TitleHyperglucagonemia Mitigates the Effect of Metformin on Glucose Production in Prediabetes.
Publication TypeJournal Article
Year of Publication2016
AuthorsKonopka, AR, Esponda, RRuiz, Robinson, MM, Johnson, ML, Carter, RE, Schiavon, M, Cobelli, C, Wondisford, FE, Lanza, IR, K Nair, S
JournalCell Rep
Date Published2016 May 17

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.

Alternate JournalCell Rep
PubMed ID27160898
PubMed Central IDPMC4871720
Grant ListR01 DK041973 / DK / NIDDK NIH HHS / United States
P30 DK050456 / DK / NIDDK NIH HHS / United States
U24 DK100469 / DK / NIDDK NIH HHS / United States
UL1 TR000135 / TR / NCATS NIH HHS / United States
T32 DK007352 / DK / NIDDK NIH HHS / United States