Abstract
Objective: Metformin is a commonly prescribed antidiabetic drug that inhibits hepatic glucose production (HGP). The effect of metformin on other key metabolic functions of the liver and the extent of inter-individual variation are largely unknown.
Methods: We used our mathematical model HEPATOKIN1 of liver metabolism, developed and validated in a previously published study, to assess the effect of metformin on liver metabolism in adolescent patients with non-alcoholic fatty liver disease.
Results: On average, a single dose of metformin reduced diurnal hepatic glucose production (HGP) by 19%. Based on the z(1) score, 15% of patients were classified as low responders or high responders. During elevated metformin plasma levels for about four hours after metformin ingestion, energy metabolism, cystosolic and mitochondrial redox potential, urea synthesis and ketone body synthesis were reduced by 10-30%, but averaged over 24 hours, these metabolic side effects were not significant. The reduction in HGP correlated strongly with the reduction in lactate uptake, making the increase in plasma lactate after drug ingestion a likely indicator of metformin efficacy. Of the 50 clinical parameters tested, only plasma lactate and plasma insulin activity correlated positively with the reduction in HGP.
Conclusion: On a daily average, metformin selectively affects hepatic glucose production, glycogen storage and lactate uptake, while numerous other metabolic functions are significantly altered for several hours after administration of the drug. Our method provides a patient-specific analysis of the potential effects of metformin therapy on central hepatic metabolism and may therefore help guide the physician's therapeutic decision.