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.
Keywords: 75‐g oral glucose tolerance test (OGTT) with double tracers; hyperinsulinemic–euglycemic clamp; imeglimin; insulin clearance; tissue‐specific insulin sensitivity.
© 2026 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.