 0.169 | 1.42 × 10−6 | 0.00025 |
Gamma-glutamylglutamine | Peptide | Gamma-glutamyl Amino Acid | 0.871 | 0.183 | 5.67 × 10−6 | 0.000827 |
1-carboxyethylphenylalanine | Amino Acid | Phenylalanine Metabolism | −0.579 | 0.123 | 6.99 × 10−6 | 0.000875 |
Mannonate * | Xenobiotics | Food Component/Plant | −0.660 | 0.142 | 9.41 × 10−6 | 0.00103 |
Sphingomyelin (d18:2/24:2) * | Lipid | Sphingomyelins | 0.699 | 0.157 | 2.08 × 10−5 | 0.002027 |
1-(1-enyl-palmitoyl)-GPC (P-16:0) * | Lipid | Lysoplasmalogen | 0.748 | 0.173 | 3.38 × 10−5 | 0.002963 |
Hydroxypalmitoyl sphingomyelin (d18:1/16:0(OH)) ** | Lipid | Sphingomyelins | 0.670 | 0.161 | 6.52 × 10−5 | 0.004444 |
Arachidonoylcholine | Lipid | Fatty Acid Metabolism (Acyl Choline) | 0.734 | 0.177 | 6.85 × 10−5 | 0.004444 |
Pyruvate | Carbohydrate | Glycolysis, Gluconeogenesis, and Pyruvate Metabolism | −0.704 | 0.171 | 7.10 × 10−5 | 0.004444 |
3-methyl-2-oxobutyrate | Amino Acid | Leucine, Isoleucine and Valine Metabolism | −0.743 | 0.181 | 7.90 × 10−5 | 0.004612 |
Palmitoyl sphingomyelin (d18:1/16:0) | Lipid | Sphingomyelins | 0.543 | 0.136 | 0.00012 | 0.006159 |
Sphingomyelin (d18:2/24:1, d18:1/24:2) * | Lipid | Sphingomyelins | 0.559 | 0.140 | 0.000124 | 0.006159 |
Pseudouridine | Nucleotide | Pyrimidine Metabolism, Uracil containing | 0.689 | 0.174 | 0.000128 | 0.006159 |
Glutamate | Amino Acid | Glutamate Metabolism | −0.574 | 0.145 | 0.000134 | 0.006159 |
Sphingomyelin (d18:1/20:1, d18:2/20:0) * | Lipid | Sphingomyelins | 0.592 | 0.151 | 0.000153 | 0.006721 |
Sphingomyelin (d18:1/22:2, d18:2/22:1, d16:1/24:2) * | Lipid | Sphingomyelins | 0.551 | 0.143 | 0.000189 | 0.007892 |
2-aminooctanoate | Lipid | Fatty Acid, Amino | 0.631 | 0.164 | 0.0002 | 0.007967 |
Alpha-ketobutyrate | Amino Acid | Methionine, Cysteine, SAM and Taurine Metabolism | −0.709 | 0.184 | 0.000209 | 0.007967 |
Palmitoylcholine | Lipid | Fatty Acid Metabolism (Acyl Choline) | 0.661 | 0.174 | 0.000246 | 0.008988 |
Glutamine | Amino Acid | Glutamate Metabolism | 0.673 | 0.181 | 0.000326 | 0.011422 |
Gamma-glutamylcitrulline * | Peptide | Gamma-glutamyl Amino Acid | 0.679 | 0.184 | 0.000347 | 0.011683 |
N-acetylthreonine | Amino Acid | Glycine, Serine, and Threonine Metabolism | 0.572 | 0.155 | 0.000361 | 0.011699 |
Fructose | Carbohydrate | Fructose, Mannose, and Galactose Metabolism | −0.577 | 0.157 | 0.000384 | 0.01202 |
Cysteine-glutathione disulfide | Amino Acid | Glutathione Metabolism | 0.584 | 0.161 | 0.000434 | 0.013119 |
Pro-hydroxy-pro | Amino Acid | Urea cycle; Arginine and Proline Metabolism | 0.640 | 0.185 | 0.000774 | 0.021566 |
Sphingomyelin (d18:1/20:2, d18:2/20:1, d16:1/22:2) * | Lipid | Sphingomyelins | 0.495 | 0.143 | 0.000776 | 0.021566 |
N, N, N-trimethyl-alanylproline betaine (TMAP) | Amino Acid | Urea cycle; Arginine and Proline Metabolism | 0.516 | 0.149 | 0.000788 | 0.021566 |
Methyl glucopyranoside (alpha + beta) | Xenobiotics | Food Component/Plant | 0.721 | 0.213 | 0.001034 | 0.026924 |
Glycerol 3-phosphate | Lipid | Glycerolipid Metabolism | 0.670 | 0.199 | 0.001045 | 0.026924 |
Perfluorooctanoate (PFOA) | Xenobiotics | Chemical | 0.555 | 0.166 | 0.001141 | 0.028559 |
Glycine | Amino Acid | Glycine, Serine and Threonine Metabolism | 0.661 | 0.200 | 0.001269 | 0.030868 |
1-(1-enyl-palmitoyl)-2-linoleoyl-GPC (P-16:0/18:2) * | Lipid | Plasmalogen | 0.470 | 0.144 | 0.001466 | 0.034713 |
Sphingomyelin (d18:2/14:0, d18:1/14:1) * | Lipid | Sphingomyelins | 0.377 | 0.117 | 0.001664 | 0.038324 |
Sphingomyelin (d18:2/16:0, d18:1/16:1) * | Lipid | Sphingomyelins | 0.377 | 0.117 | 0.001719 | 0.038324 |
3-methyl-2-oxovalerate | Amino Acid | Leucine, Isoleucine and Valine Metabolism | −0.582 | 0.181 | 0.00175 | 0.038324 |
5-oxoproline | Amino Acid | Glutathione Metabolism | 0.575 | 0.180 | 0.001873 | 0.039081 |
Maltose | Carbohydrate | Glycogen Metabolism | −0.483 | 0.152 | 0.001874 | 0.039081 |
Orotidine | Nucleotide | Pyrimidine Metabolism, Orotate containing | 0.522 | 0.165 | 0.002111 | 0.042617 |
1-ribosyl-imidazoleacetate * | Amino Acid | Histidine Metabolism | 0.438 | 0.139 | 0.002141 | 0.042617 |
Gamma-glutamylglycine | Peptide | Gamma-glutamyl Amino Acid | 0.625 | 0.200 | 0.002242 | 0.043638 |
Sphingomyelin (d18:1/22:1, d18:2/22:0, d16:1/24:1) * | Lipid | Sphingomyelins | 0.390 | 0.126 | 0.002427 | 0.046226 |
Sphingomyelin (d18:1/18:1, d18:2/18:0) | Lipid | Sphingomyelins | 0.462 | 0.150 | 0.002696 | 0.049799 |
Ribitol | Carbohydrate | Pentose Metabolism | −0.516 | 0.168 | 0.002729 | 0.049799 |
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Naja, K.; Anwardeen, N.; Al-Hariri, M.; Al Thani, A.A.; Elrayess, M.A. Pharmacometabolomic Approach to Investigate the Response to Metformin in Patients with Type 2 Diabetes: A Cross-Sectional Study. Biomedicines 2023, 11, 2164. https://doi.org/10.3390/biomedicines11082164
Naja K, Anwardeen N, Al-Hariri M, Al Thani AA, Elrayess MA. Pharmacometabolomic Approach to Investigate the Response to Metformin in Patients with Type 2 Diabetes: A Cross-Sectional Study. Biomedicines. 2023; 11(8):2164. https://doi.org/10.3390/biomedicines11082164
Chicago/Turabian StyleNaja, Khaled, Najeha Anwardeen, Moustafa Al-Hariri, Asmaa A. Al Thani, and Mohamed A. Elrayess. 2023. "Pharmacometabolomic Approach to Investigate the Response to Metformin in Patients with Type 2 Diabetes: A Cross-Sectional Study" Biomedicines 11, no. 8: 2164. https://doi.org/10.3390/biomedicines11082164