A Metabolic Pattern in Healthy Subjects Given a Single Dose of Metformin: A Metabolomics Approach

Lina A Dahabiyeh; Muhammad Mujammami; Tawfiq Arafat; Hicham Benabdelkamel; Assim A Alfadda; Anas M Abdel Rahman

doi:10.3389/fphar.2021.705932

A Metabolic Pattern in Healthy Subjects Given a Single Dose of Metformin: A Metabolomics Approach

Front Pharmacol. 2021 Jul 15:12:705932. doi: 10.3389/fphar.2021.705932. eCollection 2021.

Authors

Lina A Dahabiyeh¹, Muhammad Mujammami^{2

3}, Tawfiq Arafat⁴, Hicham Benabdelkamel⁵, Assim A Alfadda^{2

5}, Anas M Abdel Rahman^{6

7

8}

Affiliations

¹ Department of Pharmaceutical Sciences, School of Pharmacy, The University of Jordan, Amman, Jordan.
² Endocrinology and Diabetes Unit, Department of Medicine, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
³ University Diabetes Center, King Saud University Medical City, King Saud University, Riyadh, Saudi Arabia.
⁴ Jordan Center for Pharmaceutical Research, Amman, Jordan.
⁵ Proteomics Resource Unit, Obesity Research Center, College of Medicine, King Saud University, Riyadh, Saudi Arabia.
⁶ Metabolomics Section, Department of Clinical Genomics, Center for Genome Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh, Saudi Arabia.
⁷ Department of Biochemistry and Molecular Medicine, College of Medicine, Al Faisal University, Riyadh, Saudi Arabia.
⁸ Department of Chemistry, Memorial University of Newfoundland, St. John's, NL, Canada.

Abstract

Metformin is a widely prescribed medication for the treatment of type 2 diabetes mellitus (T2DM). It possesses effective roles in various disorders, including cancer, dyslipidemia, and obesity. However, the underlying mechanisms of metformin's multiple benefits are not fully understood. Herein, a mass spectrometry-based untargeted metabolomics approach was used to investigate the metabolic changes associated with the administration of a single dose of metformin in the plasma of 26 healthy subjects at five-time points; pre-dose, before the maximum concentration of metformin (C_max), C_max, after C_max, and 36 h post-dose. A total of 111 metabolites involved in various biochemical processes were perturbed, with branched-chain amino acid (BCAA) being the most significantly altered pathway. Additionally, the Pearson similarity test revealed that 63 metabolites showed a change in their levels dependent on metformin level. Out of these 63, the level of 36 metabolites was significantly altered by metformin. Significantly altered metformin-dependent metabolites, including hydroxymethyl uracil, propionic acid, glycerophospholipids, and eicosanoids, pointed to fundamental biochemical processes such as lipid network signaling, energy homeostasis, DNA lesion repair mechanisms, and gut microbiota functions that could be linked to the multiple beneficial roles of metformin. Thus, the distinctive metabolic pattern linked to metformin administration can be used as a metabolic signature to predict the potential effect and mechanism of actions of new chemical entities during drug development.

Keywords: branched-chain amino acids; cancer; eicosanoids; glycerophospholipid; mass spectrometry; metabolomics; metformin; type 2 diabetes mellitus.