Metformin Scavenges Methylglyoxal to Form a Novel Imidazolinone Metabolite in Humans

Owen R. Kinsky, Tiffanie L. Hargraves, Tarun Anumol, Neil E. Jacobsen, Jixun Dai, Shane A Snyder, Terrence Monks, Serrine Lau

Research output: Contribution to journalArticle

27 Citations (Scopus)

Abstract

Methylglyoxal (MG) is a highly reactive dicarbonyl compound involved in the formation of advanced glycation endproducts (AGE). Levels of MG are elevated in patients with type-2 diabetes mellitus (T2DM), and AGE have been implicated in the progression of diabetic complications. The antihyperglycemic drug metformin (MF) has been suggested to be a scavenger of MG. The present work examined and characterized unequivocally the resulting scavenged product from the metformin-MG reaction. The primary product was characterized by 1H, 13C, 2D-HSQC, and HMBC NMR and tandem mass spectrometry. X-ray diffraction analysis determined the structure of the metformin and MG-derived imidazolinone compound as (E)-1,1-dimethyl-2-(5-methyl-4-oxo-4,5-dihydro-1H-imidazol-2-yl)guanidine (IMZ). A LC-MS/MS multiple reaction monitoring method was developed to detect and quantify the presence of IMZ in metformin-treated T2DM patients. Urine from >90 MF-treated T2DM patients was analyzed, with increased levels of MF directly correlating with elevations in IMZ. Urinary MF was detected in the range of 0.17 μM to 23.0 mM, and simultaneous measurement of IMZ concentrations were in the range of 18.8 nM to 4.3 μM. Since plasma concentrations of MG range from 40 nM to 4.5 μM, the level of IMZ production may be of therapeutic significance. Thus, in addition to lowering hepatic gluconeogenesis, metformin also scavenges the highly reactive MG in vivo, thereby reducing potentially detrimental MG protein adducts, with subsequent reductions in diabetic complications.

Original languageEnglish (US)
Pages (from-to)227-234
Number of pages8
JournalChemical Research in Toxicology
Volume29
Issue number2
DOIs
StatePublished - Feb 15 2016

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Pyruvaldehyde
Metformin
Metabolites
Medical problems
Type 2 Diabetes Mellitus
Diabetes Complications
Gluconeogenesis
Guanidine
Tandem Mass Spectrometry
Hypoglycemic Agents
X-Ray Diffraction
X ray diffraction analysis
Mass spectrometry
Nuclear magnetic resonance
Urine
Plasmas
Monitoring
Liver

ASJC Scopus subject areas

  • Toxicology

Cite this

Metformin Scavenges Methylglyoxal to Form a Novel Imidazolinone Metabolite in Humans. / Kinsky, Owen R.; Hargraves, Tiffanie L.; Anumol, Tarun; Jacobsen, Neil E.; Dai, Jixun; Snyder, Shane A; Monks, Terrence; Lau, Serrine.

In: Chemical Research in Toxicology, Vol. 29, No. 2, 15.02.2016, p. 227-234.

Research output: Contribution to journalArticle

Kinsky, Owen R. ; Hargraves, Tiffanie L. ; Anumol, Tarun ; Jacobsen, Neil E. ; Dai, Jixun ; Snyder, Shane A ; Monks, Terrence ; Lau, Serrine. / Metformin Scavenges Methylglyoxal to Form a Novel Imidazolinone Metabolite in Humans. In: Chemical Research in Toxicology. 2016 ; Vol. 29, No. 2. pp. 227-234.
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