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A novel metformin‐methylglyoxal imidazolinone metabolite (IMZ) sensitizes cells to insulin; a potential role in alleviating T2DM complications
Author(s) -
Hargraves Tiffanie L.,
Mastrandrea Nicholas J.,
Lau Serrine S.,
Monks Terrence J.
Publication year - 2018
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.2018.32.1_supplement.571.8
Subject(s) - methylglyoxal , insulin , metformin , insulin receptor , medicine , endocrinology , metabolite , chemistry , type 2 diabetes mellitus , glucose homeostasis , pharmacology , diabetes mellitus , insulin resistance , protein kinase b , biochemistry , signal transduction , enzyme
Reactive dicarbonyls, such as methylglyoxal (MG), are elevated in type‐two 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 adverse diabetic endpoints and mortality more effectively than other anti‐hyperglycemic agents, the mechanism(s) of which remain unclear. We previously identified and characterized the product of the MF and MG reaction as a novel five‐membered imidazolinone (IMZ) metabolite. IMZ was detected via LC/MS in all MF‐treated T2DM patients, and increased MF urinary levels directly correlated with elevations in urinary IMZ. Scavenging of MG by MF represents a possible alternative mechanism of MF drug efficacy, in addition to its antigluconeogenesis properties. Imidazoline receptor subtypes (I 1 R, I 2 R, and I 3 R) are novel targets for drug development in disorders associated with T2DM because they are involved in insulin sensitization, insulin secretion, and glucose homeostasis. Thus, we examined the ability of IMZ to modulate insulin‐mediated cell signaling pathways via western blot in PC12 cells, which express high levels of I 1 R and lack the α2‐adrenergic receptor, which many I 1 R agonists also activate. Combination treatment of insulin and IMZ at physiologically relevant concentrations increased AKT and ERK1/2 phosphorylation above levels seen with insulin treatment alone. This potentiation was not observed in the presence of I 1 R antagonists. Moreover, IMZ restores insulin sensitivity in an insulin resistant HEPG2 cell model. The results revealed that IMZ may enhance insulin action in the insulin‐dependent AKT and ERK1/2 pathways through I 1 R activation. Preliminary in vivo pharmacokinetic studies show that IMZ (IP; 10mg/kg and 20mg/kg) is rapidly absorbed, with an elimination half‐life of 12–16.5 minutes. In addition, IMZ enhanced hepatic pAKT 40 minutes after the 10mg/kg dose. In summary, the formation of IMZ in T2DM patients provides evidence that MF scavenges MG, potentially reducing detrimental protein modifications. This property of MF may play a role in the reduction of diabetic complications and represent a potential alternative mechanism of MF drug efficacy. Further, IMZ itself may have the ability to enhance insulin action, suggesting possible clinical utility in the treatment of T2DM. Support or Funding Information R24DK0090958, T32ES007091, P30ES006694 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .