GC-MS analysis of 4-hydroxyproline : elevated proline hydroxylation in metformin-associated lactic acidosis and metformin-treated Becker muscular dystrophy patients
© 2024. The Author(s)..
Metformin (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.
Medienart: |
E-Artikel |
---|
Erscheinungsjahr: |
2024 |
---|---|
Erschienen: |
2024 |
Enthalten in: |
Zur Gesamtaufnahme - volume:56 |
---|---|
Enthalten in: |
Amino acids - 56(2024), 1 vom: 10. März, Seite 21 |
Sprache: |
Englisch |
---|
Beteiligte Personen: |
Baskal, Svetlana [VerfasserIn] |
---|
Links: |
---|
Anmerkungen: |
Date Completed 12.03.2024 Date Revised 13.03.2024 published: Electronic Citation Status MEDLINE |
---|
doi: |
10.1007/s00726-024-03383-9 |
---|
funding: |
|
---|---|
Förderinstitution / Projekttitel: |
|
PPN (Katalog-ID): |
NLM369511522 |
---|
LEADER | 01000caa a22002652 4500 | ||
---|---|---|---|
001 | NLM369511522 | ||
003 | DE-627 | ||
005 | 20240313234657.0 | ||
007 | cr uuu---uuuuu | ||
008 | 240311s2024 xx |||||o 00| ||eng c | ||
024 | 7 | |a 10.1007/s00726-024-03383-9 |2 doi | |
028 | 5 | 2 | |a pubmed24n1326.xml |
035 | |a (DE-627)NLM369511522 | ||
035 | |a (NLM)38461423 | ||
040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
041 | |a eng | ||
100 | 1 | |a Baskal, Svetlana |e verfasserin |4 aut | |
245 | 1 | 0 | |a GC-MS analysis of 4-hydroxyproline |b elevated proline hydroxylation in metformin-associated lactic acidosis and metformin-treated Becker muscular dystrophy patients |
264 | 1 | |c 2024 | |
336 | |a Text |b txt |2 rdacontent | ||
337 | |a ƒaComputermedien |b c |2 rdamedia | ||
338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
500 | |a Date Completed 12.03.2024 | ||
500 | |a Date Revised 13.03.2024 | ||
500 | |a published: Electronic | ||
500 | |a Citation Status MEDLINE | ||
520 | |a © 2024. The Author(s). | ||
520 | |a Metformin (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 | ||
650 | 4 | |a Journal Article | |
650 | 4 | |a 4-Hydroxyproline | |
650 | 4 | |a Amino acids | |
650 | 4 | |a BMD | |
650 | 4 | |a Dialysis | |
650 | 4 | |a GC–MS | |
650 | 4 | |a Intoxication | |
650 | 4 | |a Kidney injury | |
650 | 4 | |a MALA | |
650 | 4 | |a Mass spectrometry | |
650 | 4 | |a PTM | |
650 | 4 | |a Renal replacement therapy (RTR) | |
650 | 7 | |a Metformin |2 NLM | |
650 | 7 | |a 9100L32L2N |2 NLM | |
650 | 7 | |a Hydroxyproline |2 NLM | |
650 | 7 | |a RMB44WO89X |2 NLM | |
650 | 7 | |a Proline |2 NLM | |
650 | 7 | |a 9DLQ4CIU6V |2 NLM | |
650 | 7 | |a Lactic Acid |2 NLM | |
650 | 7 | |a 33X04XA5AT |2 NLM | |
650 | 7 | |a Mixed Function Oxygenases |2 NLM | |
650 | 7 | |a EC 1.- |2 NLM | |
650 | 7 | |a Hypoglycemic Agents |2 NLM | |
700 | 1 | |a Posma, Rene A |e verfasserin |4 aut | |
700 | 1 | |a Bollenbach, Alexander |e verfasserin |4 aut | |
700 | 1 | |a Dieperink, Willem |e verfasserin |4 aut | |
700 | 1 | |a Bakker, Stephan J L |e verfasserin |4 aut | |
700 | 1 | |a Nijsten, Maarten W |e verfasserin |4 aut | |
700 | 1 | |a Touw, Daan J |e verfasserin |4 aut | |
700 | 1 | |a Tsikas, Dimitrios |e verfasserin |4 aut | |
773 | 0 | 8 | |i Enthalten in |t Amino acids |d 1991 |g 56(2024), 1 vom: 10. März, Seite 21 |w (DE-627)NLM09155182X |x 1438-2199 |7 nnns |
773 | 1 | 8 | |g volume:56 |g year:2024 |g number:1 |g day:10 |g month:03 |g pages:21 |
856 | 4 | 0 | |u http://dx.doi.org/10.1007/s00726-024-03383-9 |3 Volltext |
912 | |a GBV_USEFLAG_A | ||
912 | |a GBV_NLM | ||
951 | |a AR | ||
952 | |d 56 |j 2024 |e 1 |b 10 |c 03 |h 21 |