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Expression of islet iNOS and inhibition of glucose stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27.

Qader, Saleem LU ; Jimenez, Javier LU ; Ekelund, Mats LU ; Lundquist, Ingmar LU and Salehi, Albert (2007) In American Journal of Physiology: Endocrinology and Metabolism 292(5). p.1447-1455
Abstract
Chronic exposure of pancreatic islets to elevated plasma lipids ( lipotoxicity) can lead to beta-cell dysfunction, with overtime becoming irreversible. We examined, by confocal microscopy and biochemistry, whether the expression of islet inducible nitric oxide synthase ( iNOS) and the concomitant inhibition of glucose-stimulated insulin release seen after lipid infusion in rats was modulated by the islet neuropeptide pituitary adenylate cyclase-activating polypeptide ( PACAP) 27. Lipid infusion for 8 days induced a strong expression of islet iNOS, which was mainly confined to beta-cells and was still evident after incubating islets at 8.3 mmol/l glucose. This was accompanied by a high iNOS-derived NO generation, a decreased insulin... (More)
Chronic exposure of pancreatic islets to elevated plasma lipids ( lipotoxicity) can lead to beta-cell dysfunction, with overtime becoming irreversible. We examined, by confocal microscopy and biochemistry, whether the expression of islet inducible nitric oxide synthase ( iNOS) and the concomitant inhibition of glucose-stimulated insulin release seen after lipid infusion in rats was modulated by the islet neuropeptide pituitary adenylate cyclase-activating polypeptide ( PACAP) 27. Lipid infusion for 8 days induced a strong expression of islet iNOS, which was mainly confined to beta-cells and was still evident after incubating islets at 8.3 mmol/l glucose. This was accompanied by a high iNOS-derived NO generation, a decreased insulin release, and increased cyclic GMP accumulation. No iNOS expression was found in control islets. Addition of PACAP27 to incubated islets from lipid-infused rats resulted in loss of iNOS protein expression, increased cyclic AMP, decreased cyclic GMP, and suppression of the activities of neuronal constitutive ( nc) NOS and iNOS and increased glucose-stimulated insulin response. These effects were reversed by the PKA inhibitor H-89. The suppression of islet iNOS expression induced by PACAP27 was not affected by the proteasome inhibitor MG-132, which by itself induced the loss of iNOS protein, making a direct proteasomal involvement less likely. Our results suggest that PACAP27 through its cyclic AMP- and PKA-stimulating capacity strongly suppresses not only ncNOS but, importantly, also the lipid-induced stimulation of iNOS expression, possibly by a nonproteasomal mechanism. Thus PACAP27 restores the impairment of glucose-stimulated insulin release and additionally might induce cytoprotection against deleterious actions of iNOS-derived NO in beta-cells. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
pituitary adenylate cyclase-activating polypeptide 27, pancreatic islets, synthase, isoforms of nitric oxide, insulin secretion
in
American Journal of Physiology: Endocrinology and Metabolism
volume
292
issue
5
pages
1447 - 1455
publisher
American Physiological Society
external identifiers
  • wos:000247938900026
  • scopus:34247568937
ISSN
1522-1555
DOI
10.1152/ajpendo.00172.2006
language
English
LU publication?
yes
id
3deeb84f-c96f-489a-95f7-2a13b207be87 (old id 166023)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=17264229&dopt=Abstract
date added to LUP
2007-07-24 09:08:06
date last changed
2017-01-01 07:14:41
@article{3deeb84f-c96f-489a-95f7-2a13b207be87,
  abstract     = {Chronic exposure of pancreatic islets to elevated plasma lipids ( lipotoxicity) can lead to beta-cell dysfunction, with overtime becoming irreversible. We examined, by confocal microscopy and biochemistry, whether the expression of islet inducible nitric oxide synthase ( iNOS) and the concomitant inhibition of glucose-stimulated insulin release seen after lipid infusion in rats was modulated by the islet neuropeptide pituitary adenylate cyclase-activating polypeptide ( PACAP) 27. Lipid infusion for 8 days induced a strong expression of islet iNOS, which was mainly confined to beta-cells and was still evident after incubating islets at 8.3 mmol/l glucose. This was accompanied by a high iNOS-derived NO generation, a decreased insulin release, and increased cyclic GMP accumulation. No iNOS expression was found in control islets. Addition of PACAP27 to incubated islets from lipid-infused rats resulted in loss of iNOS protein expression, increased cyclic AMP, decreased cyclic GMP, and suppression of the activities of neuronal constitutive ( nc) NOS and iNOS and increased glucose-stimulated insulin response. These effects were reversed by the PKA inhibitor H-89. The suppression of islet iNOS expression induced by PACAP27 was not affected by the proteasome inhibitor MG-132, which by itself induced the loss of iNOS protein, making a direct proteasomal involvement less likely. Our results suggest that PACAP27 through its cyclic AMP- and PKA-stimulating capacity strongly suppresses not only ncNOS but, importantly, also the lipid-induced stimulation of iNOS expression, possibly by a nonproteasomal mechanism. Thus PACAP27 restores the impairment of glucose-stimulated insulin release and additionally might induce cytoprotection against deleterious actions of iNOS-derived NO in beta-cells.},
  author       = {Qader, Saleem and Jimenez, Javier and Ekelund, Mats and Lundquist, Ingmar and Salehi, Albert},
  issn         = {1522-1555},
  keyword      = {pituitary adenylate cyclase-activating polypeptide 27,pancreatic islets,synthase,isoforms of nitric oxide,insulin secretion},
  language     = {eng},
  number       = {5},
  pages        = {1447--1455},
  publisher    = {American Physiological Society},
  series       = {American Journal of Physiology: Endocrinology and Metabolism},
  title        = {Expression of islet iNOS and inhibition of glucose stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27.},
  url          = {http://dx.doi.org/10.1152/ajpendo.00172.2006},
  volume       = {292},
  year         = {2007},
}