PMID- 26771051 OWN - NLM STAT- MEDLINE DCOM- 20161028 LR - 20220408 IS - 1520-5010 (Electronic) IS - 0893-228X (Print) IS - 0893-228X (Linking) VI - 29 IP - 2 DP - 2016 Feb 15 TI - Metformin Scavenges Methylglyoxal To Form a Novel Imidazolinone Metabolite in Humans. PG - 227-34 LID - 10.1021/acs.chemrestox.5b00497 [doi] AB - 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 muM to 23.0 mM, and simultaneous measurement of IMZ concentrations were in the range of 18.8 nM to 4.3 muM. Since plasma concentrations of MG range from 40 nM to 4.5 muM, 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. FAU - Kinsky, Owen R AU - Kinsky OR AD - Southwest Environmental Health Sciences Center, Department of Pharmacology and Toxicology, College of Pharmacy, double daggerDepartment of Chemical & Environmental Engineering, section signDepartment of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States. FAU - Hargraves, Tiffanie L AU - Hargraves TL AD - Southwest Environmental Health Sciences Center, Department of Pharmacology and Toxicology, College of Pharmacy, double daggerDepartment of Chemical & Environmental Engineering, section signDepartment of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States. FAU - Anumol, Tarun AU - Anumol T AD - Southwest Environmental Health Sciences Center, Department of Pharmacology and Toxicology, College of Pharmacy, double daggerDepartment of Chemical & Environmental Engineering, section signDepartment of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States. FAU - Jacobsen, Neil E AU - Jacobsen NE AD - Southwest Environmental Health Sciences Center, Department of Pharmacology and Toxicology, College of Pharmacy, double daggerDepartment of Chemical & Environmental Engineering, section signDepartment of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States. FAU - Dai, Jixun AU - Dai J AD - Southwest Environmental Health Sciences Center, Department of Pharmacology and Toxicology, College of Pharmacy, double daggerDepartment of Chemical & Environmental Engineering, section signDepartment of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States. FAU - Snyder, Shane A AU - Snyder SA AD - Southwest Environmental Health Sciences Center, Department of Pharmacology and Toxicology, College of Pharmacy, double daggerDepartment of Chemical & Environmental Engineering, section signDepartment of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States. FAU - Monks, Terrence J AU - Monks TJ AD - Southwest Environmental Health Sciences Center, Department of Pharmacology and Toxicology, College of Pharmacy, double daggerDepartment of Chemical & Environmental Engineering, section signDepartment of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States. FAU - Lau, Serrine S AU - Lau SS AD - Southwest Environmental Health Sciences Center, Department of Pharmacology and Toxicology, College of Pharmacy, double daggerDepartment of Chemical & Environmental Engineering, section signDepartment of Chemistry and Biochemistry, University of Arizona , Tucson, Arizona 85721, United States. LA - eng GR - P30 ES006694/ES/NIEHS NIH HHS/United States GR - R24 DK090958/DK/NIDDK NIH HHS/United States GR - T32 ES007091/ES/NIEHS NIH HHS/United States GR - R24DK090958/DK/NIDDK NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20160127 PL - United States TA - Chem Res Toxicol JT - Chemical research in toxicology JID - 8807448 RN - 0 (Hypoglycemic Agents) RN - 0 (Imidazolines) RN - 722KLD7415 (Pyruvaldehyde) RN - 9100L32L2N (Metformin) SB - IM MH - Adult MH - Aged MH - Aged, 80 and over MH - Chromatography, High Pressure Liquid MH - Crystallography, X-Ray MH - Diabetes Mellitus, Type 2/drug therapy/pathology MH - Female MH - Humans MH - Hypoglycemic Agents/chemistry/*metabolism/therapeutic use MH - Imidazolines/urine MH - Male MH - Metformin/chemistry/*metabolism/therapeutic use MH - Middle Aged MH - Molecular Conformation MH - Pyruvaldehyde/blood/*chemistry MH - Tandem Mass Spectrometry MH - Young Adult PMC - PMC5444333 MID - NIHMS858868 COIS- Notes The authors declare no competing financial interest. EDAT- 2016/01/16 06:00 MHDA- 2016/11/01 06:00 PMCR- 2017/05/25 CRDT- 2016/01/16 06:00 PHST- 2016/01/16 06:00 [entrez] PHST- 2016/01/16 06:00 [pubmed] PHST- 2016/11/01 06:00 [medline] PHST- 2017/05/25 00:00 [pmc-release] AID - 10.1021/acs.chemrestox.5b00497 [doi] PST - ppublish SO - Chem Res Toxicol. 2016 Feb 15;29(2):227-34. doi: 10.1021/acs.chemrestox.5b00497. Epub 2016 Jan 27.