Premium
Identification of a novel metformin‐methylglyoxal imidazolinone metabolite in T2DM patients and its potential roles in alleviating T2DM complications
Author(s) -
Hargraves Tiffanie Leann,
Kinsky Owen R.,
Monks Terrence J.,
Lau Serrine S.
Publication year - 2017
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.31.1_supplement.675.1
Subject(s) - methylglyoxal , metformin , chemistry , ampk , metabolite , insulin , protein kinase b , type 2 diabetes mellitus , pharmacology , medicine , endocrinology , diabetes mellitus , biochemistry , protein kinase a , kinase , phosphorylation , enzyme
Reactive dicarbonyls, such as methylglyoxal (MG), are elevated in type‐2 diabetes mellitus (T2DM) patients. These endogenous electrophiles covalently modify proteins, which may contribute to diabetic complications. The T2DM first‐line therapy, metformin (MF), significantly reduces diabetic endpoints and mortality more effectively than other anti‐hyperglycemic agents. Based upon its structure, we examined whether MF directly scavenges MG as an alternative mechanism of drug efficacy, in addition to its antigluconeogenesis properties. We synthesized and characterized a MF/MG imidazolinone product (IMZ) by 13 C, 1 H and HMBC NMR, LC‐MS/MS and X‐ray diffraction. We measured MF and the IMZ product in human urine using a LC/MS multiple reaction monitoring (MRM) method. IMZ was detected in >90 MF‐treated T2DM patients, with increased levels of MF directly correlating with elevations in IMZ. Urinary MF was detected in the range of 0.17 μM ‐ 23.0 mM. Simultaneously the IMZ concentration was measured between 18.8 nM and 4.3 μM. Since reported plasma concentrations of MG are in the range of 40 nM to 4.5 μM, levels of IMZ production may be of therapeutic significance. Since the I1‐imidazoline receptor is a novel target for drug development for disorders associated with T2DM we examined the ability of IMZ to modulate the AMPK, AKT, and ERK1/2 signaling pathways via western blot, following treatment of PC12 cells with IMZ. Combination treatment of insulin and IMZ increased the phosphorylation of AMPK, AKT, and ERK1/2 above levels seen with insulin treatment alone. The results reveal that IMZ may enhance insulin action in the insulin‐dependent AMPK, AKT, and ERK1/2 pathways. In summary, the concordance of IMZ concentration provides evidence that metformin is scavenging MG, thereby reducing detrimental protein modifications, which may play a role in the reduction of diabetic complications. Further, IMZ has the potential to enhance insulin action, and ongoing research may indicate IMZ has potential as a therapeutic for treating insulin resistance. Support or Funding Information R24DK0090958, T32ES007091, P30ES006694