Effects of imeglimin on mitochondrial function, AMPK activity, and gene expression in hepatocytes

Imeglimin is a recently launched antidiabetic drug structurally related to metformin. To provide insight into the pharmacological properties of imeglimin, we investigated its effects on hepatocytes and compared them with those of metformin. The effects of imeglimin on mitochondrial function and gene expression in HepG2 cells were examined with an extracellular flux analyzer and by comprehensive RNA-sequencing analysis, respectively. The effects of the drug on AMPK activity in HepG2 cells and mouse liver were also examined. Treatment of HepG2 cells with imeglimin reduced the oxygen consumption rate coupled to ATP production. Imeglimin activated AMPK in HepG2 cells with a potency similar to that of metformin. Bolus administration of imeglimin in mice also activated AMPK in the liver. Whereas the effects of imeglimin and metformin on gene expression in HepG2 cells were similar overall, the expression of genes encoding proteins of mitochondrial respiratory complex III and complex I was upregulated by imeglimin but not by metformin. Our results suggest that imeglimin and metformin exert similar pharmacological effects on mitochondrial respiration, AMPK activity, and gene expression in cultured hepatocytes, whereas the two drugs differ in their effects on the expression of certain genes related to mitochondrial function.