Methylglyoxal‐derived hydroimidazolone ( MG ‐ H1 ) is a novel marker of insulin resistance in Japanese individuals, disturbing insulin signalling via mTORC2 in cultured myocytes

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.