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Experimental Diabetes Research
Volume 2012, Article ID 465282, 8 pages
Research Article

Metformin Stimulates FGF21 Expression in Primary Hepatocytes

1Department of Pharmacology and Pharmacotherapy, University of Copenhagen, 2100 Copenhagen, Denmark
2Department of Diabetes NBEs & Obesity Biology, Novo Nordisk A/S, 2760 Måløv, Denmark
3Department of Incretin Biology, Hagedorn Research Institute, Novo Nordisk A/S, 2820 Gentofte, Denmark

Received 3 August 2012; Accepted 18 September 2012

Academic Editor: Kazuya Yamagata

Copyright © 2012 Eva B. Nygaard et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Fibroblast growth factor 21 (FGF21) is a novel metabolic regulator of glucose and lipid metabolism; however, the exact mechanism of action and regulation of FGF21 is not fully understood. Metabolic status plays an important role in the regulation of FGF21, and we therefore examined whether metformin, an indirect AMPK-activator, regulates FGF21 expression in hepatocytes. FGF21 mRNA and protein expression were determined after incubation of primary cultured rat and human hepatocytes with metformin for 24 hours. To study the role of AMPK in the putative regulation of FGF21, hepatocytes were incubated with Compound C (an AMPK inhibitor) in the presence of metformin. A strong dose-dependent increase in FGF21 expression was observed in both rat and human hepatocytes treated with metformin. This effect was blocked by addition of the AMPK-inhibitor Compound C. The study shows that metformin is a potent inducer of hepatic FGF21 expression and that the effect of metformin seems to be mediated through AMPK activation. As FGF21 therapy normalizes blood glucose in animal models of type 2 diabetes, the induction of hepatic FGF21 by metformin might play an important role in metformin’s antidiabetic effect.