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Mechanisms underlying lipotoxicity and glucotoxicity in pancreatic islets

Meidute, Sandra LU (2008) In Lund University , Faculty of Medicine Doctaral Dissertation Series 2008:98.
Abstract
Although it has been known for many years that long-term exposure of pancreatic islets to a high level of free fatty acids (FFA) or glucose negatively modulates islet hormone release, the identities of signals mediating these effects are not yet fully clarified. The overall objective of this study was to investigate signal transduction pathways involved in FFA- and glucose-exerted effects on beta-cell function during both short-term as well as long-term exposure. The data presented here confirmed that the G-protein coupled receptor 40 (GPR40) is a functional FFA receptor expressed in pancreatic islets. We now show that both the acute stimulatory action of palmitate on IP3-generation, increased [Ca2+]i and insulin release as well as the... (More)
Although it has been known for many years that long-term exposure of pancreatic islets to a high level of free fatty acids (FFA) or glucose negatively modulates islet hormone release, the identities of signals mediating these effects are not yet fully clarified. The overall objective of this study was to investigate signal transduction pathways involved in FFA- and glucose-exerted effects on beta-cell function during both short-term as well as long-term exposure. The data presented here confirmed that the G-protein coupled receptor 40 (GPR40) is a functional FFA receptor expressed in pancreatic islets. We now show that both the acute stimulatory action of palmitate on IP3-generation, increased [Ca2+]i and insulin release as well as the long-term effects of palmitate on the activation of MAPKs (SAPK/JNK and p38), iNOS expression and caspase-3 activity is mediated via activation of GPR40. A modulated expression of GPR40 in the islets i.e. overexpression (fa/fa rats) was accompanied by an exaggerated secretion of insulin, glucagon and marked suppression of somatostatin release in response to palmitate. In contrast, a low expression pattern of islet GPR40 (GK rats) was associated with a negligible hormone response to palmitate. The islet expression of iNOS seems to be, at least in part, a common signalling pathway in both lipotoxicity and glucotoxicity. Rosiglitazone (ROZ) effectively counteracted the deleterious effects of palmitate but not that of high glucose on the islet function. Glucose-induced expression of iNOS with subsequent β-cell dysfunction was markedly counteracted by the imidazoline derivative RX871024.

We conclude that, in addition to mediating acute stimulatory effects of FFA on insulin release, GPR40 is also an important mediator of dysfunctional effects of FFA overtime. The adverse effects of FFA and high glucose on the islet function involve different or at least partially different signal systems and the FFA signalling is counteracted by ROZ at GPR40, suggesting the thiazolidinediones are protective against beta-cell lipotoxicity. (Less)
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author
supervisor
opponent
  • Professor Bergsten, Peter, Dep. Medical Cell Biology, Uppsala University, Uppsala, Sweden
organization
publishing date
type
Thesis
publication status
published
subject
keywords
hormone secretion, cell stress, Pancreatic beta-cell, cellular signalling, GPR40, diabetes
in
Lund University , Faculty of Medicine Doctaral Dissertation Series
volume
2008:98
pages
146 pages
publisher
Department of Clinical Sciences, Lund University
defense location
Lilla Aulen, MFC, Ing 59, UMAS, Malmö
defense date
2008-10-31 09:15
ISSN
1652-8220
ISBN
978-91-86059-51-4
language
English
LU publication?
yes
id
e3cb8d96-945d-4595-8aa3-543b8b2f2213 (old id 1244632)
date added to LUP
2008-10-14 14:39:42
date last changed
2016-09-19 08:44:49
@phdthesis{e3cb8d96-945d-4595-8aa3-543b8b2f2213,
  abstract     = {Although it has been known for many years that long-term exposure of pancreatic islets to a high level of free fatty acids (FFA) or glucose negatively modulates islet hormone release, the identities of signals mediating these effects are not yet fully clarified. The overall objective of this study was to investigate signal transduction pathways involved in FFA- and glucose-exerted effects on beta-cell function during both short-term as well as long-term exposure. The data presented here confirmed that the G-protein coupled receptor 40 (GPR40) is a functional FFA receptor expressed in pancreatic islets. We now show that both the acute stimulatory action of palmitate on IP3-generation, increased [Ca2+]i and insulin release as well as the long-term effects of palmitate on the activation of MAPKs (SAPK/JNK and p38), iNOS expression and caspase-3 activity is mediated via activation of GPR40. A modulated expression of GPR40 in the islets i.e. overexpression (fa/fa rats) was accompanied by an exaggerated secretion of insulin, glucagon and marked suppression of somatostatin release in response to palmitate. In contrast, a low expression pattern of islet GPR40 (GK rats) was associated with a negligible hormone response to palmitate. The islet expression of iNOS seems to be, at least in part, a common signalling pathway in both lipotoxicity and glucotoxicity. Rosiglitazone (ROZ) effectively counteracted the deleterious effects of palmitate but not that of high glucose on the islet function. Glucose-induced expression of iNOS with subsequent β-cell dysfunction was markedly counteracted by the imidazoline derivative RX871024.<br/><br>
We conclude that, in addition to mediating acute stimulatory effects of FFA on insulin release, GPR40 is also an important mediator of dysfunctional effects of FFA overtime. The adverse effects of FFA and high glucose on the islet function involve different or at least partially different signal systems and the FFA signalling is counteracted by ROZ at GPR40, suggesting the thiazolidinediones are protective against beta-cell lipotoxicity.},
  author       = {Meidute, Sandra},
  isbn         = {978-91-86059-51-4},
  issn         = {1652-8220},
  keyword      = {hormone secretion,cell stress,Pancreatic beta-cell,cellular signalling,GPR40,diabetes},
  language     = {eng},
  pages        = {146},
  publisher    = {Department of Clinical Sciences, Lund University},
  school       = {Lund University},
  series       = {Lund University , Faculty of Medicine Doctaral Dissertation Series},
  title        = {Mechanisms underlying lipotoxicity and glucotoxicity in pancreatic islets},
  volume       = {2008:98},
  year         = {2008},
}