Metformin Scavenges Methylglyoxal To Form a Novel Imidazolinone Metabolite in Humans
| العنوان: | Metformin Scavenges Methylglyoxal To Form a Novel Imidazolinone Metabolite in Humans |
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| المؤلفون: | Tiffanie L. Hargraves, Jixun Dai, Terrence J. Monks, Owen R. Kinsky, Neil E. Jacobsen, Serrine S. Lau, Shane A. Snyder, Tarun Anumol |
| المصدر: | Chemical Research in Toxicology. 29:227-234 |
| بيانات النشر: | American Chemical Society (ACS), 2016. |
| سنة النشر: | 2016 |
| مصطلحات موضوعية: | Adult, Male, 0301 basic medicine, endocrine system diseases, Metabolite, Molecular Conformation, Urine, Pharmacology, Crystallography, X-Ray, Toxicology, Tandem mass spectrometry, Article, Young Adult, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Tandem Mass Spectrometry, Diabetes mellitus, medicine, Humans, Hypoglycemic Agents, Imidazolines, Guanidine, Chromatography, High Pressure Liquid, Aged, Aged, 80 and over, Methylglyoxal, Selected reaction monitoring, nutritional and metabolic diseases, General Medicine, Middle Aged, Pyruvaldehyde, medicine.disease, Metformin, 030104 developmental biology, Diabetes Mellitus, Type 2, Biochemistry, chemistry, Female, 030217 neurology & neurosurgery, medicine.drug |
| الوصف: | 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 from90 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. |
| تدمد: | 1520-5010 0893-228X |
| DOI: | 10.1021/acs.chemrestox.5b00497 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::fce3e3530ba75c8adb503ef953ec3fd6 https://doi.org/10.1021/acs.chemrestox.5b00497 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....fce3e3530ba75c8adb503ef953ec3fd6 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15205010 0893228X |
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| DOI: | 10.1021/acs.chemrestox.5b00497 |