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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 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)
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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
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
ISSN
1652-8220
ISBN
978-91-85559-26-8
language
English
LU publication?
yes
id
0c909ccc-af83-45f7-bcea-bfe798a34a39 (old id 548212)
date added to LUP
2007-09-11 16:47:55
date last changed
2016-09-19 08:44:54
@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},
  keyword      = {diabetology,secreting systems,Endocrinology,GPCR,Glucagon,GPR40,Insulin,Free fatty acid,Endokrinologi,sekretion,diabetologi},
  language     = {eng},
  pages        = {106},
  publisher    = {Department of Clinical Sciences, Lund University},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation},
  title        = {The Free Fatty Acid Receptor GPR40 - expression and role in islet hormone secretion},
  volume       = {2007:48},
  year         = {2007},
}