Nothing Special   »   [go: up one dir, main page]
Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Letter
  • Published:

Biguanides suppress hepatic glucagon signalling by decreasing production of cyclic AMP

Nature volume 494, pages 256–260 (2013)Cite this article

Subjects

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.

Access through your institution
Buy or subscribe

This is a preview of subscription content, access via your institution

Access options

Access through your institution

Buy this article

  • Purchase on SpringerLink
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. DeFronzo, R. A., Simonson, D. & Ferrannini, E. Hepatic and peripheral insulin resistance: a common feature of type 2 (non-insulin-dependent) and type 1 (insulin-dependent) diabetes mellitus. Diabetologia 23, 313–319 (1982)

    Article  CAS  Google Scholar 

  2. Postic, C., Dentin, R. & Girard, J. Role of the liver in the control of carbohydrate and lipid homeostasis. Diabetes Metab. 30, 398–408 (2004)

    Article  CAS  Google Scholar 

  3. Nathan, D. M. et al. Medical management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy: a consensus statement of the American Diabetes Association and the European Association for the Study of Diabetes. Diabetes Care 32, 193–203 (2009)

    Article  CAS  Google Scholar 

  4. Foretz, M. et al. Metformin inhibits hepatic gluconeogenesis in mice independently of the LKB1/AMPK pathway via a decrease in hepatic energy state. J. Clin. Invest. 120, –2355–2369 (2010)

    Article  CAS  Google Scholar 

  5. Inzucchi, S. E. et al. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N. Engl. J. Med. 338, 867–873 (1998)

    Article  CAS  Google Scholar 

  6. Goodarzi, M. O. & Bryer-Ash, M. Metformin revisited: re-evaluation of its properties and role in the pharmacopoeia of modern antidiabetic agents. Diabetes Obes. Metab. 7, 654–665 (2005)

    Article  CAS  Google Scholar 

  7. El-Mir, M. Y. et al. Dimethylbiguanide inhibits cell respiration via an indirect effect targeted on the respiratory chain complex I. J. Biol. Chem. 275, 223–228 (2000)

    Article  CAS  Google Scholar 

  8. Owen, M. R., Doran, E. & Halestrap, A. P. Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem. J. 348, 607–614 (2000)

    Article  CAS  Google Scholar 

  9. Shaw, R. J. et al. The kinase LKB1 mediates glucose homeostasis in liver and therapeutic effects of metformin. Science 310, 1642–1646 (2005)

    Article  ADS  CAS  Google Scholar 

  10. Zhou, G. et al. Role of AMP-activated protein kinase in mechanism of metformin action. J. Clin. Invest. 108, 1167–1174 (2001)

    Article  CAS  Google Scholar 

  11. D’Alessio, D. The role of dysregulated glucagon secretion in type 2 diabetes. Diabetes Obes. Metab. 13 (suppl. 1). 126–132 (2011)

    Article  Google Scholar 

  12. Jiang, G. & Zhang, B. B. Glucagon and regulation of glucose metabolism. Am. J. Physiol. Endocrinol. Metab. 284, E671–E678 (2003)

    Article  CAS  Google Scholar 

  13. Unger, R. H. & Cherrington, A. D. Glucagonocentric restructuring of diabetes: a pathophysiologic and therapeutic makeover. J. Clin. Invest. 122, 4–12 (2012)

    Article  CAS  Google Scholar 

  14. Tucker, G. T. et al. Metformin kinetics in healthy subjects and in patients with diabetes mellitus. Br. J. Clin. Pharmacol. 12, 235–246 (1981)

    Article  CAS  Google Scholar 

  15. Wilcock, C. & Bailey, C. J. Accumulation of metformin by tissues of the normal and diabetic mouse. Xenobiotica 24, 49–57 (1994)

    Article  CAS  Google Scholar 

  16. Allen, M. D. & Zhang, J. Subcellular dynamics of protein kinase A activity visualized by FRET-based reporters. Biochem. Biophys. Res. Commun. 348, 716–721 (2006)

    Article  CAS  Google Scholar 

  17. Fain, J. N., Pointer, R. H. & Ward, W. F. Effects of adenosine nucleosides on adenylate cyclase, phosphodiesterase, cyclic adenosine monophosphate accumulation, and lipolysis in fat cells. J. Biol. Chem. 247, 6866–6872 (1972)

    CAS  PubMed  Google Scholar 

  18. Blume, A. J. & Foster, C. J. Mouse neuroblastoma adenylate cyclase. Adenosine and adenosine analogues as potent effectors of adenylate cyclase activity. J. Biol. Chem. 250, 5003–5008 (1975)

    CAS  PubMed  Google Scholar 

  19. Londos, C. & Preston, M. S. Regulation by glucagon and divalent cations of inhibition of hepatic adenylate cyclase by adenosine. J. Biol. Chem. 252, 5951–5956 (1977)

    CAS  PubMed  Google Scholar 

  20. Johnson, R. A., Yeung, S. M., Stubner, D., Bushfield, M. & Shoshani, I. Cation and structural requirements for P site-mediated inhibition of adenylate cyclase. Mol. Pharmacol. 35, 681–688 (1989)

    CAS  PubMed  Google Scholar 

  21. Berglund, E. D. et al. Hepatic energy state is regulated by glucagon receptor signaling in mice. J. Clin. Invest. 119, 2412–2422 (2009)

    Article  CAS  Google Scholar 

  22. Stoll, B., Gerok, W., Lang, F. & Haussinger, D. Liver cell volume and protein synthesis. Biochem. J. 287, 217–222 (1992)

    Article  CAS  Google Scholar 

  23. Masson, S. & Quistorff, B. The 31P NMR visibility of ATP in perfused rat liver remains about 90%, unaffected by changes of metabolic state. Biochemistry 31, 7488–7493 (1992)

    Article  CAS  Google Scholar 

  24. Gawler, D. J., Wilson, A. & Houslay, M. D. Metformin treatment of lean and obese Zucker rats modulates the ability of glucagon and insulin to regulate hepatocyte adenylate cyclase activity. J. Endocrinol. 122, 207–212 (1989)

    Article  CAS  Google Scholar 

  25. Torres, T. P. et al. Impact of a glycogen phosphorylase inhibitor and metformin on basal and glucagon-stimulated hepatic glucose flux in conscious dogs. J. Pharmacol. Exp. Ther. 337, 610–620 (2011)

    Article  ADS  CAS  Google Scholar 

  26. Yu, B., Pugazhenthi, S. & Khandelwal, R. L. Effects of metformin on glucose and glucagon regulated gluconeogenesis in cultured normal and diabetic hepatocytes. Biochem. Pharmacol. 48, 949–954 (1994)

    Article  CAS  Google Scholar 

  27. Zhang, T. et al. Mechanisms of metformin inhibiting lipolytic response to isoproterenol in primary rat adipocytes. J. Mol. Endocrinol. 42, 57–66 (2009)

    Article  Google Scholar 

  28. Fain, J. N. & Malbon, C. C. Regulation of adenylate cyclase by adenosine. Mol. Cell. Biochem. 25, 143–169 (1979)

    Article  CAS  Google Scholar 

  29. Miller, R. A. et al. Adiponectin suppresses gluconeogenic gene expression in mouse hepatocytes independent of LKB1-AMPK signaling. J. Clin. Invest. 121, 2518–2528 (2011)

    Article  CAS  Google Scholar 

  30. Post, S. R., Ostrom, R. S. & Insel, P. A. Biochemical methods for detection and measurement of cyclic AMP and adenylyl cyclase activity. Methods Mol. Biol. 126, 363–374 (2000)

    CAS  PubMed  Google Scholar 

Download references

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.

Author information

Authors and Affiliations

  1. Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, 19104, Pennsylvania, USA

    Russell A. Miller, Qingwei Chu & Morris J. Birnbaum

  2. Cell Signaling Technology, Inc., 3 Trask Lane, Danvers, Massachusetts 01923, USA,

    Jianxin Xie

  3. Inserm, U1016, Institut Cochin, Paris, 75014, France

    Marc Foretz & Benoit Viollet

  4. Cnrs, UMR8104, Paris, 75014, France

    Marc Foretz & Benoit Viollet

  5. Université Paris Descartes, Sorbonne Paris cité, Paris 75006, France,

    Marc Foretz & Benoit Viollet

Authors
  1. Russell A. Miller
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qingwei Chu
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jianxin Xie
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marc Foretz
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Benoit Viollet
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Morris J. Birnbaum
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Morris J. Birnbaum.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Information

This file contains Supplementary Figures 1-11 and Supplementary Tables 1-2. (PDF 3864 kb)

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature11808

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing