Imeglimin enhances GLUT4-mediated glucose uptake and is more effective than metformin in 3T3-L1 adipocytes

Imeglimin, a novel oral antidiabetic agent derived from metformin, improves insulin secretion and sensitivity in patients with type 2 diabetes. Recent clinical clamp studies have identified adipose tissue as a potential target of imeglimin; however, its direct effects on adipocytes are unclear. In this study, differentiated 3T3-L1 adipocytes were treated with imeglimin or metformin. We then examined glucose concentration in the culture medium, glucose uptake, plasma membrane glucose transporter expression, and the effects of signaling inhibitors. Imeglimin enhanced glucose uptake in a dose-dependent manner and reduced glucose concentration in the culture medium. Imeglimin was more effective than metformin at equivalent concentrations. Imeglimin also exerted an additive effect in the presence of insulin. Plasma membrane fractionation and immunoblotting revealed that imeglimin increased cell-surface glucose transporter (GLUT) 4 expression selectively, without altering total GLUT4 protein or plasma membrane GLUT1 levels. This suggests that increased GLUT4 translocation contributes to enhanced glucose uptake. Further, pharmacological inhibition studies demonstrated that imeglimin-induced glucose uptake was unaffected by AMPK inhibition but attenuated by inhibition of phosphoinositide 3-kinase, Akt, or protein kinase C. Additionally, the PI3K inhibitor Ly294002 suppressed imeglimin-induced GLUT4 accumulation at the plasma membrane. These findings identify adipocytes as a relevant cellular target of imeglimin and support, at least in part, the involvement of PI3K-dependent GLUT4 regulation in facilitating glucose transport, which may contribute to favorable effects of imeglimin on adipose tissue glucose metabolism in vivo.