TABLE 1.

Imeglimin's mode of action is distinct versus metformin

Imeglimin	Metformin
In vivo (clinical)
↑Glucose‐stimulated insulin secretion (hyperglycaemic clamp) 39	No reported effect on insulin secretion 39 , 71
Evidence of insulin sensitivity ‐ QUICKI a , Stumvoll a	No clear increase in insulin sensitivity 71 , 72
In vivo (preclinical)
↑Glucose‐stimulated insulin secretion (GTT) 44 ; hyperglycaemic clamp 41 , 43	No effect on insulin secretion 71
↑Glucose disposal; ↑insulin sensitivity (Figure 3); ↑insulin signalling 41 , 44	± Insulin sensitization 71 , 72
Cell and organ
↑Glucose‐stimulated insulin secretion (islets/perfused pancreas) 41 , 43 , 45	No effect on glucose‐stimulated insulin secretion 71 , 73
Islet β‐cell protection; preserved β‐cell mass 41 , 42	In vitro β‐cell protection 74 , 75 ; no known in vivo effects on β‐cell mass 71
↑Muscle glucose uptake 41	± ↑Muscle glucose uptake 71
↓Gluconeogenesis (hepatocytes) 41	↓Gluconeogenesis (hepatocytes) 71
Intracellular
Competitive/partial mitochondrial Complex I inhibition; no decrease in mitochondrial respiration; decreased ROS b formation 44 , 51 , 55	Uncompetitive mitochondrial Complex I inhibition; decreased respiration 55 , 71 ; decreased ROS formation 76 , 77
No effect on mitochondrial glycerophosphate a	↓Mitochondrial glycerophosphate dehydrogenase 58
Increased NAD+ synthesis; potentially via NAMPT c ; increased glucose‐responsive intracellular Ca++ 45	No increase in Ca++; 73 no effect on NAD+ reported 3

^a Poxel, unpublished data.

^b Reactive oxygen species.

^c Nicotinamide phosphoribosyltransferase.

Abbreviations: GTT, glucose tolerance test; NAD⁺, nicotinamide adenine dinucleotide; NAMPT, nicotinamide phosphoribosyltransferase; ROS, reactive oxygen species.