Free fatty acids regulate insulin secretion from pancreatic β cells through GPR40 (original) (raw)
- Letter
- Published: 23 February 2003
- Yuji Kawamata1 na1,
- Masataka Harada1,
- Makoto Kobayashi1,
- Ryo Fujii1,
- Shoji Fukusumi1,
- Kazuhiro Ogi1,
- Masaki Hosoya1,
- Yasuhiro Tanaka1,
- Hiroshi Uejima1,
- Hideyuki Tanaka1,
- Minoru Maruyama1,
- Rie Satoh1,
- Shoichi Okubo1,
- Hideki Kizawa1,
- Hidetoshi Komatsu1,
- Fumika Matsumura1,
- Yuko Noguchi1,
- Tokuyuki Shinohara1,
- Shuji Hinuma1,
- Yukio Fujisawa1 &
- …
- Masahiko Fujino1
Nature volume 422, pages 173–176 (2003)Cite this article
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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.
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References
- Gadsby, R. Epidemiology of diabetes. Adv. Drug Deliv. Rev. 54, 1165–1172 (2002)
Article CAS Google Scholar - 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 - Henquin, J. C. Triggering and amplifying pathways of regulation of insulin secretion by glucose. Diabetes 49, 1751–1760 (2000)
Article CAS Google Scholar - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - 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 - Hinuma, S. et al. A prolactin-releasing peptide in the brain. Nature 393, 272–276 (1998)
Article ADS CAS Google Scholar - 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 - 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)
- Spector, A. A. & Hoak, J. C. Fatty acids, platelets, and microcirculatory obstruction. Science 190, 490–492 (1975)
Article ADS CAS Google Scholar - 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 - 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 - 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 - Ashcroft, F. M. et al. Stimulus-secretion coupling in pancreatic beta cells. J. Cell Biochem. 55, 54–65 (1994)
Article CAS Google Scholar - 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 - 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 - 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 - Kawamata, Y. et al. A G protein-coupled receptor responsive to bile acids. J. Biol. Chem. published online, 10 January 2003 (doi:209706200)
Acknowledgements
We thank Y. Sumino, T. Soda, K. Kato, H. Odaka, F. Itoh, M. Kajino, K. Fukatsu and N. Suzuki for their discussions.
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- Yasuaki Itoh and Yuji Kawamata: These authors contributed equally to this work
Authors and Affiliations
- Discovery Research Laboratories I, Pharmaceutical Research Division, Takeda Chemical Industries, Ltd, Wadai 10, Tsukuba, Ibaraki, 300-4293, Japan
Yasuaki Itoh, Yuji Kawamata, Masataka Harada, Makoto Kobayashi, Ryo Fujii, Shoji Fukusumi, Kazuhiro Ogi, Masaki Hosoya, Yasuhiro Tanaka, Hiroshi Uejima, Hideyuki Tanaka, Minoru Maruyama, Rie Satoh, Shoichi Okubo, Hideki Kizawa, Hidetoshi Komatsu, Fumika Matsumura, Yuko Noguchi, Tokuyuki Shinohara, Shuji Hinuma, Yukio Fujisawa & Masahiko Fujino
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- Yasuaki Itoh
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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
- Received: 02 January 2003
- Accepted: 11 February 2003
- Published: 23 February 2003
- Issue Date: 13 March 2003
- DOI: https://doi.org/10.1038/nature01478