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Palmitate-induced beta-cell dysfunction is associated with excessive NO pro-duction and is reversed by thiazolidinedione-mediated inhibition of GPR40 transduction mechanisms

Meidute, Sandra LU ; Lundquist, Ingmar LU ; Galvanovskis, Juris ; Flodgren, Erik LU ; Olde, Björn LU and Salehi, S Albert LU orcid (2008) In PLoS ONE
Abstract
Background: Type 2 diabetes often displays hyperlipidemia. We examined palmitate effects on pancreatic islet function in relation to FFA receptor GPR40, NO generation, insulin release, and the PPARgama agonistic thiazolidinedione, rosiglitazone. Principal findings: Rosiglitazone suppressed acute palmitate-stimulated GPR40-transduced PI hydrolysis in HEK293 cells and insulin release from MIN6c cells and mouse islets. Culturing islets 24 h with palmitate at 5 mmol/l glucose induced beta-cell iNOS expression as revealed by confocal microscopy and in-creased the activities of ncNOS and iNOS associated with suppression of glucose-stimulated insulin response. Rosiglitazone reversed these effects. The expression of iNOS after high-glucose... (More)
Background: Type 2 diabetes often displays hyperlipidemia. We examined palmitate effects on pancreatic islet function in relation to FFA receptor GPR40, NO generation, insulin release, and the PPARgama agonistic thiazolidinedione, rosiglitazone. Principal findings: Rosiglitazone suppressed acute palmitate-stimulated GPR40-transduced PI hydrolysis in HEK293 cells and insulin release from MIN6c cells and mouse islets. Culturing islets 24 h with palmitate at 5 mmol/l glucose induced beta-cell iNOS expression as revealed by confocal microscopy and in-creased the activities of ncNOS and iNOS associated with suppression of glucose-stimulated insulin response. Rosiglitazone reversed these effects. The expression of iNOS after high-glucose culturing was unaffected by rosiglitazone. Downregulation of GPR40 by antisense treatment abrogated GPR40 expression and suppressed palmitate-induced iNOS activity and insulin release. Conclusion: We conclude that, in addition to mediating acute FFA-stimulated insulin release, GPR40 is an important regulator of iNOS expression and dysfunctional insulin release during long-term exposure to FFA. The adverse effects of palmitate were counteracted by rosiglitazone at GPR40, suggesting that thiazolidinediones are beneficial for beta-cell function in hyperlipidemic type 2 diabetes. (Less)
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author
; ; ; ; and
organization
publishing date
type
Contribution to specialist publication or newspaper
publication status
published
subject
keywords
inducible nitric oxide synthase (iNOS), neural constitutive nitric ox-ide synthase (ncNOS), GPR40, palmitate, glucose-stimulated insulin release
categories
Popular Science
in
PLoS ONE
publisher
Public Library of Science (PLoS)
language
English
LU publication?
yes
id
3783f14d-22a2-46c8-906f-a8f6d914868e (old id 1157362)
alternative location
http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0002182
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2366067/
http://www.ncbi.nlm.nih.gov/pubmed/18478115
date added to LUP
2016-04-04 14:18:57
date last changed
2023-04-18 18:02:40
@misc{3783f14d-22a2-46c8-906f-a8f6d914868e,
  abstract     = {{Background: Type 2 diabetes often displays hyperlipidemia. We examined palmitate effects on pancreatic islet function in relation to FFA receptor GPR40, NO generation, insulin release, and the PPARgama agonistic thiazolidinedione, rosiglitazone. Principal findings: Rosiglitazone suppressed acute palmitate-stimulated GPR40-transduced PI hydrolysis in HEK293 cells and insulin release from MIN6c cells and mouse islets. Culturing islets 24 h with palmitate at 5 mmol/l glucose induced beta-cell iNOS expression as revealed by confocal microscopy and in-creased the activities of ncNOS and iNOS associated with suppression of glucose-stimulated insulin response. Rosiglitazone reversed these effects. The expression of iNOS after high-glucose culturing was unaffected by rosiglitazone. Downregulation of GPR40 by antisense treatment abrogated GPR40 expression and suppressed palmitate-induced iNOS activity and insulin release. Conclusion: We conclude that, in addition to mediating acute FFA-stimulated insulin release, GPR40 is an important regulator of iNOS expression and dysfunctional insulin release during long-term exposure to FFA. The adverse effects of palmitate were counteracted by rosiglitazone at GPR40, suggesting that thiazolidinediones are beneficial for beta-cell function in hyperlipidemic type 2 diabetes.}},
  author       = {{Meidute, Sandra and Lundquist, Ingmar and Galvanovskis, Juris and Flodgren, Erik and Olde, Björn and Salehi, S Albert}},
  keywords     = {{inducible nitric oxide synthase (iNOS); neural constitutive nitric ox-ide synthase (ncNOS); GPR40; palmitate; glucose-stimulated insulin release}},
  language     = {{eng}},
  publisher    = {{Public Library of Science (PLoS)}},
  series       = {{PLoS ONE}},
  title        = {{Palmitate-induced beta-cell dysfunction is associated with excessive NO pro-duction and is reversed by thiazolidinedione-mediated inhibition of GPR40 transduction mechanisms}},
  url          = {{http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0002182}},
  year         = {{2008}},
}