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Cited by 833

The DOI matches its Crossref record; 29 of the 29 references it cites were found in a registry or an index.

Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP

Open access
Miller, Russell A., Chu, Qingwei, Xie, Jianxin, Foretz, Marc, Viollet, Benoit, Birnbaum, Morris J.·2013·Nature
DOI 10.1038/nature11808
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Abstract

Glucose production by the liver is essential for providing a substrate for the brain during fasting. The inability of insulin to suppress hepatic glucose output is a major aetiological factor in the hyperglycaemia of type-2 diabetes mellitus and other diseases of insulin resistance. For fifty years, one of the few classes of therapeutics effective in reducing glucose production has been the biguanides, which include phenformin and metformin, the latter the most frequently prescribed drug for type-2 diabetes. Nonetheless, the mechanism of action of biguanides remains imperfectly understood. The suggestion a decade ago that metformin reduces glucose synthesis through activation of the enzyme AMP-activated protein kinase (AMPK) has recently been challenged by genetic loss-of-function experiments. Here we provide a novel mechanism by which metformin antagonizes the action of glucagon, thus reducing fasting glucose levels. In mouse hepatocytes, metformin leads to the accumulation of AMP and related nucleotides, which inhibit adenylate cyclase, reduce levels of cyclic AMP and protein kinase A (PKA) activity, abrogate phosphorylation of critical protein targets of PKA, and block glucagon-dependent glucose output from hepatocytes. These data support a mechanism of action for metformin involving antagonism of glucagon, and suggest an approach for the development of antidiabetic drugs.

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Metadata

Authors
Miller, R. A., Chu, Q., Xie, J., Foretz, M., Viollet, B., & Birnbaum, M. J.
Venue
Nature
Publisher
Springer Science and Business Media LLC
Published
2013-01-06
Volume
494
Issue
7436
Pages
256-260
ISSN
  • 0028-0836 (ISSN-L)
  • 1476-4687
DOI
10.1038/nature11808
OpenAlex
W2026413615
Cited by
833
References
29
FWCI
39.13
Type
journal article
Language
en
Open access
green

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CoChat. (2026). Citation check: Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. https://app.cochat.ai/papers/10.1038/nature11808
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Miller, R. A., Chu, Q., Xie, J., Foretz, M., Viollet, B., & Birnbaum, M. J. (2013). Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature. https://doi.org/10.1038/nature11808

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Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).

Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.