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The Free Fatty Acid Receptor GPR40 - expression and role in islet hormone secretion

Flodgren, Erik LU (2007) In Lund University Faculty of Medicine Doctoral Dissertation Series 2007:48.
Abstract
Type 2 diabetes (T2D) is a serious condition of growing proportions. Developing via an increasing imbalance between insulin sensitivity in the peripheral tissues and insulin release from pancreatic beta-cells, it ultimately renders the individual incapable of regulating the blood glucose concentration, e.g. after a meal. The increased prevalence of T2D is associated with an increase in the prevalence of obesity, with obesity being the single largest risk factor for the development of T2D. This work describes a molecule in the border zone between T2D and obesity. Our initial characterization of GPR40 identified it as a receptor for medium- to long-chain free fatty acids (FFAs). With a marked expression in pancreatic beta-cell lines, we... (More)
Type 2 diabetes (T2D) is a serious condition of growing proportions. Developing via an increasing imbalance between insulin sensitivity in the peripheral tissues and insulin release from pancreatic beta-cells, it ultimately renders the individual incapable of regulating the blood glucose concentration, e.g. after a meal. The increased prevalence of T2D is associated with an increase in the prevalence of obesity, with obesity being the single largest risk factor for the development of T2D. This work describes a molecule in the border zone between T2D and obesity. Our initial characterization of GPR40 identified it as a receptor for medium- to long-chain free fatty acids (FFAs). With a marked expression in pancreatic beta-cell lines, we expected GPR40 to be involved in FFA-mediated augmentation of insulin release. This was confirmed when we examined the dose-response relationship between FFA stimulation of GPR40 and both intracellular second messengers in a beta-cell line and insulin release from isolated pancreatic islets. A similarly increased glucagon secretion from alpha-cells was demonstrated after we established that these cells also express GPR40. Antisense knock-down of GPR40 abolished the effect of FFA stimulation on hormone secretion from both cell types. In the final part of this work, FFAs that activate GPR40 were shown to negatively regulate its mRNA expression, indicating a mechanism of protection from detrimental effects of sustained GPR40 stimulation. FFAs mediate effects on both alpha- and beta-cells that are potentially harmful in the development of T2D and it is possible that at least part of those occur via GPR40. (Less)
Please use this url to cite or link to this publication:
author
supervisor
opponent
  • Professor Grill, Valdemar, The Norwegian University of Science and Technology, Trondheim, Norway
organization
publishing date
type
Thesis
publication status
published
subject
keywords
diabetology, secreting systems, Endocrinology, GPCR, Glucagon, GPR40, Insulin, Free fatty acid, Endokrinologi, sekretion, diabetologi
in
Lund University Faculty of Medicine Doctoral Dissertation Series
volume
2007:48
pages
106 pages
publisher
Department of Clinical Sciences, Lund University
defense location
Segerfalksalen Wallenberg Neurocentrum Sölvegatan 17 Lund
defense date
2007-03-23 09:00:00
ISSN
1652-8220
ISBN
978-91-85559-26-8
language
English
LU publication?
yes
additional info
Knut Kotarsky, Niclas E. Nilsson, Erik Flodgren, Christer Owman and Björn Olde. 2003. A human cell surface receptor activated by free fatty acids and thiazolidinedione drugs Biochemical and Biophysical Research Communications, vol 301 pp 406-410. Clinical Sciences, Lund and Experimental Medical Science Fauclty of Medicine Lund University
Albert Salehi, Erik Flodgren, Niclas E. Nilsson, Javier Jimenez-Feltström, Jun-ichi Miyazaki, Christer Owman and Björn Olde. 2005. Free fatty acid receptor 1 (FFA1R/GPR40) and its involvement in fatty-acid-stimulated insulin secretion Cell and Tissue Research, vol 322 pp 207-215. Clinical Sciences, Lund and Experimental Medical Science Fauclty of Medicine Lund University
Erik Flodgren, Björn Olde, Sandra Meidute-Abaraviciene, Maria Sörhede Winzell, Bo Ahrén and Albert Salehi. 2007. GPR40 is expressed in glucagon producing cells and affects glucagon secretion Biochemical and Biophysical Research Communications, vol 354 pp 240-245. Clinical Sciences, Lund and Experimental Medical Science Fauclty of Medicine Lund University
Erik Flodgren, Bo Ahrén and Maria Sörhede Winzell. . GPR40 in mouse islets is transcriptionally down-regulated by agonistic free fatty acids pp 1-6. Clinical Sciences, Lund and Experimental Medical Science Fauclty of Medicine Lund University (manuscript)
id
0c909ccc-af83-45f7-bcea-bfe798a34a39 (old id 548212)
date added to LUP
2016-04-01 15:55:24
date last changed
2023-04-18 19:47:40
@phdthesis{0c909ccc-af83-45f7-bcea-bfe798a34a39,
  abstract     = {{Type 2 diabetes (T2D) is a serious condition of growing proportions. Developing via an increasing imbalance between insulin sensitivity in the peripheral tissues and insulin release from pancreatic beta-cells, it ultimately renders the individual incapable of regulating the blood glucose concentration, e.g. after a meal. The increased prevalence of T2D is associated with an increase in the prevalence of obesity, with obesity being the single largest risk factor for the development of T2D. This work describes a molecule in the border zone between T2D and obesity. Our initial characterization of GPR40 identified it as a receptor for medium- to long-chain free fatty acids (FFAs). With a marked expression in pancreatic beta-cell lines, we expected GPR40 to be involved in FFA-mediated augmentation of insulin release. This was confirmed when we examined the dose-response relationship between FFA stimulation of GPR40 and both intracellular second messengers in a beta-cell line and insulin release from isolated pancreatic islets. A similarly increased glucagon secretion from alpha-cells was demonstrated after we established that these cells also express GPR40. Antisense knock-down of GPR40 abolished the effect of FFA stimulation on hormone secretion from both cell types. In the final part of this work, FFAs that activate GPR40 were shown to negatively regulate its mRNA expression, indicating a mechanism of protection from detrimental effects of sustained GPR40 stimulation. FFAs mediate effects on both alpha- and beta-cells that are potentially harmful in the development of T2D and it is possible that at least part of those occur via GPR40.}},
  author       = {{Flodgren, Erik}},
  isbn         = {{978-91-85559-26-8}},
  issn         = {{1652-8220}},
  keywords     = {{diabetology; secreting systems; Endocrinology; GPCR; Glucagon; GPR40; Insulin; Free fatty acid; Endokrinologi; sekretion; diabetologi}},
  language     = {{eng}},
  publisher    = {{Department of Clinical Sciences, Lund University}},
  school       = {{Lund University}},
  series       = {{Lund University Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{The Free Fatty Acid Receptor GPR40 - expression and role in islet hormone secretion}},
  url          = {{https://lup.lub.lu.se/search/files/4513899/548213.pdf}},
  volume       = {{2007:48}},
  year         = {{2007}},
}