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Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming beta cell function in humans

Nature Medicine volume 17, pages 888–892 (2011)Cite this article

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Abstract

Acetylcholine is a neurotransmitter that has a major role in the function of the insulin-secreting pancreatic beta cell1,2. Parasympathetic innervation of the endocrine pancreas, the islets of Langerhans, has been shown to provide cholinergic input to the beta cell in several species1,3,4, but the role of autonomic innervation in human beta cell function is at present unclear. Here we show that, in contrast to the case in mouse islets, cholinergic innervation of human islets is sparse. Instead, we find that the alpha cells of human islets provide paracrine cholinergic input to surrounding endocrine cells. Human alpha cells express the vesicular acetylcholine transporter and release acetylcholine when stimulated with kainate or a lowering in glucose concentration. Acetylcholine secretion by alpha cells in turn sensitizes the beta cell response to increases in glucose concentration. Our results demonstrate that in human islets acetylcholine is a paracrine signal that primes the beta cell to respond optimally to subsequent increases in glucose concentration. Cholinergic signaling within islets represents a potential therapeutic target in diabetes5, highlighting the relevance of this advance to future drug development.

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Figure 1: Endocrine cells in human pancreatic islets express cholinergic markers.
Figure 2: Human alpha cells express vAChT and ChAT.
Figure 3: Isolated human islets secrete acetylcholine (ACh) in response to alpha cell–specific stimuli.
Figure 4: Endogenously released ACh amplifies glucose-induced insulin secretion in human islets.

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References

  1. Gilon, P. & Henquin, J. Mechanisms and physiological significance of the cholinergic control of pancreatic beta-cell function. Endocr. Rev. 22, 565–604 (2001).

    Google Scholar 

  2. Gautam, D. et al. A critical role for beta cell M3 muscarinic acetylcholine receptors in regulating insulin release and blood glucose homeostasis in vivo. Cell Metab. 3, 449–461 (2006).

    Google Scholar 

  3. Ahrén, B. Autonomic regulation of islet hormone secretion—implications for health and disease. Diabetologia 43, 393–410 (2000).

    Google Scholar 

  4. Conn, P.M., Goodman, H.M. & Kostyo, J.L. The Endocrine System: The Endocrine Pancreas and Regulation of Metabolism. 153 (Oxford University Press, New York, 1998).

  5. Gautam, D. et al. Role of the M3 muscarinic acetylcholine receptor in beta-cell function and glucose homeostasis. Diabetes Obes. Metab. 9 (Suppl 2), 158–169 (2007).

    Google Scholar 

  6. Guenifi, A., Simonsson, E., Karlsson, S., Ahrén, B. & Abdel-Halim, S. Carbachol restores insulin release in diabetic GK rat islets by mechanisms largely involving hydrolysis of diacylglycerol and direct interaction with the exocytotic machinery. Pancreas 22, 164–171 (2001).

    Google Scholar 

  7. Doliba, N.M. et al. Restitution of defective glucose-stimulated insulin release of sulfonylurea type 1 receptor knockout mice by acetylcholine. Am. J. Physiol. Endocrinol. Metab. 286, E834–E843 (2004).

    Google Scholar 

  8. Guo, Y. et al. CHRM3 gene variation is associated with decreased acute insulin secretion and increased risk for early-onset type 2 diabetes in Pima Indians. Diabetes 55, 3625–3629 (2006).

    Google Scholar 

  9. Woods, S.C. & Porte, D.J. Neural control of the endocrine pancreas. Physiol. Rev. 54, 596–619 (1974).

    Google Scholar 

  10. Coupland, R.E. The innervation of pan creas of the rat, cat and rabbit as revealed by the cholinesterase technique. J. Anat. 92, 143–149 (1958).

    Google Scholar 

  11. Amenta, F., Cavallotti, C., de Rossi, M., Tonelli, F. & Vatrella, F. The cholinergic innervation of human pancreatic islets. Acta Histochem. 73, 273–278 (1983).

    Google Scholar 

  12. Ahrén, B., Taborsky, G.J. & Porte, D.J. Neuropeptidergic versus cholinergic and adrenergic regulation of islet hormone secretion. Diabetologia 29, 827–836 (1986).

    Google Scholar 

  13. Brunicardi, F.C., Shavelle, D. & Andersen, D. Neural regulation of the endocrine pancreas. Int. J. Pancreatol. 18, 177–195 (1995).

    Google Scholar 

  14. Weihe, E., Tao-Cheng, J., Schäfer, M., Erickson, J. & Eiden, L. Visualization of the vesicular acetylcholine transporter in cholinergic nerve terminals and its targeting to a specific population of small synaptic vesicles. Proc. Natl. Acad. Sci. USA 93, 3547–3552 (1996).

    Google Scholar 

  15. Karlsson, S., Myrsén, U., Nieuwenhuizen, A., Sundler, F. & Ahrén, B. Presynaptic sympathetic mechanism in the insulinostatic effect of epinephrine in mouse pancreatic islets. Am. J. Physiol. 272, R1371–R1378 (1997).

    Google Scholar 

  16. Cabrera, O. et al. Glutamate is a positive autocrine signal for glucagon release. Cell Metab. 7, 545–554 (2008).

    Google Scholar 

  17. Eiden, L.E. The cholinergic gene locus. J. Neurochem. 70, 2227–2240 (1998).

    Google Scholar 

  18. Barlow, A.L., Macleod, A., Noppen, S., Sanderson, J. & Guérin, C.J. Colocalization analysis in fluorescence micrographs: verification of a more accurate calculation of pearson's correlation coefficient. Microsc. Microanal. 16, 710–724 (2010).

    Google Scholar 

  19. Liu, Y. & Edwards, R. Differential localization of vesicular acetylcholine and monoamine transporters in PC12 cells but not CHO cells. J. Cell Biol. 139, 907–916 (1997).

    Google Scholar 

  20. Krantz, D.E. et al. A phosphorylation site regulates sorting of the vesicular acetylcholine transporter to dense core vesicles. J. Cell Biol. 149, 379–396 (2000).

    Google Scholar 

  21. Greider, M.H., Bencosme, S. & Lechago, J. The human pancreatic islet cells and their tumors. I. The normal pancreatic islets. Lab. Invest. 22, 344–354 (1970).

    Google Scholar 

  22. Cabrera, O. et al. Automated, high-throughput assays for evaluation of human pancreatic islet function. Cell Transplant. 16, 1039–1048 (2008).

    Google Scholar 

  23. Jacques-Silva, M.C. et al. ATP-gated P2X3 receptors constitute a positive autocrine signal for insulin release in the human pancreatic beta cell. Proc. Natl. Acad. Sci. USA 107, 6465–6470 (2010).

    Google Scholar 

  24. Zawalich, W.S., Zawalich, K. & Rasmussen, H. Cholinergic agonists prime the beta-cell to glucose stimulation. Endocrinology 125, 2400–2406 (1989).

    Google Scholar 

  25. Cabrera, O. et al. The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc. Natl. Acad. Sci. USA 103, 2334–2339 (2006).

    Google Scholar 

  26. Stagner, J.I., Samols, E. & Weir, G.C. Sustained oscillations of insulin, glucagon, and somatostatin from the isolated canine pancreas during exposure to a constant glucose concentration. J. Clin. Invest. 65, 939–942 (1980).

    Google Scholar 

  27. Lang, D.A., Matthews, D.R., Peto, J. & Turner, R.C. Cyclic oscillations of basal plasma glucose and insulin concentrations in human beings. N. Engl. J. Med. 301, 1023–1027 (1979).

    Google Scholar 

  28. Wessler, I. & Kirkpatrick, C. Acetylcholine beyond neurons: the non-neuronal cholinergic system in humans. Br. J. Pharmacol. 154, 1558–1571 (2008).

    Google Scholar 

  29. Brissova, M. et al. Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy. J. Histochem. Cytochem. 53, 1087–1097 (2005).

    Google Scholar 

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

    Google Scholar 

  31. Pisania, A. et al. Quantitative analysis of cell composition and purity of human pancreatic islet preparations. Lab. Invest. 90, 1661–1675 (2010).

    Google Scholar 

  32. Stagner, J.I. & Samols, E. The vascular order of islet cellular perfusion in the human pancreas. Diabetes 41, 93–97 (1992).

    Google Scholar 

  33. Taylor, I.L. & Feldman, M. Effect of cephalic-vagal stimulation on insulin, gastric inhibitory polypeptide, and pancreatic polypeptide release in humans. J. Clin. Endocrinol. Metab. 55, 1114–1117 (1982).

    Google Scholar 

  34. Teff, K.L., Mattes, R., Engelman, K. & Mattern, J. Cephalic-phase insulin in obese and normal-weight men: relation to postprandial insulin. Metabolism 42, 1600–1608 (1993).

    Google Scholar 

  35. Becker, H.D., Börger, H. & Schafmayer, A. Effect of vagotomy on gastrointestinal hormones. World J. Surg. 3, 615–622 (1979).

    Google Scholar 

  36. Pozza, G. et al. Metabolic control of type I (insulin dependent) diabetes after pancreas transplantation. Br. Med. J. (Clin. Res. Ed.) 291, 510–513 (1985).

    Google Scholar 

  37. Diem, P. et al. Glucagon, catecholamine and pancreatic polypeptide secretion in type I diabetic recipients of pancreas allografts. J. Clin. Invest. 86, 2008–2013 (1990).

    Google Scholar 

  38. Blackman, J.D. et al. Insulin secretory profiles and C-peptide clearance kinetics at 6 months and 2 years after kidney-pancreas transplantation. Diabetes 41, 1346–1354 (1992).

    Google Scholar 

  39. Huang, Y.J. et al. Mouse taste buds use serotonin as a neurotransmitter. J. Neurosci. 25, 843–847 (2005).

    Google Scholar 

  40. Buck, M.A. & Fraser, C. Muscarinic acetylcholine receptor subtypes which selectively couple to phospholipase C: pharmacological and biochemical properties. Biochem. Biophys. Res. Commun. 173, 666–672 (1990).

    Google Scholar 

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Acknowledgements

We thank A. Formoso for help with data analyses, K. Johnson for histological work and M. Correa-Medina for assistance with RT-PCR. This work was funded by the Diabetes Research Institute Foundation, US National Institutes of Health grants R56DK084321 (A.C.), R01DK084321 (A.C.), R01DC000374 (S.D.R.), R01DC007630 (S.D.R.), F32DK083226 (M.H.A.) and 5U01DK070460-07 (C.R.), the Juvenile Diabetes Research Foundation, the Swedish Research Council, the Novo Nordisk Foundation, the Swedish Diabetes Association, the Family Erling-Persson Foundation and the World Class University program through the National Research Foundation of Korea funded by the Ministry of Education, Science and Technology (R31-2008-000-10105-0). Human islets were made available through the Islet Cell Resource basic science islet distribution program, Islet Cell Resource Centers Consortium, Division of Clinical Research, National Center for Research Resources, US National Institutes of Health.

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Author notes

  1. Rayner Rodriguez-Diaz and Robin Dando: These authors contributed equally to this work.

Authors and Affiliations

  1. Diabetes Research Institute, Miller School of Medicine, University of Miami, Miami, Florida, USA

    Rayner Rodriguez-Diaz, M Caroline Jacques-Silva, Alberto Fachado, Midhat H Abdulreda, Camillo Ricordi, Per-Olof Berggren & Alejandro Caicedo

  2. The Rolf Luft Research Center for Diabetes and Endocrinology, Karolinska Institutet, Stockholm, Sweden

    Rayner Rodriguez-Diaz, Camillo Ricordi & Per-Olof Berggren

  3. Department of Physiology and Biophysics, Miller School of Medicine, University of Miami, Miami, Florida, USA

    Robin Dando, Stephen D Roper & Alejandro Caicedo

  4. Division of Endocrinology, Department of Medicine, Diabetes and Metabolism, Miller School of Medicine, University of Miami, Miami, Florida, USA

    Judith Molina & Alejandro Caicedo

  5. Program in Neuroscience, Miller School of Medicine, University of Miami, Miami, Florida, USA

    Stephen D Roper & Alejandro Caicedo

  6. Division of Integrative Biosciences and Biotechnology, World Class University Program, University of Science and Technology, Pohang, Korea

    Per-Olof Berggren

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Contributions

R.R.-D., M.C.J.-S., A.F. and J.M. performed hormone assay experiments and ELISAs; R.D. performed experiments with biosensor cells to detect acetylcholine secretion; R.R.-D. and M.C.J.-S. conducted Amplex assays to measure acetylcholine secretion; R.R.-D. and M.H.A. collected, analyzed and quantified immunohistochemical data, and R.R.-D. performed RT-PCR and western blotting. R.R.-D., R.D., M.H.A., C.R., S.D.R., P.-O.B. and A.C. designed the study, analyzed data and wrote the paper. R.R.-D. and R.D. contributed equally to the study. All authors discussed the results and commented on the manuscript.

Corresponding authors

Correspondence to Per-Olof Berggren or Alejandro Caicedo.

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The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 (PDF 662 kb)

Supplementary Video 1

Three-dimensional rendering of the vAChT immunostaining pattern in a mouse islet. Nerve fibers immunostained for vAChT are visualized as they enter the core of the islet to innervate beta cells. Reconstruction based on 45 confocal images (z step = 0.3 µm) was performed using Volocity Visualization software. (AVI 89557 kb)

Supplementary Video 2

Three-dimensional rendering of the vAChT immunostaining pattern in a human islet. Strong immunostaining is present in cells expressing glucagon. Immunostained nerve fibers cannot be seen in the islet but are visible in the exocrine tissue. Reconstruction based on 45 confocal images (z step = 0.3 µm) was performed using Volocity Visualization software. (AVI 99452 kb)

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Rodriguez-Diaz, R., Dando, R., Jacques-Silva, M. et al. Alpha cells secrete acetylcholine as a non-neuronal paracrine signal priming beta cell function in humans. Nat Med 17, 888–892 (2011). https://doi.org/10.1038/nm.2371

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