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Imidazoline-induced amplification of glucose- and carbachol-stimulated insulin release includes a marked suppression of islet NO generation in the mouse.

Meidute, Sandra LU ; Mosén, Henrik LU ; Lundquist, Ingmar LU and Salehi, S Albert LU (2009) In Acta Physiologica2006-01-01+01:002013-01-01+01:00 195(3). p.375-383
Abstract
Aim: The role of islet nitric oxide (NO) production in insulin releasing mechanisms is unclear. We examined whether the beneficial effects of the imidazoline derivative RX 871024 (RX) on beta-cell function might be related to perturbations of islet NO production. Methods: Experiments were performed with isolated islets or intact mice challenged with glucose or carbachol with or without RX treatment. Insulin was determined with radioimmunoassay, NO generation with high-performance liquid chromatography and expression of inducible NO-synthase (iNOS) with confocal microscopy. Results: RX treatment, in doses lacking effects on basal insulin, greatly amplified insulin release stimulated by the NO-generating secretagogues glucose and carbachol... (More)
Aim: The role of islet nitric oxide (NO) production in insulin releasing mechanisms is unclear. We examined whether the beneficial effects of the imidazoline derivative RX 871024 (RX) on beta-cell function might be related to perturbations of islet NO production. Methods: Experiments were performed with isolated islets or intact mice challenged with glucose or carbachol with or without RX treatment. Insulin was determined with radioimmunoassay, NO generation with high-performance liquid chromatography and expression of inducible NO-synthase (iNOS) with confocal microscopy. Results: RX treatment, in doses lacking effects on basal insulin, greatly amplified insulin release stimulated by the NO-generating secretagogues glucose and carbachol both in vitro and in vivo. RX also improved the glucose tolerance curve. Islets incubated at high glucose (20 mmol/l) displayed increased NO production derived from both neuronal constitutive NO-synthase (ncNOS) and iNOS. RX abrogated this glucose-induced NO production concomitant with amplification of insulin release. Confocal microscopy revealed abundant iNOS expression in beta-cells after incubation of islets at high but not low glucose. This was abolished after RX treatment. Similarly, islets cultured for 24 h at high glucose showed intense iNOS expression in beta-cells. This was abrogated with RX and followed by an amplified glucose-induced insulin release. Conclusion: RX effectively counteracts the negative impact of beta-cell NO generation on insulin release stimulated by glucose and carbachol suggesting imidazoline compounds by virtue of NOS-inhibitory properties being of potential therapeutic value for treatment of beta-cell dysfunction in hyperglycaemia and type 2 diabetes. (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
islet nitric oxide synthase isoenzymes, insulin release, imidazoline RX 871024, cholinergic stimulation, glucose stimulation
in
Acta Physiologica2006-01-01+01:002013-01-01+01:00
volume
195
issue
3
pages
375 - 383
publisher
Wiley-Blackwell
external identifiers
  • wos:000262938900007
  • pmid:18764864
  • scopus:59149095001
ISSN
1748-1708
DOI
10.1111/j.1748-1716.2008.01896.x
language
English
LU publication?
yes
id
5d8adacb-e4c0-4bf2-9e8f-ca94b038b5ff (old id 1243485)
alternative location
http://www.ncbi.nlm.nih.gov/sites/entrez
date added to LUP
2008-10-03 15:27:58
date last changed
2017-07-30 03:34:08
@article{5d8adacb-e4c0-4bf2-9e8f-ca94b038b5ff,
  abstract     = {Aim: The role of islet nitric oxide (NO) production in insulin releasing mechanisms is unclear. We examined whether the beneficial effects of the imidazoline derivative RX 871024 (RX) on beta-cell function might be related to perturbations of islet NO production. Methods: Experiments were performed with isolated islets or intact mice challenged with glucose or carbachol with or without RX treatment. Insulin was determined with radioimmunoassay, NO generation with high-performance liquid chromatography and expression of inducible NO-synthase (iNOS) with confocal microscopy. Results: RX treatment, in doses lacking effects on basal insulin, greatly amplified insulin release stimulated by the NO-generating secretagogues glucose and carbachol both in vitro and in vivo. RX also improved the glucose tolerance curve. Islets incubated at high glucose (20 mmol/l) displayed increased NO production derived from both neuronal constitutive NO-synthase (ncNOS) and iNOS. RX abrogated this glucose-induced NO production concomitant with amplification of insulin release. Confocal microscopy revealed abundant iNOS expression in beta-cells after incubation of islets at high but not low glucose. This was abolished after RX treatment. Similarly, islets cultured for 24 h at high glucose showed intense iNOS expression in beta-cells. This was abrogated with RX and followed by an amplified glucose-induced insulin release. Conclusion: RX effectively counteracts the negative impact of beta-cell NO generation on insulin release stimulated by glucose and carbachol suggesting imidazoline compounds by virtue of NOS-inhibitory properties being of potential therapeutic value for treatment of beta-cell dysfunction in hyperglycaemia and type 2 diabetes.},
  author       = {Meidute, Sandra and Mosén, Henrik and Lundquist, Ingmar and Salehi, S Albert},
  issn         = {1748-1708},
  keyword      = {islet nitric oxide synthase isoenzymes,insulin release,imidazoline RX 871024,cholinergic stimulation,glucose stimulation},
  language     = {eng},
  number       = {3},
  pages        = {375--383},
  publisher    = {Wiley-Blackwell},
  series       = {Acta Physiologica2006-01-01+01:002013-01-01+01:00},
  title        = {Imidazoline-induced amplification of glucose- and carbachol-stimulated insulin release includes a marked suppression of islet NO generation in the mouse.},
  url          = {http://dx.doi.org/10.1111/j.1748-1716.2008.01896.x},
  volume       = {195},
  year         = {2009},
}