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Islet constitutive nitric oxide synthase and glucose regulation of insulin release in mice

Åkesson, Bengt LU ; Henningsson, Ragnar LU ; Salehi, S Albert LU and Lundquist, Ingmar LU (1999) In Journal of Endocrinology 163(1). p.39-48
Abstract
We have studied, by a combined in vitro and in vivo approach, the relation between the inhibitory action of N(G)-nitro-l-arginine methyl ester (L-NAME), a selective inhibitor of nitric oxide synthase (NOS), on the activity of islet constitutive NOS (cNOS) and glucose regulation of islet hormone release in mice. The cNOS activity in islets incubated in vitro at 20 mM glucose was not appreciably affected by 0.05 or 0.5 mM L-NAME, but was greatly suppressed (-60%) by 5 mM L-NAME. Similarly, glucose-stimulated insulin release was unaffected by the lower concentrations of L-NAME but greatly enhanced in the presence of 5 mM of the NOS inhibitor. In incubated islets inhibition of cNOS activity resulted in a modestly enhanced insulin release in... (More)
We have studied, by a combined in vitro and in vivo approach, the relation between the inhibitory action of N(G)-nitro-l-arginine methyl ester (L-NAME), a selective inhibitor of nitric oxide synthase (NOS), on the activity of islet constitutive NOS (cNOS) and glucose regulation of islet hormone release in mice. The cNOS activity in islets incubated in vitro at 20 mM glucose was not appreciably affected by 0.05 or 0.5 mM L-NAME, but was greatly suppressed (-60%) by 5 mM L-NAME. Similarly, glucose-stimulated insulin release was unaffected by the lower concentrations of L-NAME but greatly enhanced in the presence of 5 mM of the NOS inhibitor. In incubated islets inhibition of cNOS activity resulted in a modestly enhanced insulin release in the absence of glucose, did not display any effect at physiological or subphysiological glucose concentrations, but resulted in a markedly potentiated insulin release at hyperglycaemic glucose concentrations. In the absence of glucose, glucagon secretion was suppressed by L-NAME. The dynamics of glucose-induced insulin release and (45)Ca(2+) efflux from perifused islets revealed that L-NAME caused an immediate potentiation of insulin release, and a slight increase in (45)Ca(2+) efflux. In islets depolarized with 30 mM K(+) in the presence of the K(+)(ATP) channel opener, diazoxide, L-NAME still greatly potentiated glucose-induced insulin release. Finally, an i.v. injection of glucose to mice pretreated with L-NAME was followed by a markedly potentiated insulin response, and an improved glucose tolerance. In accordance, islets isolated directly ex vivo after L-NAME injection displayed a markedly reduced cNOS activity. In conclusion, we have shown here, for the first time, that biochemically verified suppression of islet cNOS activity, induced by the NOS inhibitor L-NAME, is accompanied by a marked potentiation of glucose-stimulated insulin release both in vitro and in vivo. The major action of NO to inhibit glucose-induced insulin release is probably not primarily linked to changes in Ca(2+) fluxes and is exerted mainly independently of membrane depolarization events. (Less)
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author
organization
publishing date
type
Contribution to journal
publication status
published
subject
in
Journal of Endocrinology
volume
163
issue
1
pages
39 - 48
publisher
Society for Endocrinology
external identifiers
  • pmid:10495405
  • scopus:0032885856
ISSN
1479-6805
DOI
10.1677/joe.0.1630039
language
English
LU publication?
yes
id
ed1892d7-c859-44bc-83ec-f1af576eeeb3 (old id 1115107)
date added to LUP
2008-07-07 14:09:19
date last changed
2017-01-01 04:41:02
@article{ed1892d7-c859-44bc-83ec-f1af576eeeb3,
  abstract     = {We have studied, by a combined in vitro and in vivo approach, the relation between the inhibitory action of N(G)-nitro-l-arginine methyl ester (L-NAME), a selective inhibitor of nitric oxide synthase (NOS), on the activity of islet constitutive NOS (cNOS) and glucose regulation of islet hormone release in mice. The cNOS activity in islets incubated in vitro at 20 mM glucose was not appreciably affected by 0.05 or 0.5 mM L-NAME, but was greatly suppressed (-60%) by 5 mM L-NAME. Similarly, glucose-stimulated insulin release was unaffected by the lower concentrations of L-NAME but greatly enhanced in the presence of 5 mM of the NOS inhibitor. In incubated islets inhibition of cNOS activity resulted in a modestly enhanced insulin release in the absence of glucose, did not display any effect at physiological or subphysiological glucose concentrations, but resulted in a markedly potentiated insulin release at hyperglycaemic glucose concentrations. In the absence of glucose, glucagon secretion was suppressed by L-NAME. The dynamics of glucose-induced insulin release and (45)Ca(2+) efflux from perifused islets revealed that L-NAME caused an immediate potentiation of insulin release, and a slight increase in (45)Ca(2+) efflux. In islets depolarized with 30 mM K(+) in the presence of the K(+)(ATP) channel opener, diazoxide, L-NAME still greatly potentiated glucose-induced insulin release. Finally, an i.v. injection of glucose to mice pretreated with L-NAME was followed by a markedly potentiated insulin response, and an improved glucose tolerance. In accordance, islets isolated directly ex vivo after L-NAME injection displayed a markedly reduced cNOS activity. In conclusion, we have shown here, for the first time, that biochemically verified suppression of islet cNOS activity, induced by the NOS inhibitor L-NAME, is accompanied by a marked potentiation of glucose-stimulated insulin release both in vitro and in vivo. The major action of NO to inhibit glucose-induced insulin release is probably not primarily linked to changes in Ca(2+) fluxes and is exerted mainly independently of membrane depolarization events.},
  author       = {Åkesson, Bengt and Henningsson, Ragnar and Salehi, S Albert and Lundquist, Ingmar},
  issn         = {1479-6805},
  language     = {eng},
  number       = {1},
  pages        = {39--48},
  publisher    = {Society for Endocrinology},
  series       = {Journal of Endocrinology},
  title        = {Islet constitutive nitric oxide synthase and glucose regulation of insulin release in mice},
  url          = {http://dx.doi.org/10.1677/joe.0.1630039},
  volume       = {163},
  year         = {1999},
}