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Glucose stimulates the expression and activities of nitric oxide synthases in incubated rat islets: an effect counteracted by GLP-1 through the cyclic AMP/PKA pathway

Jimenez, Javier LU ; Lundquist, Ingmar LU and Salehi, S Albert LU (2005) In Cell and Tissue Research 319(2). p.221-230
Abstract
We have examined the expression and activity of inducible nitric oxide synthase ( iNOS) and the activity of neuronal constitutive NOS ( ncNOS) in isolated rat pancreatic islets, stimulated by a "hyperglycaemic" concentration of glucose, and whether the NOS activities could be modulated by activation of the cyclic AMP/ protein kinase A ( cyclic AMP/PKA) system in relation to the insulin secretory process. Here, we show that glucose stimulation ( 20 mmol/l) induces iNOS and increases ncNOS activity. No iNOS is detectable at basal glucose levels (3.3 mmol/l). The addition of glucagon-like-peptide 1 (GLP-1) or dibutyryl-cAMP to islets incubated with 20 mmol/l glucose results in a marked suppression of iNOS expression and activity, a reduction... (More)
We have examined the expression and activity of inducible nitric oxide synthase ( iNOS) and the activity of neuronal constitutive NOS ( ncNOS) in isolated rat pancreatic islets, stimulated by a "hyperglycaemic" concentration of glucose, and whether the NOS activities could be modulated by activation of the cyclic AMP/ protein kinase A ( cyclic AMP/PKA) system in relation to the insulin secretory process. Here, we show that glucose stimulation ( 20 mmol/l) induces iNOS and increases ncNOS activity. No iNOS is detectable at basal glucose levels (3.3 mmol/l). The addition of glucagon-like-peptide 1 (GLP-1) or dibutyryl-cAMP to islets incubated with 20 mmol/l glucose results in a marked suppression of iNOS expression and activity, a reduction in ncNOS activity and increased insulin release. The GLP-1-induced suppression of glucose-stimulated iNOS activity and expression and its stimulation of insulin release is, at least in part, PKA dependent, since the PKA inhibitor H-89 reverses the effects of GLP-1. These observations have been confirmed by confocal microscopy showing the glucose-stimulated expression of iNOS, its suppression by GLP-1 and its reversion by H-89 in beta-cells. We have also found that the NO scavenger cPTIO and the NOS inhibitor L-NAME potentiate the insulin response to glucose, again suggesting that NO is a negative modulator of glucose-stimulated insulin release. We conclude that the induction of iNOS and the increase in ncNOS activity caused by glucose in rat islets is suppressed by the cyclic AMP/ PKA system. The inhibition of iNOS expression by the GLP-1/ cyclic AMP/ PKA pathway might possibly be of therapeutic potential in NO-mediated beta-cell dysfunction and destruction. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
iNOS, cNOS, glucose toxicity, (male Sprague Dawley), rat, pancreatic islets, insulin secretion
in
Cell and Tissue Research
volume
319
issue
2
pages
221 - 230
publisher
Springer
external identifiers
  • pmid:15558323
  • wos:000226321600005
  • scopus:12944303107
ISSN
1432-0878
DOI
10.1007/s00441-004-1013-4
language
English
LU publication?
yes
id
84a8e10b-9caf-4919-b2ba-3dac05c21bf6 (old id 255407)
alternative location
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=15558323&dopt=Abstract
date added to LUP
2007-08-14 09:17:42
date last changed
2017-09-10 03:49:32
@article{84a8e10b-9caf-4919-b2ba-3dac05c21bf6,
  abstract     = {We have examined the expression and activity of inducible nitric oxide synthase ( iNOS) and the activity of neuronal constitutive NOS ( ncNOS) in isolated rat pancreatic islets, stimulated by a "hyperglycaemic" concentration of glucose, and whether the NOS activities could be modulated by activation of the cyclic AMP/ protein kinase A ( cyclic AMP/PKA) system in relation to the insulin secretory process. Here, we show that glucose stimulation ( 20 mmol/l) induces iNOS and increases ncNOS activity. No iNOS is detectable at basal glucose levels (3.3 mmol/l). The addition of glucagon-like-peptide 1 (GLP-1) or dibutyryl-cAMP to islets incubated with 20 mmol/l glucose results in a marked suppression of iNOS expression and activity, a reduction in ncNOS activity and increased insulin release. The GLP-1-induced suppression of glucose-stimulated iNOS activity and expression and its stimulation of insulin release is, at least in part, PKA dependent, since the PKA inhibitor H-89 reverses the effects of GLP-1. These observations have been confirmed by confocal microscopy showing the glucose-stimulated expression of iNOS, its suppression by GLP-1 and its reversion by H-89 in beta-cells. We have also found that the NO scavenger cPTIO and the NOS inhibitor L-NAME potentiate the insulin response to glucose, again suggesting that NO is a negative modulator of glucose-stimulated insulin release. We conclude that the induction of iNOS and the increase in ncNOS activity caused by glucose in rat islets is suppressed by the cyclic AMP/ PKA system. The inhibition of iNOS expression by the GLP-1/ cyclic AMP/ PKA pathway might possibly be of therapeutic potential in NO-mediated beta-cell dysfunction and destruction.},
  author       = {Jimenez, Javier and Lundquist, Ingmar and Salehi, S Albert},
  issn         = {1432-0878},
  keyword      = {iNOS,cNOS,glucose toxicity,(male Sprague Dawley),rat,pancreatic islets,insulin secretion},
  language     = {eng},
  number       = {2},
  pages        = {221--230},
  publisher    = {Springer},
  series       = {Cell and Tissue Research},
  title        = {Glucose stimulates the expression and activities of nitric oxide synthases in incubated rat islets: an effect counteracted by GLP-1 through the cyclic AMP/PKA pathway},
  url          = {http://dx.doi.org/10.1007/s00441-004-1013-4},
  volume       = {319},
  year         = {2005},
}