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Role of nitric oxide synthase isoforms in glucose-stimulated insulin release.

Henningsson, Ragnar LU ; Salehi, Albert and Lundquist, Ingmar LU (2002) In American Journal of Physiology: Cell Physiology 283(1). p.296-304
Abstract
The role of islet constitutive nitric oxide synthase (cNOS) in insulin-releasing mechanisms is controversial. By measuring enzyme activities and protein expression of NOS isoforms [i.e., cNOS and inducible NOS (iNOS)] in islets of Langerhans cells in relation to insulin secretion, we show that glucose dose-dependently stimulates islet activities of both cNOS and iNOS, that cNOS-derived nitric oxide (NO) strongly inhibits glucose-stimulated insulin release, and that short-term hyperglycemia in mice induces islet iNOS activity. Moreover, addition of NO gas or an NO donor inhibited glucose-stimulated insulin release, and different NOS inhibitors effected a potentiation. These effects were evident also in K+-depolarized islets in the presence... (More)
The role of islet constitutive nitric oxide synthase (cNOS) in insulin-releasing mechanisms is controversial. By measuring enzyme activities and protein expression of NOS isoforms [i.e., cNOS and inducible NOS (iNOS)] in islets of Langerhans cells in relation to insulin secretion, we show that glucose dose-dependently stimulates islet activities of both cNOS and iNOS, that cNOS-derived nitric oxide (NO) strongly inhibits glucose-stimulated insulin release, and that short-term hyperglycemia in mice induces islet iNOS activity. Moreover, addition of NO gas or an NO donor inhibited glucose-stimulated insulin release, and different NOS inhibitors effected a potentiation. These effects were evident also in K+-depolarized islets in the presence of the ATP-sensitive K+ channel opener diazoxide. Furthermore, our results emphasize the necessity of measuring islet NOS activity when using NOS inhibitors, because certain concentrations of certain NOS inhibitors might unexpectedly stimulate islet NO production. This is shown by the observation that 0.5 mmol/l of the NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA) stimulated cNOS activity in parallel with an inhibition of the first phase of glucose-stimulated insulin release in perifused rats islets, whereas 5.0 mmol/l of L-NMMA markedly suppressed cNOS activity concomitant with a great potentiation of the insulin secretory response. The data strongly suggest, but do not definitely prove, that glucose indeed has the ability to stimulate both cNOS and iNOS in the islets and that NO might serve as a negative feedback inhibitor of glucose-stimulated insulin release. The results also suggest that hyperglycemia-evoked islet NOS activity might be one of multiple factors involved in the impairment of glucose-stimulated insulin release in type II diabetes mellitus. (Less)
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Isoenzymes : antagonists & inhibitors, Islets of Langerhans : enzymology, Insulin : secretion, Indazoles : pharmacology, In Vitro, Glucose : pharmacology, Female, Enzyme Inhibitors : pharmacology, Diazoxide : pharmacology, Animal, Adenosine Triphosphate : physiology, Nitric-Oxide Synthase : antagonists & inhibitors, Nitric-Oxide Synthase : physiology, Potassium Channels : drug effects, Rats, omega-N-Methylarginine : pharmacology, Non-U.S. Gov't, Support, Sprague-Dawley, Isoenzymes : physiology, Mice, Inbred Strains, NG-Nitroarginine Methyl Ester : pharmacology, Nitric Oxide Donors : pharmacology
in
American Journal of Physiology: Cell Physiology
volume
283
issue
1
pages
296 - 304
publisher
American Physiological Society
external identifiers
  • wos:000176070800032
  • pmid:12055099
  • scopus:0036089387
ISSN
1522-1563
DOI
10.1152/ajpcell.00537.2001
language
English
LU publication?
yes
id
52d56af4-068e-44b6-98b7-688879bb6e7b (old id 108703)
alternative location
http://www.ncbi.nlm.nih.gov:80/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=12055099&dopt=Abstract
date added to LUP
2007-07-12 16:06:10
date last changed
2017-09-17 07:02:25
@article{52d56af4-068e-44b6-98b7-688879bb6e7b,
  abstract     = {The role of islet constitutive nitric oxide synthase (cNOS) in insulin-releasing mechanisms is controversial. By measuring enzyme activities and protein expression of NOS isoforms [i.e., cNOS and inducible NOS (iNOS)] in islets of Langerhans cells in relation to insulin secretion, we show that glucose dose-dependently stimulates islet activities of both cNOS and iNOS, that cNOS-derived nitric oxide (NO) strongly inhibits glucose-stimulated insulin release, and that short-term hyperglycemia in mice induces islet iNOS activity. Moreover, addition of NO gas or an NO donor inhibited glucose-stimulated insulin release, and different NOS inhibitors effected a potentiation. These effects were evident also in K+-depolarized islets in the presence of the ATP-sensitive K+ channel opener diazoxide. Furthermore, our results emphasize the necessity of measuring islet NOS activity when using NOS inhibitors, because certain concentrations of certain NOS inhibitors might unexpectedly stimulate islet NO production. This is shown by the observation that 0.5 mmol/l of the NOS inhibitor N(G)-monomethyl-L-arginine (L-NMMA) stimulated cNOS activity in parallel with an inhibition of the first phase of glucose-stimulated insulin release in perifused rats islets, whereas 5.0 mmol/l of L-NMMA markedly suppressed cNOS activity concomitant with a great potentiation of the insulin secretory response. The data strongly suggest, but do not definitely prove, that glucose indeed has the ability to stimulate both cNOS and iNOS in the islets and that NO might serve as a negative feedback inhibitor of glucose-stimulated insulin release. The results also suggest that hyperglycemia-evoked islet NOS activity might be one of multiple factors involved in the impairment of glucose-stimulated insulin release in type II diabetes mellitus.},
  author       = {Henningsson, Ragnar and Salehi, Albert and Lundquist, Ingmar},
  issn         = {1522-1563},
  keyword      = {Isoenzymes : antagonists & inhibitors,Islets of Langerhans : enzymology,Insulin : secretion,Indazoles : pharmacology,In Vitro,Glucose : pharmacology,Female,Enzyme Inhibitors : pharmacology,Diazoxide : pharmacology,Animal,Adenosine Triphosphate : physiology,Nitric-Oxide Synthase : antagonists & inhibitors,Nitric-Oxide Synthase : physiology,Potassium Channels : drug effects,Rats,omega-N-Methylarginine : pharmacology,Non-U.S. Gov't,Support,Sprague-Dawley,Isoenzymes : physiology,Mice,Inbred Strains,NG-Nitroarginine Methyl Ester : pharmacology,Nitric Oxide Donors : pharmacology},
  language     = {eng},
  number       = {1},
  pages        = {296--304},
  publisher    = {American Physiological Society},
  series       = {American Journal of Physiology: Cell Physiology},
  title        = {Role of nitric oxide synthase isoforms in glucose-stimulated insulin release.},
  url          = {http://dx.doi.org/10.1152/ajpcell.00537.2001},
  volume       = {283},
  year         = {2002},
}