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Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells

Nature Medicine volume 17, pages 1481–1489 (2011)Cite this article

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Abstract

Exercise, obesity and type 2 diabetes are associated with elevated plasma concentrations of interleukin-6 (IL-6). Glucagon-like peptide-1 (GLP-1) is a hormone that induces insulin secretion. Here we show that administration of IL-6 or elevated IL-6 concentrations in response to exercise stimulate GLP-1 secretion from intestinal L cells and pancreatic alpha cells, improving insulin secretion and glycemia. IL-6 increased GLP-1 production from alpha cells through increased proglucagon (which is encoded by GCG) and prohormone convertase 1/3 expression. In models of type 2 diabetes, the beneficial effects of IL-6 were maintained, and IL-6 neutralization resulted in further elevation of glycemia and reduced pancreatic GLP-1. Hence, IL-6 mediates crosstalk between insulin-sensitive tissues, intestinal L cells and pancreatic islets to adapt to changes in insulin demand. This previously unidentified endocrine loop implicates IL-6 in the regulation of insulin secretion and suggests that drugs modulating this loop may be useful in type 2 diabetes.

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Figure 1: Effect of acute IL-6 on GLP-1 and insulin secretion in vivo.
Figure 2: Effect of twice daily IL-6 injections over 1 week on glucose homeostasis and GLP-1 production.
Figure 3: Effects of IL-6 on GLP-1 secretion in GLUTag cells.
Figure 4: Effects of IL-6 on GLP-1 secretion in human islets and human alpha cells.
Figure 5: Effect of acute IL-6 on insulin secretion in animal models of prediabetes and diabetes.
Figure 6: Effect of IL-6 antagonism in mice fed a high-fat diet and in db/db mice.

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References

  1. Spranger, J. et al. Inflammatory cytokines and the risk to develop type 2 diabetes: results of the prospective population-based European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam Study. Diabetes 52, 812–817 (2003).

    Article  CAS  PubMed  Google Scholar 

  2. Herder, C. et al. Association of systemic chemokine concentrations with impaired glucose tolerance and type 2 diabetes: results from the Cooperative Health Research in the Region of Augsburg Survey S4 (KORA S4). Diabetes 54 (suppl. 2), S11–S17 (2005).

    Article  CAS  PubMed  Google Scholar 

  3. Mohamed-Ali, V. et al. Subcutaneous adipose tissue releases interleukin-6, but not tumor necrosis factor-α, in vivo. J. Clin. Endocrinol. Metab. 82, 4196–4200 (1997).

    CAS  PubMed  Google Scholar 

  4. Lazar, M.A. How obesity causes diabetes: not a tall tale. Science 307, 373–375 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Ostrowski, K., Rohde, T., Zacho, M., Asp, S. & Pedersen, B.K. Evidence that interleukin-6 is produced in human skeletal muscle during prolonged running. J. Physiol. (Lond.) 508, 949–953 (1998).

    Article  CAS  Google Scholar 

  6. Pedersen, B.K. & Febbraio, M.A. Muscle as an endocrine organ: focus on muscle-derived interleukin-6. Physiol. Rev. 88, 1379–1406 (2008).

    Article  CAS  PubMed  Google Scholar 

  7. Febbraio, M.A. et al. Glucose ingestion attenuates interleukin-6 release from contracting skeletal muscle in humans. J. Physiol. (Lond.) 549, 607–612 (2003).

    Article  CAS  Google Scholar 

  8. Carey, A.L. et al. Interleukin-6 increases insulin-stimulated glucose disposal in humans and glucose uptake and fatty acid oxidation in vitro via AMP-activated protein kinase. Diabetes 55, 2688–2697 (2006).

    Article  CAS  PubMed  Google Scholar 

  9. Mooney, R.A. Counterpoint: interleukin-6 does not have a beneficial role in insulin sensitivity and glucose homeostasis. J. Appl. Physiol. 102, 816–818, discussion 818–819 (2007).

    Article  CAS  PubMed  Google Scholar 

  10. Jansson, J.O. & Wallenius, V. Point-counterpoint: interleukin-6 does/does not have a beneficial role in insulin sensitivity and glucose homeostasis. J. Appl. Physiol. 102, 821 (2007).

    PubMed  Google Scholar 

  11. Pedersen, B.K. & Febbraio, M.A. Point: interleukin-6 does have a beneficial role in insulin sensitivity and glucose homeostasis. J. Appl. Physiol. 102, 814–816 (2007).

    Article  CAS  PubMed  Google Scholar 

  12. Weigert, C., Lehmann, R. & Schleicher, E.D. Point-counterpoint: interleukin-6 does/does not have a beneficial role in insulin sensitivity and glucose homeostasis. J. Appl. Physiol. 102, 820–821, author reply 825 (2007).

    Article  PubMed  Google Scholar 

  13. Ellingsgaard, H. et al. Interleukin-6 regulates pancreatic alpha-cell mass expansion. Proc. Natl. Acad. Sci. USA 105, 13163–13168 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Creutzfeldt, W. The incretin concept today. Diabetologia 16, 75–85 (1979).

    Article  CAS  PubMed  Google Scholar 

  15. Kieffer, T.J. & Habener, J.F. The glucagon-like peptides. Endocr. Rev. 20, 876–913 (1999).

    Article  CAS  PubMed  Google Scholar 

  16. Lund, P.K., Goodman, R.H., Dee, P.C. & Habener, J.F. Pancreatic preproglucagon cDNA contains two glucagon-related coding sequences arranged in tandem. Proc. Natl. Acad. Sci. USA 79, 345–349 (1982).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Bell, G.I., Santerre, R.F. & Mullenbach, G.T. Hamster preproglucagon contains the sequence of glucagon and two related peptides. Nature 302, 716–718 (1983).

    Article  CAS  PubMed  Google Scholar 

  18. Rouillé, Y., Kantengwa, S., Irminger, J.C. & Halban, P.A. Role of the prohormone convertase PC3 in the processing of proglucagon to glucagon-like peptide 1. J. Biol. Chem. 272, 32810–32816 (1997).

    Article  PubMed  Google Scholar 

  19. Zhu, X. et al. Disruption of PC1/3 expression in mice causes dwarfism and multiple neuroendocrine peptide processing defects. Proc. Natl. Acad. Sci. USA 99, 10293–10298 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Rouillé, Y., Martin, S. & Steiner, D.F. Differential processing of proglucagon by the subtilisin-like prohormone convertases PC2 and PC3 to generate either glucagon or glucagon-like peptide. J. Biol. Chem. 270, 26488–26496 (1995).

    Article  PubMed  Google Scholar 

  21. Furuta, M. et al. Severe defect in proglucagon processing in islet A-cells of prohormone convertase 2 null mice. J. Biol. Chem. 276, 27197–27202 (2001).

    Article  CAS  PubMed  Google Scholar 

  22. Thyssen, S., Arany, E. & Hill, D.J. Ontogeny of regeneration of beta-cells in the neonatal rat after treatment with streptozotocin. Endocrinology 147, 2346–2356 (2006).

    Article  CAS  PubMed  Google Scholar 

  23. De León, D.D. et al. Role of endogenous glucagon-like peptide-1 in islet regeneration after partial pancreatectomy. Diabetes 52, 365–371 (2003).

    Article  PubMed  Google Scholar 

  24. Nie, Y. et al. Regulation of pancreatic PC1 and PC2 associated with increased glucagon-like peptide 1 in diabetic rats. J. Clin. Invest. 105, 955–965 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Kilimnik, G., Kim, A., Steiner, D.F., Friedman, T.C. & Hara, M. Intraislet production of GLP-1 by activation of prohormone convertase 1/3 in pancreatic alpha-cells in mouse models of ss-cell regeneration. Islets 2, 149–155 (2010).

    Article  PubMed  Google Scholar 

  26. Hansen, A.M. et al. Upregulation of alpha cell glucagon-like peptide 1 (GLP-1) in Psammomys obesus-an adaptive response to hyperglycaemia? Diabetologia 54, 1379–1387 (2011).

    Article  CAS  PubMed  Google Scholar 

  27. Anini, Y. & Brubaker, P.L. Role of leptin in the regulation of glucagon-like peptide-1 secretion. Diabetes 52, 252–259 (2003).

    Article  CAS  PubMed  Google Scholar 

  28. Ehses, J.A. et al. Increased number of islet-associated macrophages in type 2 diabetes. Diabetes 56, 2356–2370 (2007).

    Article  CAS  PubMed  Google Scholar 

  29. Li, M. et al. Successful modulation of type 2 diabetes in db/db mice with intra-bone marrow–bone marrow transplantation plus concurrent thymic transplantation. J. Autoimmun. 35, 414–423 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Sabio, G. et al. A stress signaling pathway in adipose tissue regulates hepatic insulin resistance. Science 322, 1539–1543 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Wueest, S. et al. Deletion of Fas in adipocytes relieves adipose tissue inflammation and hepatic manifestations of obesity in mice. J. Clin. Invest. 120, 191–202 (2010).

    Article  CAS  PubMed  Google Scholar 

  32. Reimann, F. et al. Glucose sensing in L cells: a primary cell study. Cell Metab. 8, 532–539 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Yamaguchi, K. et al. Blockade of IL-6 signaling exacerbates liver injury and suppresses antiapoptotic gene expression in methionine choline-deficient diet-Fed db/db mice. Lab. Invest. 91, 609–618 (2011).

    Article  CAS  PubMed  Google Scholar 

  34. Ueda, S.Y. et al. Changes in gut hormone levels and negative energy balance during aerobic exercise in obese young males. J. Endocrinol. 201, 151–159 (2009).

    Article  CAS  PubMed  Google Scholar 

  35. Adam, T.C. & Westerterp-Plantenga, M.S. Activity-induced GLP-1 release in lean and obese subjects. Physiol. Behav. 83, 459–466 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Martins, C., Morgan, L.M., Bloom, S.R. & Robertson, M.D. Effects of exercise on gut peptides, energy intake and appetite. J. Endocrinol. 193, 251–258 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Chanoine, J.P. et al. GLP-1 and appetite responses to a meal in lean and overweight adolescents following exercise. Obesity (Silver Spring) 16, 202–204 (2008).

    Article  Google Scholar 

  38. Dela, F., von Linstow, M.E., Mikines, K.J. & Galbo, H. Physical training may enhance beta-cell function in type 2 diabetes. Am. J. Physiol. Endocrinol. Metab. 287, E1024–E1031 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Delmeire, D. et al. Prior in vitro exposure to GLP-1 with or without GIP can influence the subsequent beta cell responsiveness. Biochem. Pharmacol. 68, 33–39 (2004).

    Article  CAS  PubMed  Google Scholar 

  40. Hinke, S.A., Hellemans, K. & Schuit, F.C. Plasticity of the beta cell insulin secretory competence: preparing the pancreatic beta cell for the next meal. J. Physiol. (Lond.) 558, 369–380 (2004).

    Article  CAS  Google Scholar 

  41. Holz, G.G., Kuhtreiber, W.M. & Habener, J.F. Pancreatic beta-cells are rendered glucose-competent by the insulinotropic hormone glucagon-like peptide-1(7–37). Nature 361, 362–365 (1993).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Di Gregorio, G.B., Hensley, L., Lu, T., Ranganathan, G. & Kern, P.A. Lipid and carbohydrate metabolism in mice with a targeted mutation in the IL-6 gene: absence of development of age-related obesity. Am. J. Physiol. Endocrinol. Metab. 287, E182–E187 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Bosco, D. et al. Unique arrangement of alpha- and beta-cells in human islets of Langerhans. Diabetes 59, 1202–1210 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Rodriguez-Diaz, R. et al. Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming beta cell function in humans. Nat. Med. 17, 888–892 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kieffer, T.J. et al. Degradation of glucose-dependent insulinotropic polypeptide and truncated glucagon-like peptide 1 in vitro and in vivo by dipeptidyl peptidase IV. Endocrinology 136, 3585–3596 (1995).

    Article  CAS  PubMed  Google Scholar 

  46. Holmes, A.G. et al. Prolonged interleukin-6 administration enhances glucose tolerance and increases skeletal muscle PPARα and UCP2 expression in rats. J. Endocrinol. 198, 367–374 (2008).

    Article  CAS  PubMed  Google Scholar 

  47. Franckhauser, S. et al. Overexpression of Il6 leads to hyperinsulinaemia, liver inflammation and reduced body weight in mice. Diabetologia 51, 1306–1316 (2008).

    Article  CAS  PubMed  Google Scholar 

  48. Sadagurski, M. et al. Human IL6 enhances leptin action in mice. Diabetologia 53, 525–535 (2010).

    Article  CAS  PubMed  Google Scholar 

  49. Wallenius, V. et al. Interleukin-6-deficient mice develop mature-onset obesity. Nat. Med. 8, 75–79 (2002).

    Article  CAS  PubMed  Google Scholar 

  50. Weigert, C. et al. Direct cross-talk of interleukin-6 and insulin signal transduction via insulin receptor substrate-1 in skeletal muscle cells. J. Biol. Chem. 281, 7060–7067 (2006).

    Article  CAS  PubMed  Google Scholar 

  51. Schuler, B. et al. Optimal hematocrit for maximal exercise performance in acute and chronic erythropoietin-treated mice. Proc. Natl. Acad. Sci. USA 107, 419–423 (2010).

    Article  CAS  PubMed  Google Scholar 

  52. Jevdjovic, T. et al. Effects of insulin–like growth factor-I treatment on the endocrine pancreas of hypophysectomized rats: comparison with growth hormone replacement. Eur. J. Endocrinol. 151, 223–231 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Jevdjovic, T. et al. The effect of hypophysectomy on pancreatic islet hormone and insulin-like growth factor I content and mRNA expression in rat. Histochem. Cell Biol. 123, 179–188 (2005).

    Article  CAS  PubMed  Google Scholar 

  54. Sporeno, E. et al. Human interleukin-6 receptor super-antagonists with high potency and wide spectrum on multiple myeloma cells. Blood 87, 4510–4519 (1996).

    Article  CAS  PubMed  Google Scholar 

  55. Parnaud, G. et al. Proliferation of sorted human and rat beta cells. Diabetologia 51, 91–100 (2008).

    Article  CAS  PubMed  Google Scholar 

  56. Gribble, F.M., Williams, L., Simpson, A.K. & Reimann, F. A novel glucose-sensing mechanism contributing to glucagon-like peptide-1 secretion from the GLUTag cell line. Diabetes 52, 1147–1154 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Rudich, A. et al. Indinavir uncovers different contributions of GLUT4 and GLUT1 towards glucose uptake in muscle and fat cells and tissues. Diabetologia 46, 649–658 (2003).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We acknowledge O. Madsen and D. Steiner for their suggestion to investigate the role of IL-6 on GLP-1 and PC1/3. We thank R. Prazak and M. Borsigova for technical assistance and M. Niessen for discussions. This work was supported by grants from the Swiss National Science Foundation and by the Merck Investigator Studies Program. J.A.E. was supported by grants from the Hartman Muller organization, the Child and Family Research Institute and the University of British Columbia and has salary support from the Canadian Diabetes Association. We obtained human islets thanks to grant 31-2008-416 from the Juvenile Diabetes Research Foundation. D.J.D. is supported by the Canada Research Chair in Regulatory Peptides, the Banting and Best Diabetes Centre–Novo Nordisk Chair in Incretin Biology and Canadian Institutes of Health Research operating grant 93749. F.M.G., F.R. and A.M.H. are supported by grants from the Wellcome Trust (WT088357 to F.M.G. and WT084210 to F.R.) and EU FP7 grant 266408.

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Authors and Affiliations

  1. Diabetes & Metabolism and Department Biomedicine, Clinic for Endocrinology, University Hospital Basel, Basel, Switzerland

    Helga Ellingsgaard, Irina Hauselmann, Daniel T Meier & Marc Y Donath

  2. Institute of Veterinary Physiology, Vetsuisse Faculty and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland

    Beat Schuler & Max Gassmann

  3. Cambridge Institute for Medical Research and Department of Clinical Biochemistry, Addenbrooke's Hospital, Cambridge, UK

    Abdella M Habib, Frank Reimann & Fiona M Gribble

  4. Department of Medicine, Samuel Lunenfeld Research Institute, Toronto, Ontario, Canada

    Laurie L Baggio & Daniel J Drucker

  5. Research Group Neuro-Endocrine-Immune Interactions, Institute of Anatomy, University of Zurich, Zurich, Switzerland

    Elisabeth Eppler & Manfred Reinecke

  6. Department of Genetic Medicine and Development, University Medical Center, University of Geneva, Geneva, Switzerland

    Karim Bouzakri & Philippe A Halban

  7. Division of Pediatric Endocrinology and Diabetology, University Children's Hospital and Zurich Center for Integrative Human Physiology, University of Zurich, Zurich, Switzerland

    Stephan Wueest & Daniel Konrad

  8. Department of Surgery, Cell Isolation and Transplantation Center, University Medical Center, University of Geneva, Geneva, Switzerland

    Yannick D Muller

  9. Diabetes Research Unit, Novo Nordisk A/S, Måløv, Denmark

    Ann Maria Kruse Hansen

  10. Cardiovascular and Metabolism Disease Area, Novartis Institutes for Biomedical Research, Cambridge, Massachusetts, USA

    Jesper Gromada

  11. Department of Surgery, Faculty of Medicine, University of British Columbia, Child & Family Research Institute, Vancouver, British Columbia, Canada

    Jan A Ehses

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Contributions

H.E. designed and performed experiments, analyzed data and wrote the manuscript. I.H., B.S., A.M.H., L.L.B., D.T.M., E.E., J.G., S.W., A.M.K.H., D.K., M.R., M.G., D.J.D., F.R. and F.M.G. performed experiments. Y.D.M. isolated human islets. K.B. and P.A.H. provided FACS-sorted human islet cells. D.J.D., F.M.G. and F.R. provided mice for this study. J.A.E. and M.Y.D. designed experiments and wrote the paper.

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Correspondence to Helga Ellingsgaard.

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Ellingsgaard, H., Hauselmann, I., Schuler, B. et al. Interleukin-6 enhances insulin secretion by increasing glucagon-like peptide-1 secretion from L cells and alpha cells. Nat Med 17, 1481–1489 (2011). https://doi.org/10.1038/nm.2513

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