The Free Fatty Acid Receptor GPR40 - expression and role in islet hormone secretion
(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:
https://lup.lub.lu.se/record/548212
- author
- Flodgren, Erik LU
- supervisor
-
- Bo Ahrén LU
- opponent
-
- Professor Grill, Valdemar, The Norwegian University of Science and Technology, Trondheim, Norway
- organization
- publishing date
- 2007
- 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 UniversityAlbert 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 UniversityErik 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 UniversityErik 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}}, }