Advertisement

Molecular Medicine

, Volume 21, Issue 1, pp 702–708 | Cite as

Galantamine Attenuates Type 1 Diabetes and Inhibits Anti-Insulin Antibodies in Nonobese Diabetic Mice

  • William M. Hanes
  • Peder S. Olofsson
  • Kevin Kwan
  • LaQueta K. Hudson
  • Sangeeta S. Chavan
  • Valentin A. Pavlov
  • Kevin J. Tracey
Research Article

Abstract

Type 1 diabetes in mice is characterized by autoimmune destruction of insulin-producing pancreatic β-cells. Disease pathogenesis involves invasion of pancreatic islets by immune cells, including macrophages and T cells, and production of antibodies to self-antigens, including insulin. Activation of the inflammatory reflex, the neural circuit that inhibits inflammation, culminates on cholinergic receptor signals on immune cells to attenuate cytokine release and inhibit B-cell antibody production. Here, we show that galantamine, a centrally acting acetylcholinesterase inhibitor and an activator of the inflammatory reflex, attenuates murine experimental type 1 diabetes. Administration of galantamine to animals immunized with keyhole limpet hemocyanin (KLH) significantly suppressed splenocyte release of immunoglobulin G (IgG) and interleukin (IL)-4 and IL-6 during KLH challenge ex vivo. Administration of galantamine beginning at 1 month of age in nonobese diabetic (NOD) mice significantly delayed the onset of hyperglycemia, attenuated immune cell infiltration in pancreatic islets and decreased anti-insulin antibodies in serum. These observations indicate that galantamine attenuates experimental type 1 diabetes in mice and suggest that activation of the inflammatory reflex should be further studied as a potential therapeutic approach.

Notes

Acknowledgments

This work was supported by a grant from the Juvenile Diabetes Research Fund and the following grants from the National Institute of General Medical Sciences, National Institutes of Health: R01GM057226 (to KJ Tracey) and R01GM089807 (to KJ Tracey and VA Pavlov).

Supplementary material

10020_2015_2101702_MOESM1_ESM.pdf (407 kb)
Supplementary material, approximately 406 KB.

References

  1. 1.
    Orchard TJ, et al. (2006) Type 1 diabetes and coronary artery disease. Diabetes Care. 29:2528–38.CrossRefGoogle Scholar
  2. 2.
    Secrest AM, et al. (2010) All-cause mortality trends in a large population-based cohort with long-standing childhood-onset type 1 diabetes: the Allegheny County type 1 diabetes registry. Diabetes Care. 33:2573–9.CrossRefGoogle Scholar
  3. 3.
    Soedamah-Muthu SS, et al. (2006) All-cause mortality rates in patients with type 1 diabetes mellitus compared with a non-diabetic population from the UK general practice research database, 1992–1999. Diabetologia. 49:660–6.CrossRefGoogle Scholar
  4. 4.
    Laing SP, et al. (2003) Mortality from heart disease in a cohort of 23,000 patients with insulin-treated diabetes. Diabetologia. 46:760–5.CrossRefGoogle Scholar
  5. 5.
    Laing SP, et al. (1999) The British Diabetic Association Cohort Study, I: all-cause mortality in patients with insulin-treated diabetes mellitus. Diabet. Med. 16:459–65.CrossRefGoogle Scholar
  6. 6.
    Skrivarhaug T, et al. (2006) Long-term mortality in a nationwide cohort of childhood-onset type 1 diabetic patients in Norway. Diabetologia. 49:298–305.CrossRefGoogle Scholar
  7. 7.
    Secrest AM, et al. (2010) Cause-specific mortality trends in a large population-based cohort with long-standing childhood-onset type 1 diabetes. Diabetes. 59:3216–22.CrossRefGoogle Scholar
  8. 8.
    Livingstone SJ, et al. (2012) Risk of cardiovascular disease and total mortality in adults with type 1 diabetes: Scottish registry linkage study. PLoS Med. 9:e1001321.CrossRefGoogle Scholar
  9. 9.
    Lind M, et al. (2014) Glycemic control and excess mortality in type 1 diabetes. N. Engl. J. Med. 371:1972–82.CrossRefGoogle Scholar
  10. 10.
    Centers for Disease Control and Prevention. (2014) National diabetes statistics report, 2014: estimates of diabetes and its burden in the United States. Atlanta (GA): US Department of Health and Human Services. 12pp. Available from: https://doi.org/www.cdc.gov/diabetes/data/statistics/2014statisticsreport.htmlGoogle Scholar
  11. 11.
    Dall TM, et al. (2009) Distinguishing the economic costs associated with type 1 and type 2 diabetes. Popul. Health Manag. 12:103–10.CrossRefGoogle Scholar
  12. 12.
    Atkinson MA, Eisenbarth GS. (2001) Type 1 diabetes: new perspectives on disease pathogenesis and treatment. Lancet. 358:221–9.CrossRefGoogle Scholar
  13. 13.
    Nelson P, et al. (2009) Modeling dynamic changes in type 1 diabetes progression: quantifying beta-cell variation after the appearance of islet-specific autoimmune responses. Math. Biosci. Eng. 6:753–78.CrossRefGoogle Scholar
  14. 14.
    Morran MP, Omenn GS, Pietropaolo M. (2008) Immunology and genetics of type 1 diabetes. Mt. Sinai J. Med. 75:314–27.CrossRefGoogle Scholar
  15. 15.
    Kay TW, Campbell IL, Harrison LC. (1991) Characterization of pancreatic T lymphocytes associated with beta cell destruction in the non-obese diabetic (NOD) mouse. J. Autoimmun. 4:263–76.CrossRefGoogle Scholar
  16. 16.
    Hawkins TA, Gala RR, Dunbar JC. (1996) The lymphocyte and macrophage profile in the pancreas and spleen of NOD mice: percentage of interleukin-2 and prolactin receptors on immunocompetent cell subsets. J. Reprod. Immunol. 32:55–71.CrossRefGoogle Scholar
  17. 17.
    Anderson MS, Bluestone JA. (2005) The NOD mouse: a model of immune dysregulation. Annu. Rev. Immunol. 23:447–85.CrossRefGoogle Scholar
  18. 18.
    van Belle TL, Coppieters KT, von Herrath MG. (2011) Type 1 diabetes: etiology, immunology, and therapeutic strategies. Physiol. Rev. 91:79–118.CrossRefGoogle Scholar
  19. 19.
    Pugliese A, et al. (2001) Self-antigen-presenting cells expressing diabetes-associated autoantigens exist in both thymus and peripheral lymphoid organs. J. Clin. Invest. 107:555–64.CrossRefGoogle Scholar
  20. 20.
    Miao D, Yu L, Eisenbarth GS. (2007) Role of autoantibodies in type 1 diabetes. Front. Biosci. 12:1889–98.CrossRefGoogle Scholar
  21. 21.
    Knip M, et al. (2005) Environmental triggers and determinants of type 1 diabetes. Diabetes. 54(Suppl. 2):S125–36.CrossRefGoogle Scholar
  22. 22.
    Taplin CE, Barker JM. (2008) Autoantibodies in type 1 diabetes. Autoimmunity. 41:11–8.CrossRefGoogle Scholar
  23. 23.
    Wenzlau JM, et al. (2007) The cation efflux transporter ZnT8 (Slc30A8) is a major autoantigen in human type 1 diabetes. Proc. Natl. Acad. Sci. U. S. A. 104:17040–5.CrossRefGoogle Scholar
  24. 24.
    Atkinson MA, Eisenbarth GS, Michels AW. (2014) Type 1 diabetes. Lancet. 383:69–82.CrossRefGoogle Scholar
  25. 25.
    Pescovitz MD, et al. (2009) Rituximab, B-lymphocyte depletion, and preservation of beta-cell function. N. Engl. J. Med. 361:2143–52.CrossRefGoogle Scholar
  26. 26.
    Wherrett DK, et al. (2011) Antigen-based therapy with glutamic acid decarboxylase (GAD) vaccine in patients with recent-onset type 1 diabetes: a randomised double-blind trial. Lancet. 378:319–27.CrossRefGoogle Scholar
  27. 27.
    Ludvigsson J, et al. (2012) GAD65 antigen therapy in recently diagnosed type 1 diabetes mellitus. N. Engl. J. Med. 366:433–42.CrossRefGoogle Scholar
  28. 28.
    Bach JF. (2011) Anti-CD3 antibodies for type 1 diabetes: beyond expectations. Lancet. 378:459–60.CrossRefGoogle Scholar
  29. 29.
    Orban T, et al. (2011) Co-stimulation modulation with abatacept in patients with recent-onset type 1 diabetes: a randomised, double-blind, placebo-controlled trial. Lancet. 378:412–9.CrossRefGoogle Scholar
  30. 30.
    Sherry N, et al. (2011) Teplizumab for treatment of type 1 diabetes (Protege study): 1-year results from a randomised, placebo-controlled trial. Lancet. 378:487–97.CrossRefGoogle Scholar
  31. 31.
    Tracey KJ. (2002) The inflammatory reflex. Nature. 420:853–9.CrossRefGoogle Scholar
  32. 32.
    Pavlov VA, et al. (2003) The cholinergic anti-inflammatory pathway: a missing link in neuroimmunomodulation. Mol. Med. 9:125–34.CrossRefGoogle Scholar
  33. 33.
    Pavlov VA, Tracey KJ. (2005) The cholinergic anti-inflammatory pathway. Brain Behav. Immun. 19:493–9.CrossRefGoogle Scholar
  34. 34.
    Pavlov VA, et al. (2006) Central muscarinic cholinergic regulation of the systemic inflammatory response during endotoxemia. Proc. Natl. Acad. Sci. U. S. A. 103:5219–23.CrossRefGoogle Scholar
  35. 35.
    Pavlov VA, et al. (2009) Brain acetylcholinesterase activity controls systemic cytokine levels through the cholinergic anti-inflammatory pathway. Brain Behav. Immun. 23:41–5.CrossRefGoogle Scholar
  36. 36.
    Tracey KJ. (2007) Physiology and immunology of the cholinergic antiinflammatory pathway. J. Clin. Invest. 117:289–96.CrossRefGoogle Scholar
  37. 37.
    Parrish WR, et al. (2008) Modulation of TNF release by choline requires α7 subunit nicotinic acetylcholine receptor-mediated signaling. Mol. Med. 14:567.CrossRefGoogle Scholar
  38. 38.
    Tracey KJ. (2009) Reflex control of immunity. Nat. Rev. Immunol. 9:418–28.CrossRefGoogle Scholar
  39. 39.
    Andersson U, Tracey KJ. (2012) Neural reflexes in inflammation and immunity. J. Exp. Med. 209:1057–68.CrossRefGoogle Scholar
  40. 40.
    Wang H, et al. (2003) Nicotinic acetylcholine receptor α7 subunit is an essential regulator of inflammation. Nature. 421:384–8.CrossRefGoogle Scholar
  41. 41.
    Rosas-Ballina M, et al. (2008) Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia. Proc. Natl. Acad. Sci. U. S. A. 105:11008–13.CrossRefGoogle Scholar
  42. 42.
    Rosas-Ballina M, et al. (2011) Acetylcholine-synthesizing T cells relay neural signals in a vagus nerve circuit. Science. 334:98–101.CrossRefGoogle Scholar
  43. 43.
    Bencherif M, et al. (2011) Alpha7 nicotinic receptors as novel therapeutic targets for inflammation-based diseases. Cell Mol. Life Sci. 68:931–49.CrossRefGoogle Scholar
  44. 44.
    Olofsson PS, et al. (2012) α7 Nicotinic acetylcholine receptor (a7nAChR) expression in bone marrow-derived non-T cells is required for the inflammatory reflex. Mol. Med. 18:539–43.CrossRefGoogle Scholar
  45. 45.
    Mabley JG, et al. (2002) Nicotine reduces the incidence of type I diabetes in mice. J. Pharmacol. Exp. Ther. 300:876–81.CrossRefGoogle Scholar
  46. 46.
    Olofsson PS, et al. (2012) Rethinking inflammation: neural circuits in the regulation of immunity. Immunol. Rev. 248:188–204.CrossRefGoogle Scholar
  47. 47.
    Zitnik RJ. (2011) Treatment of chronic inflammatory diseases with implantable medical devices. Cleve. Clin. J. Med. 78(Suppl. 1):S30–4.CrossRefGoogle Scholar
  48. 48.
    Mina-Osorio P, et al. (2012) Neural signaling in the spleen controls B-cell responses to blood-borne antigen. Mol. Med. 18:618–27.CrossRefGoogle Scholar
  49. 49.
    Reichman WE. (2003) Current pharmacologic options for patients with Alzheimer’s disease. Ann. Gen. Hosp. Psychiatry. 2:1.CrossRefGoogle Scholar
  50. 50.
    Ellis JM. (2005) Cholinesterase inhibitors in the treatment of dementia. J. Am. Osteopath. Assoc. 105:145–58.PubMedGoogle Scholar
  51. 51.
    Waldburger JM, et al. (2008) Spinal p38 MAP kinase regulates peripheral cholinergic outflow. Arthritis Rheum. 58:2919–21.CrossRefGoogle Scholar
  52. 52.
    Satapathy SK, et al. (2011) Galantamine alleviates inflammation and other obesity-associated complications in high-fat diet-fed mice. Mol. Med. 17:599–606.CrossRefGoogle Scholar
  53. 53.
    Anderson MS, Bluestone JA. (2005) The NOD mouse: a model of immune dysregulation. Annu. Rev. Immunol. 23:447–85.CrossRefGoogle Scholar
  54. 54.
    Abiru N, et al. (2001) Transient insulin autoantibody expression independent of development of diabetes: comparison of NOD and NOR strains. J. Autoimmun. 17:1–6.CrossRefGoogle Scholar
  55. 55.
    Quintana FJ, Cohen IR. (2001) Autoantibody patterns in diabetes-prone NOD mice and in standard C57BL/6 mice. J. Autoimmun. 17:191–7.CrossRefGoogle Scholar
  56. 56.
    Tisch R, et al. (1993) Immune response to glutamic acid decarboxylase correlates with insulitis in non-obese diabetic mice. Nature. 366:72–5.CrossRefGoogle Scholar
  57. 57.
    Committee for the Update of the Guide for the Care and Use of Laboratory Animals, Institute for Laboratory Animal Research, Division on Earth and Life Studies, National Research Council of the National Academies. (2011) Guide for the Care and Use of Laboratory Animals. 8th ed. Washington, DC: National Academies Press.Google Scholar
  58. 58.
    Ji H, et al. (2014) Central cholinergic activation of a vagus nerve-to-spleen circuit alleviates experimental colitis. Mucosal Immunol. 7:335–47.CrossRefGoogle Scholar
  59. 59.
    Jaakkola I, Jalkanen S, Hänninen A. (2003) Diabetogenic T cells are primed both in pancreatic and gut-associated lymph nodes in NOD mice. Eur. J. Immunol. 33:3255–64.CrossRefGoogle Scholar
  60. 60.
    Holst JJ, et al. (1986) Autonomic nervous control of the endocrine secretion from the isolated, perfused pig pancreas. J. Auton. Nerv. Syst. 17:71–84.CrossRefGoogle Scholar
  61. 61.
    Miller RE. (1981) Pancreatic neuroendocrinology: peripheral neural mechanisms in the regulation of the Islets of Langerhans. Endocr. Rev. 2:471–94.CrossRefGoogle Scholar
  62. 62.
    Woods SC, Porte D Jr. (1974) Neural control of the endocrine pancreas. Physiol. Rev. 54:596–619.CrossRefGoogle Scholar
  63. 63.
    van Westerloo DJ, et al. (2006) The vagus nerve and nicotinic receptors modulate experimental pancreatitis severity in mice. Gastroenterology. 130:1822–30.CrossRefGoogle Scholar
  64. 64.
    Yi CX, et al. (2010) The role of the autonomic nervous liver innervation in the control of energy metabolism. Biochim. Biophys. Acta. 1802:416–31.CrossRefGoogle Scholar
  65. 65.
    Owyang C, Heldsinger A. (2011) Vagal control of satiety and hormonal regulation of appetite. J. Neurogastroenterol. Motil. 17:338–48.CrossRefGoogle Scholar
  66. 66.
    Wang PY, et al. (2008) Upper intestinal lipids trigger a gut-brain-liver axis to regulate glucose production. Nature. 452:1012–6.CrossRefGoogle Scholar
  67. 67.
    Pavlov VA, Tracey KJ. (2012) The vagus nerve and the inflammatory reflex: linking immunity and metabolism. Nat. Rev. Endocrinol. 8:743–54.CrossRefGoogle Scholar
  68. 68.
    Nicolson R, Craven-Thuss B, Smith J. (2006) A prospective, open-label trial of galantamine in autistic disorder. J. Child. Adolesc. Psychopharmacol. 16:621–9.CrossRefGoogle Scholar
  69. 69.
    Chakravarthy BK, Gupta S, Gode KD. (1982) Functional beta cell regeneration in the islets of pancreas in alloxan induced diabetic rats by (-)-epicatechin. Life Sci. 31:2693–7.CrossRefGoogle Scholar
  70. 70.
    Montana E, Bonner-Weir S, Weir GC. (1993) Beta cell mass and growth after syngeneic islet cell transplantation in normal and streptozocin diabetic C57BL/6 mice. J. Clin. Invest. 91:780–7.CrossRefGoogle Scholar
  71. 71.
    Yoon K-H, et al. (1998) Differentiation and expansion of beta cell mass in porcine neonatal pancreatic cell clusters transplanted into nude mice. Cell Transplant. 8:673–89.CrossRefGoogle Scholar
  72. 72.
    Xu G, et al. (1999) Exendin-4 stimulates both beta-cell replication and neogenesis, resulting in increased beta-cell mass and improved glucose tolerance in diabetic rats. Diabetes. 48:2270–6.CrossRefGoogle Scholar
  73. 73.
    Shapiro AM, et al. (2000) Islet transplantation in seven patients with type 1 diabetes mellitus using a glucocorticoid-free immunosuppressive regimen. N. Engl. J. Med. 343:230–8.CrossRefGoogle Scholar
  74. 74.
    Ramiya VK, et al. (2000) Reversal of insulin-dependent diabetes using islets generated in vitro from pancreatic stem cells. Nat. Med. 6:278–82.CrossRefGoogle Scholar
  75. 75.
    Ryan EA, et al. (2005) Five-year follow-up after clinical islet transplantation. Diabetes. 54:2060–9.CrossRefGoogle Scholar
  76. 76.
    Gibly RF, et al. (2011) Advancing islet transplantation: from engraftment to the immune response. Diabetologia. 54:2494–505.CrossRefGoogle Scholar

Copyright information

© The Author(s) 2015

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, and provide a link to the Creative Commons license. You do not have permission under this license to share adapted material derived from this article or parts of it.

The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder.

To view a copy of this license, visit (https://doi.org/creativecommons.org/licenses/by-nc-nd/4.0/)

Authors and Affiliations

  • William M. Hanes
    • 1
    • 2
  • Peder S. Olofsson
    • 1
  • Kevin Kwan
    • 1
  • LaQueta K. Hudson
    • 1
  • Sangeeta S. Chavan
    • 1
  • Valentin A. Pavlov
    • 1
  • Kevin J. Tracey
    • 1
  1. 1.Laboratory of Biomedical ScienceThe Feinstein Institute for Medical ResearchManhassetUSA
  2. 2.Department of Biochemistry and Cell BiologyStony Brook UniversityStony BrookUSA

Personalised recommendations