Imeglimin is a promising new oral antihyperglycemic agent, which has been studied in clinical trials as a possible mono- or add-on therapy to lower fasting plasma glucose and improve hemoglobin A_1c (1-3, 7). Imeglimin was shown to improve both fasting and postprandial glycemia and to increase insulin secretion in response to glucose during a hyperglycemic clamp after 1-week treatment in type 2 diabetic patients. However, whether the β-cell stimulatory effect of imeglimin is solely or partially responsible for its effects on glycemia remains to be fully confirmed. Here we show that imeglimin directly activates β-cell insulin secretion in awake rodents without affecting hepatic insulin sensitivity, body composition, or energy expenditure. These data identify a primary amplification rather than triggering β-cell mechanism that explains the acute, antidiabetic activity of imeglimin.