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Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP



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 resistance1,2. 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 diabetes3. 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 experiments4. 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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Figure 1: Biguanides inhibit cAMP accumulation.
Figure 2: Biguanides inhibit glucagon signalling.
Figure 3: Mechanism of biguanide effect on cAMP production.
Figure 4: Biguanides antagonize glucagon signalling in vivo.


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This work was supported by National Institutes of Health (NIH) grants RO1 DK56886 and PO1 DK49210 (M.J.B.) and F32 DK079572 (R.A.M.), the Association pour l’Etude des Diabètes et des Maladies Métaboliques (ALFEDIAM) (to M.F.), the Programme National de Recherche sur le Diabète (PNRD) (to M.F. and B.V.) and the Institut Benjamin Delessert (to M.F.). Microscopy was performed in the University of Pennsylvania Cell and Developmental Biology Microscopy Core Facility. The Transgenic/Knockout, Mouse Phenotyping, Viral Vector and Biomarker Cores of the University of Pennsylvania Diabetes and Endocrinology Research Center (NIH grant P30 DK19525) were instrumental in this work.

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R.A.M. and Q.C. performed experiments; R.A.M. and M.J.B. designed experiments and wrote the manuscript. J.X. generated the phospho-S33 PFKFB1 antibody. M.F. and B.V. generated the AMPK α1 and α2 floxed alleles. J.X., M.F. and B.V. critically read the manuscript.

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Correspondence to Morris J. Birnbaum.

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The authors declare no competing financial interests.

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Miller, R., Chu, Q., Xie, J. et al. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 494, 256–260 (2013).

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