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 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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Acknowledgements
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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Miller, R., Chu, Q., Xie, J. et al. Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP. Nature 494, 256–260 (2013). https://doi.org/10.1038/nature11808
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DOI: https://doi.org/10.1038/nature11808
HOMERO VELAZQUEZ CAMPOS
It is for me surprising, the results this group had achieved: First Glucagon is not only produce by alpha cells in pancreas, second glucagon produced by liver, could be interfered with biguanides,
like metformin.About 16 years ago, that I am using metformin to control glucose in blood and body weight, with success.That time I was not so old like now : I am 67 years old and the early
dosis doesn´t work like before: I have to put an extra gramm to get the same results,even against
my physician opinion, who wanted me to use insulin.My argument is quit simple: I do not need
more insulin, the enemy to defeat in my case is certainly not the lack of insulin,but the insulin
resistance ( I am diabetic type 2) But I didn´t have any idea, where and how the metformin works.
Now It a little more clear for me, where and how my physiology is failing.
What I wish for the future , for me and many people like me (we are several millions all over the world!), that such research could give other alternatives (not only biguanides!) to control this biochemical process, making us, the patients who suffer the illness, live a little more simple and pleasant