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:

Free fatty acids regulate insulin secretion from pancreatic β cells through GPR40

Abstract

Diabetes, a disease in which carbohydrate and lipid metabolism are regulated improperly by insulin, is a serious worldwide health issue1,2. Insulin is secreted from pancreatic β cells in response to elevated plasma glucose, with various factors modifying its secretion3. Free fatty acids (FFAs) provide an important energy source as nutrients, and they also act as signalling molecules in various cellular processes, including insulin secretion4,5. Although FFAs are thought to promote insulin secretion in an acute phase, this mechanism is not clearly understood6. Here we show that a G-protein-coupled receptor, GPR40, which is abundantly expressed in the pancreas, functions as a receptor for long-chain FFAs. Furthermore, we show that long-chain FFAs amplify glucose-stimulated insulin secretion from pancreatic β cells by activating GPR40. Our results indicate that GPR40 agonists and/or antagonists show potential for the development of new anti-diabetic drugs.

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

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

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

Figure 1: GPR40 mRNA is expressed abundantly in pancreatic β cells.
Figure 2: Induction of [Ca2+]i rise and MAP kinase activation by FFAs in CHO–hGPR40 cells.
Figure 3: Analyses for FFA-induced insulin secretion mechanisms.

Similar content being viewed by others

References

  1. Gadsby, R. Epidemiology of diabetes. Adv. Drug Deliv. Rev. 54, 1165–1172 (2002)

    Article  CAS  Google Scholar 

  2. Jovanovic, L. & Gondos, B. Type 2 diabetes: The epidemic of the new millennium. Ann. Clin. Lab. Sci. 29, 33–42 (1999)

    CAS  PubMed  Google Scholar 

  3. Henquin, J. C. Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes 49, 1751–1760 (2000)

    Article  CAS  Google Scholar 

  4. Nunez, E. A. Biological complexity is under the ‘strange attraction’ of non-esterified fatty acids. Prostaglandins Leukot. Essent. Fatty Acids 57, 107–110 (1997)

    Article  CAS  Google Scholar 

  5. Haber, E. P. et al. Pleiotropic effects of fatty acids on pancreatic β-cells. J. Cell Physiol. 194, 1–12 (2003)

    Article  CAS  Google Scholar 

  6. Dobbins, R. L. et al. A fatty acid-dependent step is critically important for both glucose-and non-glucose-stimulated insulin secretion. J. Clin. Invest. 101, 2370–2376 (1998)

    Article  CAS  Google Scholar 

  7. Sawzdargo, M. et al. A cluster of four novel human G protein-coupled receptor genes occurring in close proximity to CD22 gene on chromosome 19q13.1. Biochem. Biophys. Res. Commun. 239, 543–547 (1997)

    Article  CAS  Google Scholar 

  8. Fujii, R. et al. Identification of neuromedin U as the cognate ligand of the orphan G protein-coupled receptor FM-3. J. Biol. Chem. 275, 21068–21074 (2000)

    Article  CAS  Google Scholar 

  9. Wank, S. A. et al. Purification, molecular cloning, and functional expression of the cholecystokinin receptor from rat pancreas. Proc. Natl Acad. Sci. USA 89, 3125–3129 (1992)

    Article  ADS  CAS  Google Scholar 

  10. Lankat-Buttgereit, B., Goke, R., Fehmann, H. C., Richter, G. & Goke, B. Molecular cloning of a cDNA encoding for the GLP-1 receptor expressed in rat lung. Exp. Clin. Endocrinol. 102, 341–347 (1994)

    Article  CAS  Google Scholar 

  11. Aguilar-Bryan, L. et al. Cloning of the beta cell high-affinity sulfonylurea receptor: a regulator of insulin secretion. Science 268, 423–426 (1995)

    Article  ADS  CAS  Google Scholar 

  12. Braun, T., Schofield, P. R., Shivers, B. D., Pritchett, D. B. & Seeburg, P. H. A novel subtype of muscarinic receptor identified by homology screening. Biochem. Biophys. Res. Commun. 149, 125–132 (1987)

    Article  CAS  Google Scholar 

  13. Bruno, J. F., Xu, Y., Song, J. & Berelowitz, M. Tissue distribution of somatostatin receptor subtype messenger ribonucleic acid in the rat. Endocrinology 133, 2561–2567 (1993)

    Article  CAS  Google Scholar 

  14. Miyazaki, J. et al. Establishment of a pancreatic beta cell line that retains glucose-inducible insulin secretion: special reference to expression of glucose transporter isoforms. Endocrinology 127, 126–132 (1990)

    Article  CAS  Google Scholar 

  15. Hinuma, S. et al. A prolactin-releasing peptide in the brain. Nature 393, 272–276 (1998)

    Article  ADS  CAS  Google Scholar 

  16. Hinuma, S., Onda, H. & Fujino, M. The quest for novel bioactive peptides utilizing orphan seven-transmembrane-domain receptors. J. Mol. Med. 77, 495–504 (1999)

    Article  CAS  Google Scholar 

  17. Briscoe, C. P. et al. The orphan G protein-coupled receptor GPR40 is activated by medium and long-chain fatty acids. J. Biol. Chem. published online, 19 December 2002 (doi:211495200)

  18. Spector, A. A. & Hoak, J. C. Fatty acids, platelets, and microcirculatory obstruction. Science 190, 490–492 (1975)

    Article  ADS  CAS  Google Scholar 

  19. Stein, D. T. et al. Essentiality of circulating fatty acids for glucose-stimulated insulin secretion in the fasted rat. J. Clin. Invest. 97, 2728–2735 (1996)

    Article  CAS  Google Scholar 

  20. Bergman, R. N. & Ader, M. Free fatty acids and pathogenesis of type 2 diabetes mellitus. Trends Endocrinol. Metab. 11, 351–356 (2000)

    Article  CAS  Google Scholar 

  21. Newgard, C. B. & McGarry, J. D. Metabolic coupling factors in pancreatic β-cell signal transduction. Annu. Rev. Biochem. 64, 689–719 (1995)

    Article  CAS  Google Scholar 

  22. Ashcroft, F. M. et al. Stimulus-secretion coupling in pancreatic beta cells. J. Cell Biochem. 55, 54–65 (1994)

    Article  CAS  Google Scholar 

  23. Wolheim, C. B. & Biden, T. J. Signal transduction in insulin secretion: comparison between fuel stimuli and receptor agonists. Ann. NY Acad. Sci. 488, 317–333 (1986)

    Article  ADS  Google Scholar 

  24. Gutkind, J. S. Cell growth control by G protein-coupled receptors: from signal transduction to signal integration. Oncogene 17, 1331–1342 (1998)

    Article  CAS  Google Scholar 

  25. Lacy, P. E. & Kostianovsky, M. Method for the isolation of intact islets of Langerhans from the rat pancreas. Diabetes 16, 35–39 (1967)

    Article  CAS  Google Scholar 

  26. Kawamata, Y. et al. A G protein-coupled receptor responsive to bile acids. J. Biol. Chem. published online, 10 January 2003 (doi:209706200)

Download references

Acknowledgements

We thank Y. Sumino, T. Soda, K. Kato, H. Odaka, F. Itoh, M. Kajino, K. Fukatsu and N. Suzuki for their discussions.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Shuji Hinuma.

Ethics declarations

Competing interests

The authors declare that they have no competing financial interests.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Itoh, Y., Kawamata, Y., Harada, M. et al. Free fatty acids regulate insulin secretion from pancreatic β cells through GPR40. Nature 422, 173–176 (2003). https://doi.org/10.1038/nature01478

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nature01478

This article is cited by

Comments

By submitting a comment you agree to abide by our Terms and Community Guidelines. If you find something abusive or that does not comply with our terms or guidelines please flag it as inappropriate.

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