Metformin inhibits glycogen synthesis and gluconeogenesis in cultured rat hepatocytes

Aim: Glycogen synthesis, and glucose and lactate production were examined in cultured rat hepatocytes preincubated with metformin (0-500 mum) for 24 h. Methods: Cells incubated with[1-C-13]-glucose and [1-C-13]-lactate allowed us to study the effect of metformin on glucose production from glycogenolysis and gluconeogenesis in a detailed manner using NMR spectroscopy. H-1 and C-13-filtered H-1-NMR spectra were recorded by using flow-injection technique. Results: Metformin decreased glycogen synthesis in a dose-dependent manner with an IC50 value of 196.5 mum. This effect could not be reversed by the presence of the glycogen phosphorylase inhibitor DAB, suggesting that glycogenolysis was not affected. A clear correlation between glucose production and glycogen content (0.97 < R < 0.99; p < 0.001) and lactate production and glycogen content (0.97 < R < 0.99; p < 0.001) was observed. Moreover, a strong inhibition (62%, p < 0.001) of glucose produced from lactate/pyruvate (3 mm/0.3 mm) was observed in cells treated with 350 μm metformin. Conclusion: Hepatocytes preincubated for 24 h in the presence of metformin at clinically relevant concentrations showed impaired glycogenesis as well as gluconeogenesis.