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Metformin inhibits glycogen synthesis and gluconeogenesis in cultured rat hepatocytes
M Otto1, J Breinholt, N Westergaard
1Department of Hepatic Biochemistry, Novo Nordisk A/S, Novo Nordisk Park, Denmark.
Aim:
Glycogen synthesis, and glucose and lactate production were examined in cultured rat hepatocytes preincubated with metformin (0-500 micro m) for 24 h.
Methods:
Cells incubated with[1-13C]-glucose and [1-13C]-lactate allowed us to study the effect of metformin on glucose production from glycogenolysis and gluconeogenesis in a detailed manner using NMR spectroscopy. 1H and 13C-filtered 1H-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 micro m. 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 micro m metformin.
Conclusion:
Hepatocytes preincubated for 24 h in the presence of metformin at clinically relevant concentrations showed impaired glycogenesis as well as gluconeogenesis.