Dual action of imeglimin on insulin secretion and sensitivity in type 2 diabetes

Abstract Aims Imeglimin is a novel oral hypoglycemic agent approved for the treatment of type 2 diabetes in Japan, with dual actions to enhance insulin secretion and improve insulin sensitivity, suggested by preclinical evidence. However, the effect of imeglimin on tissue‐specific insulin sensitivity and glucose kinetics using glucose tracers is unclear. Materials and Methods In this single‐arm intervention study, 22 Japanese men with type 2 diabetes received imeglimin 2000 mg/day for 20 weeks. Glucose metabolism and insulin secretion were assessed by the 75‐g oral glucose tolerance test (OGTT) with double tracers at baseline, 1 week, and 20 weeks. Tissue‐specific insulin sensitivity and insulin clearance were also evaluated in 16 participants using a two‐step hyperinsulinemic–euglycemic clamp before and at 20 weeks. The primary endpoint was the change from baseline in the glucose area under the curve from 0 to 3 h (AUC 0–3h ) during the OGTT at 20 weeks. Results The glucose AUC 0–3h during the OGTT was significantly decreased at 20 weeks of imeglimin administration (median change [interquartile range]: −108.63 [−148.25, −40.75] mg·h/dL, p = 0.0002). A similar reduction was already evident at 1 week. These reductions were mainly attributable to a decreased rate of oral glucose appearance. Insulin secretion indices were increased at 1 and 20 weeks. Clamp studies showed improved insulin sensitivity in skeletal muscle, liver, and adipose tissue, and increased insulin clearance. Conclusions/Interpretation These results provide the first comprehensive evidence in humans that imeglimin improves insulin secretion and insulin sensitivity in multiple tissues.