Abstract Background and Aims Methylglyoxal‐derived hydroimidazolone (MG‐H1), one of the advanced glycation end‐products (AGEs), has been a potential biomarker of type 2 diabetes (T2DM), which is strongly related to insulin resistance. However, the relationship between the dynamics of MG‐H1 and insulin resistance has not been characterized, and its mechanism on insulin resistance is unknown. In this study, we aimed to investigate the relationship between MG‐H1 and insulin resistance in the clinical study of Japanese individuals and identify the molecular mechanisms underlying MG‐H1 associated phenomena in vitro. Methods We performed the meal tolerance test (MTT) and hyper‐insulinemic–euglycemic clamp analysis in 19 patients with T2DM and 19 participants without diabetes (non‐DM). We measured their fasting and postprandial MG‐H1 using liquid chromatography–tandem mass spectrometry (LC–MS/MS). In addition, we evaluated the effects of MG‐H1 on glucose uptake and insulin signalling in C2C12 skeletal myocytes. Results The postprandial MG‐H1 and the area under the curve (AUC) of MG‐H1 in MTTs were significantly negatively correlated with the glucose disposal rate (GDR) in clamp studies both in the T2DM ( r = −0.72 p < 0.001) and non‐DM ( r = −0.54 p < 0.05) groups. In cultured C2C12 skeletal myocytes, pre‐treatment with MG‐H1 inhibited insulin‐stimulated phosphorylation of Akt and glucose uptake, via the activation of mechanistic target of rapamycin complex 2 (mTORC2). Conclusions In clinical study findings revealed that postprandial MG‐H1 was a novel marker of insulin resistance in Japanese individuals, and in vitro findings using cultured C2C12 skeletal myocytes suggested that MG‐H1 disturbs insulin signalling via the mechanisms of mTORC2 activation.
Kitao et al. (Fri,) studied this question.