α-ketoglutarate is associated with delayed wound healing in diabetes.

Abstract

A high level of matrix metalloproteinase 9 (MMP-9) is a predictor of poor wound healing in diabetic foot ulcers. In skin keratinocytes, site-specific DNA demethylation plays an important role in MMP-9 expression. Ten-eleven translocation enzyme 2 (TET2) protein, one member of TET family, could rely on α-ketoglutarate (α-KG) as cosubstrate to exhibit catalytic activity of DNA demethylation. Here, we aimed to explore the changes of α-KG and its relationship with MMP-9 and TET2 during diabetic wound healing. Seventy-one cases of patients with diabetic foot ulcers and 53 cases of nondiabetic ulcers were enrolled. Serum, urine and wound fluids were collected for measurement of α-KG levels and MMP-9 expression. Skin tissues were collected for the measurement of TET2 and MMP-9 expression. Clinical parameters were collected, and transcutaneous oxygen pressure (TcPO2) levels of feet were detected. The levels of α-KG, TET2 and MMP-9 were significantly increased in diabetic wound compared with nondiabetic wound (P = 0·010, 0·016 and 0·025). There was a significant correlation between a low TcPO2 and a high α-KG level of wound fluids (r = -0·395, P = 0·002). Further analysis showed that α-KG concentration had a positive correlation with both haemoglobin A1c (HbA1C) and 2 h postprandial blood glucose (PBG) (r = 0·393, P = 0·005; r = 0·320, P = 0·025, respectively). The levels of α-KG, TET2 and MMP-9 were significantly increased in diabetic wound compared with nondiabetic wound. Elevated α-KG was related to local hypoxia ischaemia status and systematic poor glycaemic control.