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.

  • Review Article
  • Published:

Adenosine signalling in diabetes mellitus—pathophysiology and therapeutic considerations

Nature Reviews Endocrinology volume 11, pages 228–241 (2015)Cite this article

Subjects

Key Points

  • Preclinical studies have highlighted a critical role for the adenosine system in the regulation of glucose homeostasis and the pathophysiology of diabetes mellitus

  • Adenosine signalling regulates β-cell homeostasis by controlling the proliferation and regeneration of these cells, as well as by promoting their survival in an inflammatory microenvironment

  • Adenosine modulates insulin secretion mainly via A1 and A2A adenosine receptors

  • Signalling through the A2A adenosine receptor increases proliferation and survival of β cells and promotes β-cell regeneration

  • A2B adenosine receptors modulate glucose and lipid homeostasis and regulate the activity of resident macrophages in adipose tissue in type 2 diabetes mellitus

  • Adenosine contributes to endothelial dysfunction in endothelial cells from the umbilical veins of patients with gestational diabetes mellitus

Abstract

Adenosine is a key extracellular signalling molecule that regulates several aspects of tissue function by activating four G-protein-coupled receptors, A1, A2A, A2B and A1 adenosine receptors. Accumulating evidence highlights a critical role for the adenosine system in the regulation of glucose homeostasis and the pathophysiology of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM). Although adenosine signalling is known to affect insulin secretion, new data indicate that adenosine signalling also contributes to the regulation of β-cell homeostasis and activity by controlling the proliferation and regeneration of these cells as well as the survival of β cells in inflammatory microenvironments. Furthermore, adenosine is emerging as a major regulator of insulin responsiveness by controlling insulin signalling in adipose tissue, muscle and liver; adenosine also indirectly mediates effects on inflammatory and/or immune cells in these tissues. This Review critically discusses the role of the adenosine–adenosine receptor system in regulating both the onset and progression of T1DM and T2DM, and the potential of pharmacological manipulation of the adenosinergic system as an approach to manage T1DM, T2DM and their associated complications.

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

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

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

Figure 1: Adenosinergic pathways.
Figure 2: Adenosine regulation of β-cell function.
Figure 3: Regulation of adipose tissue, skeletal muscle and liver functions by adenosine receptors.

Similar content being viewed by others

References

  1. Shaw, J. E., Sicree, R. A. & Zimmet, P. Z. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res. Clin. Pract. 87, 4–14 (2010).

    Article  CAS  PubMed  Google Scholar 

  2. Centers for Disease Control and Prevention. National diabetes statistics report, 2014 [online], (2014).

  3. Zimmet, P. Z., Magliano, D. J., Herman, W. H. & Shaw, J. E. Diabetes: a 21st century challenge. Lancet Diabetes Endocrinol. 2, 56–64 (2014).

    Article  PubMed  Google Scholar 

  4. Canivell, S. & Gomis, R. Diagnosis and classification of autoimmune diabetes mellitus. Autoimmun. Rev. 13, 403–407 (2014).

    Article  CAS  PubMed  Google Scholar 

  5. Tuomi, T. et al. The many faces of diabetes: a disease with increasing heterogeneity. Lancet 383, 1084–1094 (2014).

    Article  PubMed  Google Scholar 

  6. American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care 37 (Suppl. 1), S81–S90 (2014).

  7. Antonioli, L., Blandizzi, C., Pacher, P. & Hasko, G. Immunity, inflammation and cancer: a leading role for adenosine. Nat. Rev. Cancer 13, 842–857 (2013).

    Article  CAS  PubMed  Google Scholar 

  8. Koupenova, M. & Ravid, K. Adenosine, adenosine receptors and their role in glucose homeostasis and lipid metabolism. J. Cell. Physiol. http://dx.doi.org/10.1002/jcp.24352.

  9. Grden, M., Podgorska, M., Szutowicz, A. & Pawelczyk, T. Diabetes-induced alterations of adenosine receptors expression level in rat liver. Exp. Mol. Pathol. 83, 392–398 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Eisenstein, A. & Ravid, K. G protein-coupled receptors and adipogenesis: a focus on adenosine receptors. J. Cell. Physiol. 229, 414–421 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Hasko, G., Linden, J., Cronstein, B. & Pacher, P. Adenosine receptors: therapeutic aspects for inflammatory and immune diseases. Nat. Rev. Drug Discov. 7, 759–770 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Yip, L., Taylor, C., Whiting, C. C. & Fathman, C. G. Diminished adenosine A1 receptor expression in pancreatic α-cells may contribute to the pathology of type 1 diabetes. Diabetes 62, 4208–4219 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Csoka, B. et al. A2B adenosine receptors prevent insulin resistance by inhibiting adipose tissue inflammation via maintaining alternative macrophage activation. Diabetes 63, 850–866 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Johnston-Cox, H. et al. The A2b adenosine receptor modulates glucose homeostasis and obesity. PLoS ONE 7, e40584 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ohtani, M., Oka, T. & Ohura, K. Possible involvement of A2A and A3 receptors in modulation of insulin secretion and β-cell survival in mouse pancreatic islets. Gen. Comp. Endocrinol. 187, 86–94 (2013).

    Article  CAS  PubMed  Google Scholar 

  16. Yang, G. K., Fredholm, B. B., Kieffer, T. J. & Kwok, Y. N. Improved blood glucose disposal and altered insulin secretion patterns in adenosine A1 receptor knockout mice. Am. J. Physiol. Endocrinol. Metab. 303, E180–E190 (2012).

    Article  CAS  PubMed  Google Scholar 

  17. Johansson, S. M. et al. A1 receptor deficiency causes increased insulin and glucagon secretion in mice. Biochem. Pharmacol. 74, 1628–1635 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Andersson, O. Role of adenosine signalling and metabolism in β-cell regeneration. Exp. Cell Res. 321, 3–10 (2014).

    Article  CAS  PubMed  Google Scholar 

  19. Faulhaber-Walter, R. et al. Impaired glucose tolerance in the absence of adenosine A1 receptor signaling. Diabetes 60, 2578–2587 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Figler, R. A. et al. Links between insulin resistance, adenosine A2B receptors, and inflammatory markers in mice and humans. Diabetes 60, 669–679 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Antonioli, L. et al. The role of purinergic pathways in the pathophysiology of gut diseases: pharmacological modulation and potential therapeutic applications. Pharmacol. Ther. 139, 157–188 (2013).

    Article  CAS  PubMed  Google Scholar 

  22. Antonioli, L. et al. Regulation of enteric functions by adenosine: pathophysiological and pharmacological implications. Pharmacol. Ther. 120, 233–253 (2008).

    Article  CAS  PubMed  Google Scholar 

  23. Antonioli, L., Pacher, P., Vizi, E. S. & Hasko, G. CD39 and CD73 in immunity and inflammation. Trends Mol. Med. 19, 355–367 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Antonioli, L. et al. Adenosine deaminase in the modulation of immune system and its potential as a novel target for treatment of inflammatory disorders. Curr. Drug Targets 13, 842–862 (2012).

    Article  CAS  PubMed  Google Scholar 

  25. Boison, D. Adenosine kinase: exploitation for therapeutic gain. Pharmacol. Rev. 65, 906–943 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Hardie, D. G. AMPK: a key regulator of energy balance in the single cell and the whole organism. Int. J. Obes. (Lond.) 32 (Suppl. 4), S7–S12 (2008).

    Article  CAS  Google Scholar 

  27. Brezar, V., Carel, J. C., Boitard, C. & Mallone, R. Beyond the hormone: insulin as an autoimmune target in type 1 diabetes. Endocr. Rev. 32, 623–669 (2011).

    Article  CAS  PubMed  Google Scholar 

  28. Wallberg, M. & Cooke, A. Immune mechanisms in type 1 diabetes. Trends Immunol. 34, 583–591 (2013).

    Article  CAS  PubMed  Google Scholar 

  29. Chia, J. S., McRae, J. L., Cowan, P. J. & Dwyer, K. M. The CD39-adenosinergic axis in the pathogenesis of immune and nonimmune diabetes. J. Biomed. Biotechnol. 2012, 320495 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Peiris, H., Bonder, C. S., Coates, P. T., Keating, D. J. & Jessup, C. F. The β-cell/EC axis: how do islet cells talk to each other? Diabetes 63, 3–11 (2014).

    Article  CAS  PubMed  Google Scholar 

  31. Wang, Z. & Thurmond, D. C. Mechanisms of biphasic insulin-granule exocytosis—roles of the cytoskeleton, small GTPases and SNARE proteins. J. Cell Sci. 122, 893–903 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Novak, I. Purinergic receptors in the endocrine and exocrine pancreas. Purinergic Signal. 4, 237–253 (2008).

    Article  CAS  PubMed  Google Scholar 

  33. Nemeth, Z. H. et al. Adenosine receptor activation ameliorates type 1 diabetes. FASEB J. 21, 2379–2388 (2007).

    Article  CAS  PubMed  Google Scholar 

  34. Topfer, M., Burbiel, C. E., Muller, C. E., Knittel, J. & Verspohl, E. J. Modulation of insulin release by adenosine A1 receptor agonists and antagonists in INS-1 cells: the possible contribution of 86Rb+ efflux and 45Ca2+ uptake. Cell Biochem. Funct. 26, 833–843 (2008).

    Article  CAS  PubMed  Google Scholar 

  35. Hillaire-Buys, D., Bertrand, G., Gross, R. & Loubatieres-Mariani, M. M. Evidence for an inhibitory A1 subtype adenosine receptor on pancreatic insulin-secreting cells. Eur. J. Pharmacol. 136, 109–112 (1987).

    Article  CAS  PubMed  Google Scholar 

  36. Bertrand, G., Petit, P., Bozem, M. & Henquin, J. C. Membrane and intracellular effects of adenosine in mouse pancreatic β-cells. Am. J. Physiol. 257, E473–E478 (1989).

    CAS  PubMed  Google Scholar 

  37. Verspohl, E. J., Johannwille, B., Waheed, A. & Neye, H. Effect of purinergic agonists and antagonists on insulin secretion from INS-1 cells (insulinoma cell line) and rat pancreatic islets. Can. J. Physiol. Pharmacol. 80, 562–568 (2002).

    Article  CAS  PubMed  Google Scholar 

  38. Rusing, D. et al. The impact of adenosine and A2B receptors on glucose homeostasis. J. Pharm. Pharmacol. 58, 1639–1645 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. Annes, J. P. et al. Adenosine kinase inhibition selectively promotes rodent and porcine islet β-cell replication. Proc. Natl Acad. Sci. USA 109, 3915–3920 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  40. Andersson, O. et al. Adenosine signaling promotes regeneration of pancreatic β cells in vivo. Cell Metab. 15, 885–894 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Lehuen, A., Diana, J., Zaccone, P. & Cooke, A. Immune cell crosstalk in type 1 diabetes. Nat. Rev. Immunol. 10, 501–513 (2010).

    Article  CAS  PubMed  Google Scholar 

  42. Ghaemi Oskouie, F. et al. High levels of adenosine deaminase on dendritic cells promote autoreactive T cell activation and diabetes in nonobese diabetic mice. J. Immunol. 186, 6798–6806 (2011).

    Article  CAS  PubMed  Google Scholar 

  43. Sakowicz-Burkiewicz, M. & Pawelczyk, T. Recent advances in understanding the relationship between adenosine metabolism and the function of T and B lymphocytes in diabetes. J. Physiol. Pharmacol. 62, 505–512 (2011).

    CAS  PubMed  Google Scholar 

  44. Novitskiy, S. V. et al. Adenosine receptors in regulation of dendritic cell differentiation and function. Blood 112, 1822–1831 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kumar, V. Adenosine as an endogenous immunoregulator in cancer pathogenesis: where to go? Purinergic Signal. 9, 145–165 (2013).

    Article  CAS  PubMed  Google Scholar 

  46. Linden, J. & Cekic, C. Regulation of lymphocyte function by adenosine. Arterioscler. Thromb. Vasc. Biol. 32, 2097–2103 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Naganuma, M. et al. Cutting edge: critical role for A2A adenosine receptors in the T cell-mediated regulation of colitis. J. Immunol. 177, 2765–2769 (2006).

    Article  CAS  PubMed  Google Scholar 

  48. Sevigny, C. P. et al. Activation of adenosine 2A receptors attenuates allograft rejection and alloantigen recognition. J. Immunol. 178, 4240–4249 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Lappas, C. M., Rieger, J. M. & Linden, J. A2A adenosine receptor induction inhibits IFN-γ production in murine CD4+ T cells. J. Immunol. 174, 1073–1080 (2005).

    Article  CAS  PubMed  Google Scholar 

  50. Csoka, B. et al. Adenosine A2A receptor activation inhibits T helper 1 and T helper 2 cell development and effector function. FASEB J. 22, 3491–3499 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Linnemann, C. et al. Adenosine regulates CD8 T-cell priming by inhibition of membrane-proximal T-cell receptor signalling. Immunology 128, e728–e737 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  52. Huang, S., Apasov, S., Koshiba, M. & Sitkovsky, M. Role of A2a extracellular adenosine receptor-mediated signaling in adenosine-mediated inhibition of T-cell activation and expansion. Blood 90, 1600–1610 (1997).

    CAS  PubMed  Google Scholar 

  53. Koshiba, M., Kojima, H., Huang, S., Apasov, S. & Sitkovsky, M. V. Memory of extracellular adenosine A2A purinergic receptor-mediated signaling in murine T cells. J. Biol. Chem. 272, 25881–25889 (1997).

    Article  CAS  PubMed  Google Scholar 

  54. Tai, N., Wong, F. S. & Wen, L. TLR9 deficiency promotes CD73 expression in T cells and diabetes protection in nonobese diabetic mice. J. Immunol. 191, 2926–2937 (2013).

    Article  CAS  PubMed  Google Scholar 

  55. Chia, J. S. et al. The protective effects of CD39 overexpression in multiple low-dose streptozotocin-induced diabetes in mice. Diabetes 62, 2026–2035 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Morel, P. A. Dendritic cell subsets in type 1 diabetes: friend or foe? Front. Immunol. 4, 415 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Wilson, J. M. et al. The A2B adenosine receptor impairs the maturation and immunogenicity of dendritic cells. J. Immunol. 182, 4616–4623 (2009).

    Article  CAS  PubMed  Google Scholar 

  58. Desrosiers, M. D. et al. Adenosine deamination sustains dendritic cell activation in inflammation. J. Immunol. 179, 1884–1892 (2007).

    Article  CAS  PubMed  Google Scholar 

  59. Tsai, S., Shameli, A. & Santamaria, P. CD8+ T cells in type 1 diabetes. Adv. Immunol. 100, 79–124 (2008).

    Article  CAS  PubMed  Google Scholar 

  60. McCarthy, M. I. Genomics, type 2 diabetes, and obesity. N. Engl. J. Med. 363, 2339–2350 (2010).

    Article  CAS  PubMed  Google Scholar 

  61. Esser, N., Legrand-Poels, S., Piette, J., Scheen, A. J. & Paquot, N. Inflammation as a link between obesity, metabolic syndrome and type 2 diabetes. Diabetes Res. Clin. Pract. 105, 141–150 (2014).

    Article  CAS  PubMed  Google Scholar 

  62. Guilherme, A., Virbasius, J. V., Puri, V. & Czech, M. P. Adipocyte dysfunctions linking obesity to insulin resistance and type 2 diabetes. Nat. Rev. Mol. Cell Biol. 9, 367–377 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Karsak, M. et al. Attenuation of allergic contact dermatitis through the endocannabinoid system. Science 316, 1494–1497 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. Capogrossi, M. C. et al. Adenosine release from isolated rat adipocytes: influence of fat cell concentration and cell size. Proc. Soc. Exp. Biol. Med. 182, 15–22 (1986).

    Article  CAS  PubMed  Google Scholar 

  65. Schwabe, U., Ebert, R. & Erbler, H. C. Adenosine release from fat cells: effect on cyclic AMP levels and hormone actions. Adv. Cyclic Nucleotide Res. 5, 569–584 (1975).

    CAS  PubMed  Google Scholar 

  66. Gharibi, B., Abraham, A. A., Ham, J. & Evans, B. A. Contrasting effects of A1 and A2b adenosine receptors on adipogenesis. Int. J. Obes. (Lond.) 36, 397–406 (2012).

    Article  CAS  Google Scholar 

  67. Schoelch, C. et al. Characterization of adenosine-A1 receptor-mediated antilipolysis in rats by tissue microdialysis, 1H-spectroscopy, and glucose clamp studies. Diabetes 53, 1920–1926 (2004).

    Article  CAS  PubMed  Google Scholar 

  68. Dhalla, A. K. et al. Antilipolytic activity of a novel partial A1 adenosine receptor agonist devoid of cardiovascular effects: comparison with nicotinic acid. J. Pharmacol. Exp. Ther. 321, 327–333 (2007).

    Article  CAS  PubMed  Google Scholar 

  69. Dhalla, A. K., Wong, M. Y., Voshol, P. J., Belardinelli, L. & Reaven, G. M. A1 adenosine receptor partial agonist lowers plasma FFA and improves insulin resistance induced by high-fat diet in rodents. Am. J. Physiol. Endocrinol. Metab. 292, E1358–E1363 (2007).

    Article  CAS  PubMed  Google Scholar 

  70. Gnad, T. et al. Adenosine activates brown adipose tissue and recruits beige adipocytes via A2A receptors. Nature 516, 395–399 (2014).

    Article  CAS  PubMed  Google Scholar 

  71. Johnston-Cox, H., Eisenstein, A. S., Koupenova, M., Carroll, S. & Ravid, K. The macrophage A2b adenosine receptor regulates tissue insulin sensitivity. PLoS ONE 9, e98775 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Csoka, B. et al. Adenosine promotes alternative macrophage activation via A2A and A2B receptors. FASEB J. 26, 376–386 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Chawla, A., Nguyen, K. D. & Goh, Y. P. Macrophage-mediated inflammation in metabolic disease. Nat. Rev. Immunol. 11, 738–749 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Thong, F. S. & Graham, T. E. The putative roles of adenosine in insulin- and exercise-mediated regulation of glucose transport and glycogen metabolism in skeletal muscle. Can. J. Appl. Physiol. 27, 152–178 (2002).

    Article  CAS  PubMed  Google Scholar 

  75. Leighton, B. et al. Effects of adenosine deaminase on the sensitivity of glucose transport, glycolysis and glycogen synthesis to insulin in muscles of the rat. Int. J. Biochem. 20, 23–27 (1988).

    Article  CAS  PubMed  Google Scholar 

  76. Stace, P. B., Marchington, D. R., Kerbey, A. L. & Randle, P. J. Long term culture of rat soleus muscle in vitro. Its effects on glucose utilization and insulin sensitivity. FEBS Lett. 273, 91–94 (1990).

    Article  CAS  PubMed  Google Scholar 

  77. Thong, F. S. et al. Activation of the A1 adenosine receptor increases insulin-stimulated glucose transport in isolated rat soleus muscle. Appl. Physiol. Nutr. Metab. 32, 701–710 (2007).

    Article  CAS  PubMed  Google Scholar 

  78. Vergauwen, L., Hespel, P. & Richter, E. A. Adenosine receptors mediate synergistic stimulation of glucose uptake and transport by insulin and by contractions in rat skeletal muscle. J. Clin. Invest. 93, 974–981 (1994).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Han, D. H., Hansen, P. A., Nolte, L. A. & Holloszy, J. O. Removal of adenosine decreases the responsiveness of muscle glucose transport to insulin and contractions. Diabetes 47, 1671–1675 (1998).

    Article  CAS  PubMed  Google Scholar 

  80. Challiss, R. A., Richards, S. J. & Budohoski, L. Characterization of the adenosine receptor modulating insulin action in rat skeletal muscle. Eur. J. Pharmacol. 226, 121–128 (1992).

    Article  CAS  PubMed  Google Scholar 

  81. Turcotte, L. P. & Fisher, J. S. Skeletal muscle insulin resistance: roles of fatty acid metabolism and exercise. Phys. Ther. 88, 1279–1296 (2008).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Nuttall, F. Q., Ngo, A. & Gannon, M. C. Regulation of hepatic glucose production and the role of gluconeogenesis in humans: is the rate of gluconeogenesis constant? Diabetes Metab. Res. Rev. 24, 438–458 (2008).

    Article  CAS  PubMed  Google Scholar 

  83. Wilcox, G. Insulin and insulin resistance. Clin. Biochem. Rev. 26, 19–39 (2005).

    PubMed  PubMed Central  Google Scholar 

  84. Lewis, G. F., Carpentier, A., Adeli, K. & Giacca, A. Disordered fat storage and mobilization in the pathogenesis of insulin resistance and type 2 diabetes. Endocr. Rev. 23, 201–229 (2002).

    Article  CAS  PubMed  Google Scholar 

  85. McLane, M. P., Black, P. R., Law, W. R. & Raymond, R. M. Adenosine reversal of in vivo hepatic responsiveness to insulin. Diabetes 39, 62–69 (1990).

    Article  CAS  PubMed  Google Scholar 

  86. Hoffer, L. J. & Lowenstein, J. M. Effects of adenosine and adenosine analogues on glycogen metabolism in isolated rat hepatocytes. Biochem. Pharmacol. 35, 4529–4536 (1986).

    Article  CAS  PubMed  Google Scholar 

  87. Gonzalez-Benitez, E., Guinzberg, R., Diaz-Cruz, A. & Pina, E. Regulation of glycogen metabolism in hepatocytes through adenosine receptors. Role of Ca2+ and cAMP. Eur. J. Pharmacol. 437, 105–111 (2002).

    Article  CAS  PubMed  Google Scholar 

  88. Yasuda, N. et al. Functional characterization of the adenosine receptor contributing to glycogenolysis and gluconeogenesis in rat hepatocytes. Eur. J. Pharmacol. 459, 159–166 (2003).

    Article  CAS  PubMed  Google Scholar 

  89. Harada, H. et al. 2-Alkynyl-8-aryl-9-methyladenines as novel adenosine receptor antagonists: their synthesis and structure-activity relationships toward hepatic glucose production induced via agonism of the A2B receptor. J. Med. Chem. 44, 170–179 (2001).

    Article  CAS  PubMed  Google Scholar 

  90. Krauss, R. M. Lipids and lipoproteins in patients with type 2 diabetes. Diabetes Care 27, 1496–1504 (2004).

    Article  CAS  PubMed  Google Scholar 

  91. Yu, Y. H. & Ginsberg, H. N. Adipocyte signaling and lipid homeostasis: sequelae of insulin-resistant adipose tissue. Circ. Res. 96, 1042–1052 (2005).

    Article  CAS  PubMed  Google Scholar 

  92. Xu, X., So, J. S., Park, J. G. & Lee, A. H. Transcriptional control of hepatic lipid metabolism by SREBP and ChREBP. Semin. Liver Dis. 33, 301–311 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Halperin, I. J. & Feig, D. S. The role of lifestyle interventions in the prevention of gestational diabetes. Curr. Diab. Rep. 14, 452 (2014).

    Article  PubMed  Google Scholar 

  94. Pardo, F. et al. Role of equilibrative adenosine transporters and adenosine receptors as modulators of the human placental endothelium in gestational diabetes mellitus. Placenta 34, 1121–1127 (2013).

    Article  CAS  PubMed  Google Scholar 

  95. San Martin, R. & Sobrevia, L. Gestational diabetes and the adenosine/L-arginine/nitric oxide (ALANO) pathway in human umbilical vein endothelium. Placenta 27, 1–10 (2006).

    Article  CAS  PubMed  Google Scholar 

  96. Vasquez, G. et al. Role of adenosine transport in gestational diabetes-induced L-arginine transport and nitric oxide synthesis in human umbilical vein endothelium. J. Physiol. 560, 111–122 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Aguayo, C. et al. Equilibrative nucleoside transporter 2 is expressed in human umbilical vein endothelium, but is not involved in the inhibition of adenosine transport induced by hyperglycaemia. Placenta 26, 641–653 (2005).

    Article  CAS  PubMed  Google Scholar 

  98. Munoz, G. et al. Insulin restores glucose inhibition of adenosine transport by increasing the expression and activity of the equilibrative nucleoside transporter 2 in human umbilical vein endothelium. J. Cell Physiol. 209, 826–835 (2006).

    Article  CAS  PubMed  Google Scholar 

  99. Farias, M. et al. Nitric oxide reduces adenosine transporter ENT1 gene (SLC29A1) promoter activity in human fetal endothelium from gestational diabetes. J. Cell Physiol. 208, 451–460 (2006).

    Article  CAS  PubMed  Google Scholar 

  100. Farias, M. et al. Nitric oxide reduces SLC29A1 promoter activity and adenosine transport involving transcription factor complex hCHOP-C/EBPα in human umbilical vein endothelial cells from gestational diabetes. Cardiovasc. Res. 86, 45–54 (2010).

    Article  CAS  PubMed  Google Scholar 

  101. Westermeier, F. et al. Equilibrative nucleoside transporters in fetal endothelial dysfunction in diabetes mellitus and hyperglycaemia. Curr. Vasc. Pharmacol. 7, 435–449 (2009).

    Article  CAS  PubMed  Google Scholar 

  102. Wojcik, M., Zieleniak, A., Mac-Marcjanek, K., Wozniak, L. A. & Cypryk, K. The elevated gene expression level of the A2B adenosine receptor is associated with hyperglycemia in women with gestational diabetes mellitus. Diabetes Metab. Res. Rev. 30, 42–53 (2014).

    Article  CAS  PubMed  Google Scholar 

  103. Cusick, M. et al. Associations of mortality and diabetes complications in patients with type 1 and type 2 diabetes: early treatment diabetic retinopathy study report no. 27. Diabetes Care 28, 617–625 (2005).

    Article  PubMed  Google Scholar 

  104. Donnelly, R., Emslie-Smith, A. M., Gardner, I. D. & Morris, A. D. ABC of arterial and venous disease: vascular complications of diabetes. BMJ 320, 1062–1066 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Vinik, A. I., Maser, R. E., Mitchell, B. D. & Freeman, R. Diabetic autonomic neuropathy. Diabetes Care 26, 1553–1579 (2003).

    Article  PubMed  Google Scholar 

  106. Beckman, J. A., Creager, M. A. & Libby, P. Diabetes and atherosclerosis: epidemiology, pathophysiology, and management. JAMA 287, 2570–2581 (2002).

    Article  CAS  PubMed  Google Scholar 

  107. Creager, M. A., Luscher, T. F., Cosentino, F. & Beckman, J. A. Diabetes and vascular disease: pathophysiology, clinical consequences, and medical therapy: part I. Circulation 108, 1527–1532 (2003).

    Article  PubMed  Google Scholar 

  108. Falcao-Pires, I. & Leite-Moreira, A. F. Diabetic cardiomyopathy: understanding the molecular and cellular basis to progress in diagnosis and treatment. Heart Fail. Rev. 17, 325–344 (2012).

    Article  CAS  PubMed  Google Scholar 

  109. Auchampach, J. A. & Bolli, R. Adenosine receptor subtypes in the heart: therapeutic opportunities and challenges. Am. J. Physiol. 276, H1113–H1116 (1999).

    CAS  PubMed  Google Scholar 

  110. Grden, M., Podgorska, M., Kocbuch, K., Szutowicz, A. & Pawelczyk, T. Expression of adenosine receptors in cardiac fibroblasts as a function of insulin and glucose level. Arch. Biochem. Biophys. 455, 10–17 (2006).

    Article  CAS  PubMed  Google Scholar 

  111. Olanrewaju, H. A., Qin, W., Feoktistov, I., Scemama, J. L. & Mustafa, S. J. Adenosine A2A and A2B receptors in cultured human and porcine coronary artery endothelial cells. Am. J. Physiol. Heart Circ. Physiol. 279, H650–H656 (2000).

    Article  CAS  PubMed  Google Scholar 

  112. Zhao, Z., Francis, C. E. & Ravid, K. An A3-subtype adenosine receptor is highly expressed in rat vascular smooth muscle cells: its role in attenuating adenosine-induced increase in cAMP. Microvasc. Res. 54, 243–252 (1997).

    Article  CAS  PubMed  Google Scholar 

  113. Grden, M., Podgorska, M., Szutowicz, A. & Pawelczyk, T. Altered expression of adenosine receptors in heart of diabetic rat. J. Physiol. Pharmacol. 56, 587–597 (2005).

    CAS  PubMed  Google Scholar 

  114. Camelliti, P., Borg, T. K. & Kohl, P. Structural and functional characterisation of cardiac fibroblasts. Cardiovasc. Res. 65, 40–51 (2005).

    Article  CAS  PubMed  Google Scholar 

  115. MacKenna, D., Summerour, S. R. & Villarreal, F. J. Role of mechanical factors in modulating cardiac fibroblast function and extracellular matrix synthesis. Cardiovasc. Res. 46, 257–263 (2000).

    Article  CAS  PubMed  Google Scholar 

  116. Bell, D. S. Heart failure: the frequent, forgotten, and often fatal complication of diabetes. Diabetes Care 26, 2433–2441 (2003).

    Article  PubMed  Google Scholar 

  117. Toldo, S. et al. GS-6201, a selective blocker of the A2B adenosine receptor, attenuates cardiac remodeling after acute myocardial infarction in the mouse. J. Pharmacol. Exp. Ther. 343, 587–595 (2012).

    Article  CAS  PubMed  Google Scholar 

  118. Zhang, H. et al. Blockade of A2B adenosine receptor reduces left ventricular dysfunction and ventricular arrhythmias 1 week after myocardial infarction in the rat model. Heart Rhythm 11, 101–109 (2014).

    Article  PubMed  Google Scholar 

  119. Horvath, B., Mukhopadhyay, P., Hasko, G. & Pacher, P. The endocannabinoid system and plant-derived cannabinoids in diabetes and diabetic complications. Am. J. Pathol. 180, 432–442 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Dubey, R. K., Gillespie, D. G., Osaka, K., Suzuki, F. & Jackson, E. K. Adenosine inhibits growth of rat aortic smooth muscle cells. Possible role of A2b receptor. Hypertension 27, 786–793 (1996).

    Article  CAS  PubMed  Google Scholar 

  121. Dubey, R. K., Gillespie, D. G., Mi, Z. & Jackson, E. K. Adenosine inhibits growth of human aortic smooth muscle cells via A2B receptors. Hypertension 31, 516–521 (1998).

    Article  CAS  PubMed  Google Scholar 

  122. Mayer, P., Hinze, A. V., Harst, A. & von Kugelgen, I. A2B receptors mediate the induction of early genes and inhibition of arterial smooth muscle cell proliferation via Epac. Cardiovasc. Res. 90, 148–156 (2011).

    Article  CAS  PubMed  Google Scholar 

  123. Pares-Herbute, N. et al. Adenosine inhibitory effect on enhanced growth of aortic smooth muscle cells from streptozotocin-induced diabetic rats. Br. J. Pharmacol. 118, 783–789 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  124. Koupenova, M. et al. A2b adenosine receptor regulates hyperlipidemia and atherosclerosis. Circulation 125, 354–363 (2012).

    Article  CAS  PubMed  Google Scholar 

  125. Ni, W. J., Tang, L. Q. & Wei, W. Research progress on signaling pathway in diabetic nephropathy. Diabetes Metab. Res. Rev. http://dx.doi.org/10.1002/dmrr.2568.

  126. Schena, F. P. & Gesualdo, L. Pathogenetic mechanisms of diabetic nephropathy. J. Am. Soc. Nephrol. 16 (Suppl. 1), S30–S33 (2005).

    Article  CAS  PubMed  Google Scholar 

  127. Elsherbiny, N. M. & Al-Gayyar, M. M. Adenosine receptors: new therapeutic targets for inflammation in diabetic nephropathy. Inflamm. Allergy Drug Targets. 12, 153–161 (2013).

    Article  CAS  PubMed  Google Scholar 

  128. Vallon, V. & Osswald, H. Adenosine receptors and the kidney. Handb. Exp. Pharmacol. 193, 443–470 (2009).

    Article  CAS  Google Scholar 

  129. Pawelczyk, T., Grden, M., Rzepko, R., Sakowicz, M. & Szutowicz, A. Region-specific alterations of adenosine receptors expression level in kidney of diabetic rat. Am. J. Pathol. 167, 315–325 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Pawelczyk, T., Podgorska, M. & Sakowicz, M. The effect of insulin on expression level of nucleoside transporters in diabetic rats. Mol. Pharmacol. 63, 81–88 (2003).

    Article  CAS  PubMed  Google Scholar 

  131. Persson, P., Hansell, P. & Palm, F. Tubular reabsorption and diabetes-induced glomerular hyperfiltration. Acta Physiol. (Oxf.) 200, 3–10 (2010).

    CAS  Google Scholar 

  132. Faulhaber-Walter, R. et al. Lack of A1 adenosine receptors augments diabetic hyperfiltration and glomerular injury. J. Am. Soc. Nephrol. 19, 722–730 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Sallstrom, J. et al. Diabetes-induced hyperfiltration in adenosine A1-receptor deficient mice lacking the tubuloglomerular feedback mechanism. Acta Physiol. (Oxf.) 190, 253–259 (2007).

    Article  CAS  Google Scholar 

  134. Tesch, G. H. Macrophages and diabetic nephropathy. Semin. Nephrol. 30, 290–301 (2010).

    Article  CAS  PubMed  Google Scholar 

  135. Awad, A. S. et al. Adenosine A2A receptor activation attenuates inflammation and injury in diabetic nephropathy. Am. J. Physiol. Renal Physiol. 290, F828–F837 (2006).

    Article  CAS  PubMed  Google Scholar 

  136. Roa, H. et al. Adenosine mediates transforming growth factor-β 1 release in kidney glomeruli of diabetic rats. FEBS Lett. 583, 3192–3198 (2009).

    Article  CAS  PubMed  Google Scholar 

  137. Cardenas, A. et al. Adenosine A2B receptor-mediated VEGF induction promotes diabetic glomerulopathy. Lab. Invest. 93, 135–144 (2013).

    Article  CAS  PubMed  Google Scholar 

  138. Tak, E. et al. CD73-dependent generation of adenosine and endothelial Adora2b signaling attenuate diabetic nephropathy. J. Am. Soc. Nephrol. 25, 547–563 (2014).

    Article  CAS  PubMed  Google Scholar 

  139. Lois, N., McCarter, R. V., O'Neill, C., Medina, R. J. & Stitt, A. W. Endothelial progenitor cells in diabetic retinopathy. Front. Endocrinol. (Lausanne) 5, 44 (2014).

    Article  Google Scholar 

  140. Antonetti, D. A., Klein, R. & Gardner, T. W. Diabetic retinopathy. N. Engl. J. Med. 366, 1227–1239 (2012).

    Article  CAS  PubMed  Google Scholar 

  141. Vindeirinho, J., Costa, G. N., Correia, M. B., Cavadas, C. & Santos, P. F. Effect of diabetes/hyperglycemia on the rat retinal adenosinergic system. PLoS ONE 8, e67499 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  142. Elsherbiny, N. M. et al. Potential roles of adenosine deaminase-2 in diabetic retinopathy. Biochem. Biophys. Res. Commun. 436, 355–361 (2013).

    Article  CAS  PubMed  Google Scholar 

  143. Ibrahim, A. S., El-Shishtawy, M. M., Zhang, W., Caldwell, R. B. & Liou, G. I. A2A adenosine receptor (A2AAR) as a therapeutic target in diabetic retinopathy. Am. J. Pathol. 178, 2136–2145 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Elsherbiny, N. M. et al. ABT-702, an adenosine kinase inhibitor, attenuates inflammation in diabetic retinopathy. Life Sci. 93, 78–88 (2013).

    Article  CAS  PubMed  Google Scholar 

  145. Charles, B. A. et al. Variants of the adenosine A2A receptor gene are protective against proliferative diabetic retinopathy in patients with type 1 diabetes. Ophthalmic Res. 46, 1–8 (2011).

    Article  CAS  PubMed  Google Scholar 

  146. Charnogursky, G., Lee, H. & Lopez, N. Diabetic neuropathy. Handb. Clin. Neurol. 120, 773–785 (2014).

    Article  PubMed  Google Scholar 

  147. Said, G. Diabetic neuropathy—a review. Nat. Clin. Pract. Neurol. 3, 331–340 (2007).

    Article  PubMed  Google Scholar 

  148. Sawynok, J. & Liu, X. J. Adenosine in the spinal cord and periphery: release and regulation of pain. Prog. Neurobiol. 69, 313–340 (2003).

    Article  CAS  PubMed  Google Scholar 

  149. Lynch, J. J. 3rd, Jarvis, M. F. & Kowaluk, E. A. An adenosine kinase inhibitor attenuates tactile allodynia in a rat model of diabetic neuropathic pain. Eur. J. Pharmacol. 364, 141–146 (1999).

    Article  CAS  PubMed  Google Scholar 

  150. Saini, A. K., Arun, K. H., Kaul, C. L. & Sharma, S. S. Acute hyperglycemia attenuates nerve conduction velocity and nerve blood flow in male Sprague-Dawley rats: reversal by adenosine. Pharmacol. Res. 50, 593–599 (2004).

    Article  CAS  PubMed  Google Scholar 

  151. Amadio, S., Apolloni, S., D'Ambrosi, N. & Volonte, C. Purinergic signalling at the plasma membrane: a multipurpose and multidirectional mode to deal with amyotrophic lateral sclerosis and multiple sclerosis. J. Neurochem. 116, 796–805 (2011).

    Article  CAS  PubMed  Google Scholar 

  152. Grant, C. R. et al. Dysfunctional CD39POS regulatory T cells and aberrant control of T-helper type 17 cells in autoimmune hepatitis. Hepatology 59, 1007–1015 (2014).

    Article  CAS  PubMed  Google Scholar 

  153. de Galan, B. E. et al. Theophylline improves hypoglycemia unawareness in type 1 diabetes. Diabetes 51, 790–796 (2002).

    Article  CAS  PubMed  Google Scholar 

  154. Arias, A. M. et al. Aminophylline stimulates insulin secretion in patients with type 2 diabetes mellitus. Metabolism 50, 1030–1035 (2001).

    Article  CAS  PubMed  Google Scholar 

  155. Hopper, A. H., Tindall, H. & Davies, J. A. Administration of aspirin-dipyridamole reduces proteinuria in diabetic nephropathy. Nephrol. Dial. Transplant. 4, 140–143 (1989).

    CAS  PubMed  Google Scholar 

  156. Aizawa, T. et al. Dipyridamole reduces urinary albumin excretion in diabetic patients with normo- or microalbuminuria. Clin. Nephrol. 33, 130–135 (1990).

    CAS  PubMed  Google Scholar 

  157. Bonello, L. et al. Ticagrelor increases adenosine plasma concentration in patients with an acute coronary syndrome. J. Am. Coll. Cardiol. 63, 872–877 (2014).

    Article  CAS  PubMed  Google Scholar 

  158. Laine, M. et al. Ticagrelor versus prasugrel in diabetic patients with an acute coronary syndrome. A pharmacodynamic randomised study. Thromb. Haemost. 111, 273–278 (2014).

    Article  CAS  PubMed  Google Scholar 

  159. Natella, F. & Scaccini, C. Role of coffee in modulation of diabetes risk. Nutr. Rev. 70, 207–217 (2012).

    Article  PubMed  Google Scholar 

  160. Jacobson, K. A. & Gao, Z. G. Adenosine receptors as therapeutic targets. Nat. Rev. Drug Discov. 5, 247–264 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Jiang, X., Zhang, D. & Jiang, W. Coffee and caffeine intake and incidence of type 2 diabetes mellitus: a meta-analysis of prospective studies. Eur. J. Nutr. 53, 25–38 (2014).

    Article  CAS  PubMed  Google Scholar 

  162. Bhupathiraju, S. N. et al. Changes in coffee intake and subsequent risk of type 2 diabetes: three large cohorts of US men and women. Diabetologia 57, 1346–1354 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  163. van Dam, R. M. & Hu, F. B. Coffee consumption and risk of type 2 diabetes: a systematic review. JAMA 294, 97–104 (2005).

    Article  CAS  PubMed  Google Scholar 

  164. Ding, M., Bhupathiraju, S. N., Chen, M., van Dam, R. M. & Hu, F. B. Caffeinated and decaffeinated coffee consumption and risk of type 2 diabetes: a systematic review and a dose-response meta-analysis. Diabetes Care 37, 569–586 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  165. Krebs, J. D., Parry-Strong, A., Weatherall, M., Carroll, R. W. & Downie, M. A cross-over study of the acute effects of espresso coffee on glucose tolerance and insulin sensitivity in people with type 2 diabetes mellitus. Metabolism 61, 1231–1237 (2012).

    Article  CAS  PubMed  Google Scholar 

  166. Salazar-Martinez, E. et al. Coffee consumption and risk for type 2 diabetes mellitus. Ann. Intern. Med. 140, 1–8 (2004).

    Article  PubMed  Google Scholar 

  167. Yamauchi, R. et al. Coffee and caffeine ameliorate hyperglycemia, fatty liver, and inflammatory adipocytokine expression in spontaneously diabetic KK-Ay mice. J. Agric. Food Chem. 58, 5597–5603 (2010).

    Article  CAS  PubMed  Google Scholar 

  168. Okumura, T., Tsukui, T., Hosokawa, M. & Miyashita, K. Effect of caffeine and capsaicin on the blood glucose levels of obese/diabetic KK-Ay mice. J. Oleo. Sci. 61, 515–523 (2012).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

The authors' acknowledge support from the NIH (grant R01GM66189 to G.H.), the Intramural Research Program of the NIH/NIAAA (to P.P.), and the Nexus award 'Marcello Tonini' (to L.A.).

Author information

Authors and Affiliations

  1. Department of Clinical and Experimental Medicine, University of Pisa, Via Roma 55, Pisa, 56126, Italy

    Luca Antonioli & Corrado Blandizzi

  2. Department of Surgery and Center for Immunity and Inflammation, Rutgers-New Jersey Medical School, 185 South Orange Avenue, University Heights, Newark, 07103, NJ, USA

    Balázs Csóka & György Haskó

  3. Section on Oxidative Stress Tissue Injury, Laboratories of Physiological Studies, NIH/NIAAA, 5625 Fishers Lane, Bethesda, 20892, MD, USA

    Pál Pacher

Authors
  1. Luca Antonioli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Corrado Blandizzi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Balázs Csóka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pál Pacher
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. György Haskó
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

L.A., C.B., B.C., P.P. and G.H. researched data for the article, made substantial contributions to discussions of the content, wrote the article and reviewed and/or edited the manuscript before submission.

Corresponding author

Correspondence to György Haskó.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Antonioli, L., Blandizzi, C., Csóka, B. et al. Adenosine signalling in diabetes mellitus—pathophysiology and therapeutic considerations. Nat Rev Endocrinol 11, 228–241 (2015). https://doi.org/10.1038/nrendo.2015.10

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrendo.2015.10

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