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In some patients with renal insufficiency, metformin can accumulate and cause lactic acidosis, known as metformin-associated lactic acidosis (MALA, defined as lactate\u2009\u2265\u20095\u00a0mM, pH\u2009&lt;\u20097.35, and metformin concentration\u2009&gt;\u200938.7\u00a0\u00b5M). 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\u2013mass 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\u00a0\u00b5M, with a corresponding lactate concentration of 20\u00a0mM 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\u00a0h 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\u2009\u00d7\u2009500\u00a0mg per day for 6\u00a0weeks, 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.<\/jats:p>","DOI":"10.1007\/s00726-024-03383-9","type":"journal-article","created":{"date-parts":[[2024,3,10]],"date-time":"2024-03-10T08:02:07Z","timestamp":1710057727000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["GC\u2013MS analysis of 4-hydroxyproline: elevated proline hydroxylation in metformin-associated lactic acidosis and metformin-treated Becker muscular dystrophy patients"],"prefix":"10.1007","volume":"56","author":[{"given":"Svetlana","family":"Baskal","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rene A.","family":"Posma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Alexander","family":"Bollenbach","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Willem","family":"Dieperink","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Stephan J. 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Ethical approval was given by the institutional review board (METc 2014\u2013552). Ethics and health authority approvals were obtained from the local Ethics Committee (Pilotstudie zur Untersuchung der Wirksamkeit von l-Citrullin und Metformin bei Erwachsenen mit Muskeldystrophie Becker; reference No. EKBB EK17\/13) and the National Swiss Drug Agency (Swissmedic: <i>Pilotstudie bei Muskeldystrophie Becker<\/i>, reference No. 2013DR2067, release date 30 May 2013).","order":3,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethical approval"}}],"article-number":"21"}}