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Identification of a urinary cyclized metformin‐methylglyoxal metabolite in metformin‐treated diabetes patients (1142.9)
Author(s) -
Kinsky Owen,
Anumol Tarun,
Hargraves Tiffanie,
Snyder Shane,
Monks Terrence,
Lau Serrine
Publication year - 2014
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.28.1_supplement.1142.9
Subject(s) - methylglyoxal , metformin , metabolite , urine , type 2 diabetes mellitus , diabetes mellitus , chemistry , urinary system , medicine , type 2 diabetes , creatinine , biguanide , advanced glycation end product , endocrinology , pharmacology , glycation , biochemistry , enzyme
Reactive dicarbonyls such as methylglyoxal (MG) are elevated in type‐2 diabetes mellitus (T2DM) patients and their ability to covalently modify proteins contributes to diabetic complications. The T2DM first‐line drug metformin (MF) significantly reduces diabetes‐related endpoints and mortality more effectively than other glucose‐lowering medications. We have examined whether, in addition to its ability to reduce hepatic gluconeogenesis, MF directly scavenges dicarbonyls as an additional mechanism to reduce T2DM complications. We synthesized a MF/MG cyclized product (183 mw) according to a published method, and characterized the product by ESI‐MS/MS mass spectrometry (MH + , 184 m/z; Agilent 6490) and 13 C and 1 H NMR (Bruker AVIII‐400). Using an LC‐MS‐based multiple reaction monitoring analysis we measured MF and cyclized metabolite (CM) in human urine with nM sensitivity of detection. The CM was detected in all 30+ MF‐treated T2DM subjects analyzed to date. Quantitation of CM in MF subjects is ongoing, using creatinine or specific gravity normalization. Correlations between CM levels and diabetic complications will be determined. The data reveal that urine from every T2DM patient treated with MF contains this MG scavenging product. The role of the CM in the reduction of diabetic complications warrants further study. Grant Funding Source : Supported by DK090958, ABRC, ES016652, T32ES007091, P30ES006694.