Expression of islet iNOS and inhibition of glucose stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27.
(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)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/166023
- author
- Qader, Saleem LU ; Jimenez, Javier LU ; Ekelund, Mats LU ; Lundquist, Ingmar LU and Salehi, Albert
- organization
- publishing date
- 2007
- 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
- 2016-04-01 16:46:10
- date last changed
- 2022-01-28 22:01:21
@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}},
keywords = {{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 = {{https://lup.lub.lu.se/search/files/4774893/625883.pdf}},
doi = {{10.1152/ajpendo.00172.2006}},
volume = {{292}},
year = {{2007}},
}