title: Metformin Scavenges Methylglyoxal To Form a Novel Imidazolinone Metabolite in Humans.
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 (1)H, (13)C, 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.
authors.affiliation: Southwest Environmental Health Sciences Center, Department of Pharmacology and Toxicology, College of Pharmacy, ‡Department of Chemical & Environmental Engineering, §Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Owen R
authors.initials: OR
authors.lastname: Kinsky
authors.affiliation: Southwest Environmental Health Sciences Center, Department of Pharmacology and Toxicology, College of Pharmacy, ‡Department of Chemical & Environmental Engineering, §Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Tiffanie L
authors.initials: TL
authors.lastname: Hargraves
authors.affiliation: Southwest Environmental Health Sciences Center, Department of Pharmacology and Toxicology, College of Pharmacy, ‡Department of Chemical & Environmental Engineering, §Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Tarun
authors.initials: T
authors.lastname: Anumol
authors.affiliation: Southwest Environmental Health Sciences Center, Department of Pharmacology and Toxicology, College of Pharmacy, ‡Department of Chemical & Environmental Engineering, §Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Neil E
authors.initials: NE
authors.lastname: Jacobsen
authors.affiliation: Southwest Environmental Health Sciences Center, Department of Pharmacology and Toxicology, College of Pharmacy, ‡Department of Chemical & Environmental Engineering, §Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Jixun
authors.initials: J
authors.lastname: Dai
authors.affiliation: Southwest Environmental Health Sciences Center, Department of Pharmacology and Toxicology, College of Pharmacy, ‡Department of Chemical & Environmental Engineering, §Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Shane A
authors.initials: SA
authors.lastname: Snyder
authors.affiliation: Southwest Environmental Health Sciences Center, Department of Pharmacology and Toxicology, College of Pharmacy, ‡Department of Chemical & Environmental Engineering, §Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Terrence J
authors.initials: TJ
authors.lastname: Monks
authors.affiliation: Southwest Environmental Health Sciences Center, Department of Pharmacology and Toxicology, College of Pharmacy, ‡Department of Chemical & Environmental Engineering, §Department of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States.
authors.forename: Serrine S
authors.initials: SS
authors.lastname: Lau
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002851:Chromatography, High Pressure Liquid; D018360:Crystallography, X-Ray; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000473:pathology; D005260:Female; D006801:Humans; D007004:Hypoglycemic Agents / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D048288:Imidazolines / Q000652:urine; D008297:Male; D008687:Metformin / Q000737:chemistry / Q000378:metabolism* / Q000627:therapeutic use; D008875:Middle Aged; D008968:Molecular Conformation; D011765:Pyruvaldehyde / Q000097:blood / Q000737:chemistry*; D053719:Tandem Mass Spectrometry; D055815:Young Adult
chemical_list: D007004:Hypoglycemic Agents; D048288:Imidazolines; D011765:Pyruvaldehyde; D008687:Metformin