Imeglimin may improve albuminuria associated with partial suppression of inflammatory and fibrotic markers in diabetic kidney disease

Imeglimin is an oral hypoglycemic agent marketed in Japan that has shown glucose-lowering effects in Japanese patients with type 2 diabetes in TIMES trials. However, it is not well known whether imeglimin can affect diabetic kidney disease (DKD). To clarify this, we investigated the potential association between the effects of imeglimin and DKD using diabetic mice (DM) and cultured endothelial cells. Administration of imeglimin significantly lowered urinary albumin excretion in DKD but did not significantly affect blood glucose and glycated albumin. RNA sequencing analysis of the renal cortex indicated the upregulation of antioxidant, oxidative phosphorylation, and AMP-activated protein kinase (AMPK) signaling pathways and downregulation of inflammation, atherosclerosis, and reactive oxygen species. Additionally, imeglimin decreased the mRNA expression of TNF-α , F4/80 , and fibronectin in the renal cortex of mice with DKD. In parallel with the findings that imeglimin reduced the protein expression of fibronectin in the renal cortex of mice with DKD, renal histological fibrosis was significantly increased in diabetic mice compared with non-diabetic mice (NDM), which was significantly reduced in mice receiving imeglimin. In an in vitro study, high glucose (HG) induced the mRNA expression of Nlrp3 , Vcam-1 , and NOX4 , which were downregulated by imeglimin. These results suggest that imeglimin could improve albuminuria by partially suppressing inflammatory and fibrotic markers in DKD.