Hyperglucagonemia Mitigates the Effect of Metformin on Glucose Production in Prediabetes

The therapeutic mechanism of metformin action remains incompletely understood. Whether metformin inhibits glucagon-stimulated endogenous glucose production (EGP), as in preclinical studies, is unclear in humans. To test this hypothesis, we studied nine prediabetic individuals using a randomized, placebo-controlled, double-blinded, crossover study design. Metformin increased glucose tolerance, insulin sensitivity, and plasma glucagon. Metformin did not alter average basal EGP, although individual variability in EGP correlated with plasma glucagon. Metformin increased basal EGP in individuals with severe hyperglucagonemia (>150 pg/ml). Decreased fasting glucose after metformin treatment appears to increase glucagon to stimulate EGP and prevent further declines in glucose. Similarly, intravenous glucagon infusion elevated plasma glucagon (>150 pg/ml) and stimulated a greater increase in EGP during metformin therapy. Metformin also counteracted the protein-catabolic effect of glucagon. Collectively, these data indicate that metformin does not inhibit glucagon-stimulated EGP, but hyperglucagonemia may decrease the ability of the metformin to lower EGP in prediabetic individuals. Using a randomized, double-blinded, placebo-controlled, crossover study design in prediabetic individuals, Konopka et al. show that metformin improves fasting and postprandial glycemia without inhibiting glucagon-stimulated glucose production as reported in preclinical studies. During metformin therapy, increased glucagon and decreased glucogenic precursors may maintain glucose production to prevent hypoglycemia.