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

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Author

Summary, in English

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.

Publishing year

2002

Language

English

Pages

296-304

Publication/Series

American Journal of Physiology: Cell Physiology

Volume

283

Issue

1

Document type

Journal article

Publisher

American Physiological Society

Topic

  • Basic Medicine

Keywords

  • 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

Status

Published

ISBN/ISSN/Other

  • ISSN: 1522-1563