Skip to main content

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

  • Letter
  • Published:

Islet β-cell secretion determines glucagon release from neighbouring α-cells

Nature Cell Biology volume 5, pages 330–335 (2003)Cite this article

Abstract

Homeostasis of blood glucose is maintained by hormone secretion from the pancreatic islets of Langerhans. Glucose stimulates insulin secretion from β-cells but suppresses the release of glucagon, a hormone that raises blood glucose, from α-cells1. The mechanism by which nutrients stimulate insulin secretion has been studied extensively: ATP has been identified as the main messenger and the ATP-sensitive potassium channel as an essential transducer in this process2. By contrast, much less is known about the mechanisms by which nutrients modulate glucagon secretion. Here we use conventional pancreas perfusion and a transcriptional targeting strategy to analyse cell-type-specific signal transduction and the relationship between islet α- and β-cells. We find that pyruvate, a glycolytic intermediate and principal substrate of mitochondria, stimulates glucagon secretion. Our analyses indicate that, although α-cells, like β-cells, possess the inherent capacity to respond to nutrients, secretion from α-cells is normally suppressed by the simultaneous activation of β-cells. Zinc released from β-cells may be implicated in this suppression. Our results define the fundamental mechanisms of differential responses to identical stimuli between cells in a microorgan.

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: Nutrient-stimulated hormone release from perfused pancreas and isolated islets.
Figure 2: Different signal transduction in islet α- and β-cells.
Figure 3: β-cell activation inhibits the α-cell secretory response.
Figure 4: Effects of zinc on glucagon secretion.

Similar content being viewed by others

References

  1. Unger, R.H. Glucagon physiology and pathophysiology in the light of new advances. Diabetologia. 8, 574–578 (1985).

    Article  Google Scholar 

  2. Maechler, P. & Wollheim, C.B. Mitochondrial function in normal and diabetic β-cells. Nature 414, 807–812 (2001).

    Article  CAS  Google Scholar 

  3. Baetens, D., Malaisse-Lagae, F., Perrelet, A. & Orci, L. Endocrine pancreas: three-dimensional reconstitution shows two types of islets of Langerhans. Science 206, 1323–1325 (1979).

    Article  CAS  Google Scholar 

  4. Ishihara, H., Wang, H., Drewes, L.R. & Wollheim, C.B. Overexpression of monocarboxylate transporter and lactate dehydrogenase alters insulin secretory responses to pyruvate and lactate in β cells. J. Clin. Invest. 104, 1621–1629 (1999).

    Article  CAS  Google Scholar 

  5. Bokvist, K. et al. Characterization of sulfonylurea and ATP-regulated K+ channels in rat pancreatic α cells. Pflugers Arch. 438, 428–436 (1999).

    CAS  PubMed  Google Scholar 

  6. Gromada, J. et al. Adrenaline stimulates glucagon secretion in pancreatic α-cells by increasing the Ca2+ current and the number of granules close to the L-type Ca2+ channels. J. Gen. Physiol. 110, 217–228 (1997).

    Article  CAS  Google Scholar 

  7. Nettelbeck, D.M., Jerome, V. & Muller, R. Gene therapy: designer promoters for tumour targeting. Trends Genet. 16, 174–181 (2000).

    Article  CAS  Google Scholar 

  8. Pipeleers, D.G., Schuit, F.C., Van Schravendijk, C.F.H. & Van De Winkel, M. Interplay of nutrient and hormones in the regulation of glucagon release. Endocrinology 117, 817–823 (1985).

    Article  CAS  Google Scholar 

  9. Samols, E. & Stagner, J.I. Intra-islet cell–cell interactions and insulin secretion. Diabetes Rev. 4, 207–223 (1998).

    Google Scholar 

  10. Sato, Y. et al. Enhanced and specific gene expression via tissue-specific production of Cre recombinase using adenovirus vector. Biochem. Biophys. Res. Commun. 224, 455–462 (1998).

    Article  Google Scholar 

  11. Niwa, H., Yamamura, K. & Miyazaki, J. Efficient selection for high-expression transformants with a novel eukaryotic vector. Gene 108, 193–200 (1991).

    Article  CAS  Google Scholar 

  12. Bjaaland, T., Jones, P.M. & Howell, S.L. Role of intracellular mediators in glucagon secretion: studies using intact and electrically permeabilized rat islets of Langerhans. J. Mol. Endocr. 1, 171–178 (1988).

    Article  CAS  Google Scholar 

  13. Greenbaum, C.J., Havel, P.J., Taborsky, Jr., G.J. & Klaff, L.J. Intra-islet insulin permits glucose to directly suppress pancreatic A cell function. J. Clin. Invest. 88, 767–773 (1991).

    Article  CAS  Google Scholar 

  14. Rorsman, P. et al. Glucose-inhibition of glucagon secretion involves activation of GABAA-receptor chloride channels. Nature 341, 233–236 (1989).

    Article  CAS  Google Scholar 

  15. Tang, X. & Shay, N.F. Zinc has an insulin-like effect on glucose transport mediated by phosphoinositol 3-kinase and Akt in 3T3-L1 fibroblasts and adipocytes. J. Nutr. 131, 1414–1420 (2001).

    Article  CAS  Google Scholar 

  16. Vogt, K., Mellor, J., Tong, G. & Nicoll, R. The actions of synaptically released zinc at hippocampal mossy fiber synapses. Neuron 26, 187–196 (2001).

    Article  Google Scholar 

  17. Grodsky, G.M., Epstein, G.H., Fanska, R. & Karam, J.H. Pancreatic action of the sulfonylureas. Fed.Proc. 36, 2714–2719 (1977).

    CAS  PubMed  Google Scholar 

  18. Goepel, S.O., Kanno, S., Barg, S., Weng, X.-G., Gromada, J. & Rorsman, P. Regulation of glucagon release in mouse α-cells by KATP channels and inactivation of TTX-sensitive Na+ channels. J. Physiol. (Lond.) 528, 508–520 (2000).

    Google Scholar 

  19. Barg, S., Galvanovskis, J., Goepel, S.O., Rorsman, P. & Eliasson, L. Tight coupling between electrical activity and exocytosis in mouse glucagon-secreting α cells. Diabetes 49, 1500–1510 (2000).

    Article  CAS  Google Scholar 

  20. Quesada, I., Nadal, A. & Soria, B. Different effects of tolbutamide and diazoxide in α, β, and ? cells within intact islets of Langerhans. Diabetes 48, 2390–2397 (1999).

    Article  CAS  Google Scholar 

  21. Foster, M.C., Leapman, R.D., Li, M.X. & Atwater, I. Elementary composition of secretory granules in pancreatic islets of Langerhans. Biophy. J. 64, 525–532 (1993).

    Article  CAS  Google Scholar 

  22. Qian, W.J. et al. Detection of secretion from single pancreatic β-cells using extracellular fluorogenic reactions and confocal fluorescence microscopy. Anal. Chem. 72, 711–717 (2000).

    Article  CAS  Google Scholar 

  23. Hurley, L.S. Zinc deficiency in the developing rat. Am. J. Clin. Nutr. 22, 1669–1677 (1969).

    Article  Google Scholar 

  24. Lakso, M. et al. Targeted oncogene activation by site-specific recombination in transgenic mice. Proc. Natl Acad. Sci. USA 89, 6232–6236 (1992).

    Article  CAS  Google Scholar 

  25. Palmiter, R.D. et al. Cell lineage ablation in transgenic mice by cell-specific expression of a toxin gene. Cell 50, 435–443 (1987).

    Article  CAS  Google Scholar 

  26. Miyake, S. et al. Efficient generation of recombinant adenoviruses using adenovirus DNA-terminal protein complex and a cosmid bearing the full-length virus genome. Proc. Natl Acad. Sci. USA 93, 1320–1324 (1996).

    Article  CAS  Google Scholar 

  27. Gerber, P.P., Trimble, E.R., Wollheim, C.B., Renold, A.E. & Miller, R.E. Glucose and cyclic AMP as stimulators of somatostatin and insulin secretion from the isolated, perfused rat pancreas: a quantitative study. Diabetes 30, 40–44 (1981).

    Article  CAS  Google Scholar 

  28. Herrera, P.L. et al. Embriogenesis of the murine pancreas: early expression of pancreatic polypeptide gene. Development 113, 1257–1265 (1991).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank O. Dupont for technical assistance. H.I. is a recipient of a fellowship from Manpei Suzuki Foundation for Diabetes Research and a fellowship from the Juvenile Diabetes Foundation International and P.M. is a fellow of the Professor Max Cloetta Foundation. This work was supported by grants from the Swiss National Science Foundation (to C.B.W., P.M. and P.L.H.) and the Juvenile Diabetes Research Foundation (to P.L.H.).

Author information

Authors and Affiliations

  1. Division of Clinical Biochemistry, Department of Internal Medicine, University Medical Center, 1211 Geneva 4, Switzerland

    Hisamitsu Ishihara, Pierre Maechler, Asllan Gjinovci & Claes B. Wollheim

  2. Department of Morphology, University Medical Center, 1211 Geneva 4, Switzerland

    Pedro-Luis Herrera

Authors
  1. Hisamitsu Ishihara
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Pierre Maechler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Asllan Gjinovci
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Pedro-Luis Herrera
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Claes B. Wollheim
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Claes B. Wollheim.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Figure S1

Strategy to study specific cell types in heterogeneous cell populations. (PPT 360 kb)

Figure S2

Cytosolic and mitochondrial Ca2+ concentrations in response to varying concentrations of KCl in islet α- and β-cells. (PPT 362 kb)

Figure S3

Recombinant adenovirus system for expressing diphtheria toxin A (DTA) chain. (PPT 18 kb)

Figure legends (DOC 26 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Ishihara, H., Maechler, P., Gjinovci, A. et al. Islet β-cell secretion determines glucagon release from neighbouring α-cells. Nat Cell Biol 5, 330–335 (2003). https://doi.org/10.1038/ncb951

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ncb951

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