2023 Volume 158 Issue 2 Pages 193-202
Imeglimin hydrochloride (imeglimin) is an orally drug for type 2 diabetes mellitus, which was approved in Japan for the first in the world, with dual mode of actions: pancreatic action means amplifying glucose-stimulated insulin secretion (GSIS) in pancreatic β-cells, and extrapancreatic action means improving insulin sensitivity by which gluconeogenesis suppresses in hepatocytes and glucose uptake increases in skeletal muscles. Although the molecular target of imeglimin is still unknown, imeglimin exerts some of its actions through modulation of the mitochondrial function. In pancreatic islets, imeglimin enhanced adenosine triphosphate and Ca2+ under high-glucose conditions. Furthermore, imeglimin induced the synthesis of oxidized form nicotinamide adenine dinucleotide (NAD+) via the ‘salvage pathway’, and NAD+ metabolites may contribute to the increase in intracellular Ca2+. The in vivo studies indicated that imeglimin enhanced the sensitivity to insulin and modulated the mitochondrial function (restoring the deficient Complex III activity, decreasing Complex I activity and reactive oxygen species production), which contribute to the improvement of glucose metabolism in hepatocytes and skeletal muscles. In clinical trials, imeglimin’s dual effects were demonstrated in foreign type 2 diabetic patients who received 1500 mg bid, which is different from the domestic approved dose. Imeglimin has been shown to evidence of statistically significant glucose lowering, a generally favorable safety and tolerability profile in patients with type 2 diabetes by monotherapy and combination therapy with 1,000 mg bid in four Japanese trials. Since imeglimin has dual effects, it may have shown a newly effective option, regardless of the pathophysiology of type 2 diabetic patients.
