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

Erik Flodgren

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

Erik Flodgren

Medicine/Emergency Medicine, Lund

Research output: Thesis › Doctoral Thesis (compilation)

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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.

Original language	English
Qualification	Doctor
Awarding Institution	Medicine/Emergency Medicine, Lund
Supervisors/Advisors	Ahrén, Bo, Supervisor
Award date	2007 Mar 23
Publisher	Department of Clinical Sciences, Lund University
ISBN (Print)	978-91-85559-26-8
Publication status	Published - 2007

Bibliographical note

Defence details

Date: 2007-03-23
Time: 09:00
Place: Segerfalksalen Wallenberg Neurocentrum Sölvegatan 17 Lund

External reviewer(s)

Name: Grill, Valdemar
Title: Professor
Affiliation: The Norwegian University of Science and Technology, Trondheim, Norway

---

<div class="article_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</div>
<div class="article_info">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</div>
<div class="article_info">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</div>
<div class="article_info">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)</div>

Subject classification (UKÄ)

Other Clinical Medicine

Free keywords

diabetology
secreting systems
Endocrinology
GPCR
Glucagon
GPR40
Insulin
Free fatty acid
Endokrinologi
sekretion
diabetologi

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Kappan

Cite this

@phdthesis{0c909cccaf8345f7bceabfe798a34a39,

title = "The Free Fatty Acid Receptor GPR40 - expression and role in islet hormone secretion",

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.",

keywords = "diabetology, secreting systems, Endocrinology, GPCR, Glucagon, GPR40, Insulin, Free fatty acid, Endokrinologi, sekretion, diabetologi",

author = "Erik Flodgren",

note = "Defence details Date: 2007-03-23 Time: 09:00 Place: Segerfalksalen Wallenberg Neurocentrum S{\"o}lvegatan 17 Lund External reviewer(s) Name: Grill, Valdemar Title: Professor Affiliation: The Norwegian University of Science and Technology, Trondheim, Norway --- <div class={"}article_info{"}>Knut Kotarsky, Niclas E. Nilsson, Erik Flodgren, Christer Owman and Bj{\"o}rn 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</div> <div class={"}article_info{"}>Albert Salehi, Erik Flodgren, Niclas E. Nilsson, Javier Jimenez-Feltstr{\"o}m, Jun-ichi Miyazaki, Christer Owman and Bj{\"o}rn 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</div> <div class={"}article_info{"}>Erik Flodgren, Bj{\"o}rn Olde, Sandra Meidute-Abaraviciene, Maria S{\"o}rhede Winzell, Bo Ahr{\'e}n 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</div> <div class={"}article_info{"}>Erik Flodgren, Bo Ahr{\'e}n and Maria S{\"o}rhede 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)</div>",

year = "2007",

language = "English",

isbn = "978-91-85559-26-8",

series = "Lund University Faculty of Medicine Doctoral Dissertation Series ",

publisher = "Department of Clinical Sciences, Lund University",

type = "Doctoral Thesis (compilation)",

school = "Medicine/Emergency Medicine, Lund",

}

TY - THES

T1 - The Free Fatty Acid Receptor GPR40 - expression and role in islet hormone secretion

AU - Flodgren, Erik

N1 - Defence details Date: 2007-03-23 Time: 09:00 Place: Segerfalksalen Wallenberg Neurocentrum Sölvegatan 17 Lund External reviewer(s) Name: Grill, Valdemar Title: Professor Affiliation: The Norwegian University of Science and Technology, Trondheim, Norway --- <div class="article_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</div> <div class="article_info">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</div> <div class="article_info">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</div> <div class="article_info">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)</div>

PY - 2007

Y1 - 2007

N2 - 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.

AB - 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.

KW - diabetology

KW - secreting systems

KW - Endocrinology

KW - GPCR

KW - Glucagon

KW - GPR40

KW - Insulin

KW - Free fatty acid

KW - Endokrinologi

KW - sekretion

KW - diabetologi

M3 - Doctoral Thesis (compilation)

SN - 978-91-85559-26-8

T3 - Lund University Faculty of Medicine Doctoral Dissertation Series

PB - Department of Clinical Sciences, Lund University

ER -

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

Abstract

Bibliographical note

Subject classification (UKÄ)

Free keywords

UN SDGs

Access to Document

Fingerprint

Cite this