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Cell Rep. 2016 May 17;15(7):1394-1400. doi: 10.1016/j.celrep.2016.04.024. Epub 2016 May 5.

Hyperglucagonemia Mitigates the Effect of Metformin on Glucose Production in Prediabetes.

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Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA.
Division of Biomedical Statistics and Informatics, Mayo Clinic, Rochester, MN 55905, USA.
Department of Information Engineering, University of Padova, 35131 Padova, Italy.
Department of Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, NJ 08901, USA.
Division of Endocrinology, Mayo Clinic, Rochester, MN 55905, USA. Electronic address:


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.

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