GC–MS analysis of 4-hydroxyproline: elevated proline hydroxylation in metformin-associated lactic acidosis and metformin-treated Becker muscular dystrophy patients

Author:

Baskal Svetlana,Posma Rene A.,Bollenbach Alexander,Dieperink Willem,Bakker Stephan J. L.,Nijsten Maarten W.,Touw Daan J.,Tsikas Dimitrios

Abstract

AbstractMetformin (N,N-dimethylbiguanide), an inhibitor of gluconeogenesis and insulin sensitizer, is widely used for the treatment of type 2 diabetes. In some patients with renal insufficiency, metformin can accumulate and cause lactic acidosis, known as metformin-associated lactic acidosis (MALA, defined as lactate ≥ 5 mM, pH < 7.35, and metformin concentration > 38.7 µM). Here, we report on the post-translational modification (PTM) of proline (Pro) to 4-hydroxyproline (OH-Pro) in metformin-associated lactic acidosis and in metformin-treated patients with Becker muscular dystrophy (BMD). Pro and OH-Pro were measured simultaneously by gas chromatography–mass spectrometry before, during, and after renal replacement therapy in a patient admitted to the intensive care unit (ICU) because of MALA. At admission to the ICU, plasma metformin concentration was 175 µM, with a corresponding lactate concentration of 20 mM and a blood pH of 7.1. Throughout ICU admission, the Pro concentration was lower compared to healthy controls. Renal excretion of OH-Pro was initially high and decreased over time. Moreover, during the first 12 h of ICU admission, OH-Pro seems to be renally secreted while thereafter, it was reabsorbed. Our results suggest that MALA is associated with hyper-hydroxyprolinuria due to elevated PTM of Pro to OH-Pro by prolyl-hydroxylase and/or inhibition of OH-Pro metabolism in the kidneys. In BMD patients, metformin, at the therapeutic dose of 3 × 500 mg per day for 6 weeks, increased the urinary excretion of OH-Pro suggesting elevation of Pro hydroxylation to OH-Pro. Our study suggests that metformin induces specifically the expression/activity of prolyl-hydroxylase in metformin intoxication and BMD.

Funder

Medizinische Hochschule Hannover (MHH)

Publisher

Springer Science and Business Media LLC

Reference60 articles.

1. Abdelrahman S, Alghrably M, Campagna M, Hauser CAE, Jaremko M, Lachowicz JI (2021) Metal complex formation and anticancer activity of Cu(I) and Cu(II) complexes with metformin. Molecules 26(16):4730. https://doi.org/10.3390/molecules26164730

2. Andreis DT, Mallat J, Tettamanti M, Chiarla C, Giovannini I, Gatti S, Protti A (2021) Increased ratio of P[v-a]CO2 to C[a-v]O2 without global hypoxia: the case of metformin-induced lactic acidosis. Respir Physiol Neurobiol 285:103586. https://doi.org/10.1016/j.resp.2020.103586

3. Apostolova N, Iannantuoni F, Gruevska A, Muntane J, Rocha M, Victor VM (2020) Mechanisms of action of metformin in type 2 diabetes: effects on mitochondria and leukocyte-endothelium interactions. Redox Biol 34:101517. https://doi.org/10.1016/j.redox.2020.101517

4. Baskal S, Bollenbach A, Mels C, Kruger R, Tsikas D (2022a) Development, validation of a GC-MS method for the simultaneous measurement of amino acids, their PTM metabolites and AGEs in human urine, and application to the bi-ethnic ASOS study with special emphasis to lysine. Amino Acids 54(4):615–641. https://doi.org/10.1007/s00726-021-03031-6

5. Baskal S, Bollenbach A, Henzi B, Hafner P, Fischer D, Tsikas D (2022b) Stable-Isotope Dilution GC-MS measurement of metformin in human serum and urine after derivatization with pentafluoropropionic anhydride and its application in becker muscular dystrophy patients administered with metformin, L-citrulline, or their combination. Molecules 27(12):3850. https://doi.org/10.3390/molecules27123850

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