Hepatic Glucose Production Increases in Response to Metformin Treatment in the Glycogen-depleted State

Metformin is believed to reduce glucose levels primarily by inhibiting hepatic glucose production, but at the same time do not cause hypoglycemia. Recent data indicate that metformin antagonizes the major glucose counterregulatory hormone, glucagon suggesting that other mechanisms protect against hypoglycemia. Here, we examined the effect of metformin on whole-body glucose metabolism after a glycogen-depleting 40 h fast and the role of reduced-function alleles in OCT1. In a randomized cross-over trial, 34 healthy volunteers with known OCT1 genotypes (12 with two wild-type alleles, 13 with one and 9 with two reduced-function alleles) were fasted for 42 h twice. In one of the periods, before the fasting, the volunteers were titrated to steady-state with 1 g metformin twice daily for seven days. Parameters of whole-body glucose metabolism were assessed using [3-3^H] glucose, indirect calorimetry and measurement of substrates and counterregulatory hormone levels. All volunteers completed the glycogen-depleting fast without hypoglycemia. Metformin significantly stimulated glucose disposal rates (GDR) (p=3*10^-13) and non-oxidative glucose metabolism (NOGM) (p=0.001) with no effect on glucose oxidation. The increases in both GDR and NOGM were fully explained by a concomitant increase in glycolytic flux (p=1.7*10^-11). This was accompanied by increased hepatic glucose production (p=8*10^-13), most likely mediated by increased plasma lactate levels (p=0.00004), a small decrease in glucose, and increased levels of glucagon (p=0.03) and cortisol (p=0.002). There was no effect of reduced-function OCT1 alleles on any of these measures. In the glycogen-depleted fasting state, metformin stimulates glycolytic glucose utilization and lactate production. This may trigger a rise in glucose counterregulatory hormones and subsequently an increase in hepatic glucose production, which protects against hypoglycemia.