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 (AUC0–3h) during the OGTT at 20 weeks. Results: The glucose AUC0–3h 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.