Islet constitutive nitric oxide synthase and nitric oxide production. Modulatory effects on insulin and glucagon secretion.

Björn Åkesson

Research output: ThesisDoctoral Thesis (compilation)


The aim of this thesis was to elucidate the role of nitric oxide (NO) in the transduction signalling of insulin and glucagon release by stimulating or inhibiting islet endogenous NO-production as well as by using NO donors. Insulin release stimulated by L-arginine, the substrate for constitutive NO-synthase (cNOS)-catalyzed NO-production, was increased by the selective NOS-inhibitor NG-nitro-L-arginine methyl ester (L-NAME) and suppressed by the intracellular NO donor hydroxylamine. Insulin release stimulated by glucose, sulphonylurea and the cholinergic agonist carbachol as well as by protein kinase C activation was also increased by NOS-inhibition and suppressed by the NO donor. Insulin release induced by cyclic AMP activators was unaffected by NOS-inhibition and modestly increased by hydroxylamine. The potentiating effect of L-NAME on insulin release stimulated by glucose or carbachol had little influence on Ca2+-fluxes and was still evident in diazoxide-treated, K+-depolarized islets suggesting that the major inhibitory action of NO was exerted independently of membrane depolarization. Data from NO donor experiments permitted a similar conclusion. The L-NAME-induced increase in glucose-stimulated insulin release was accompanied by a corresponding decrease in islet cNOS-activity both in vitro and in vivo. Glucagon release stimulated by different glucagon secretagogues was inhibited by NOS-inhibition both in vitro and in vivo and still evident in K+-depolarized islets. NO-donation potentiated glucagon release. The results suggest a major action of NO on distal events in glucagon release. The present data indicate that NO is a negative modulator of insulin release induced by glucose, sulphonylurea, L-arginine and cholinergic stimulation but not by direct cAMP activation. This inhibitory effect is presumably exerted through S-nitrosylation of "critical" thiol groups. In contrast, NO is a positive modulator of glucagon release induced by all types of secretagogues tested. This effect is presumably exerted in part by NO facilitating the exocytotic process.
Original languageEnglish
Awarding Institution
  • Family Medicine and Clinical Epidemiology
  • [unknown], [unknown], Supervisor, External person
Award date1998 Oct 23
ISBN (Print)91-628-3148-8
Publication statusPublished - 1998

Bibliographical note

Defence details

Date: 1998-10-23
Time: 09:15
Place: Department of Pharmacology, Sölvegatan 10, Lund, Sweden

External reviewer(s)

Name: Sehlin, Janove
Title: Professor
Affiliation: University of Umeå


Subject classification (UKÄ)

  • Public Health, Global Health, Social Medicine and Epidemiology


  • pharmacognosy
  • Pharmacological sciences
  • mouse
  • carbachol
  • muscarinic agonist
  • cyclic nucleotides
  • calcium-fluxes
  • NOS-inhibitors
  • in vitro and in vivo
  • insulin and glucagon secretion
  • Nitric oxide (NO)
  • constitutive nitric oxide synthase (cNOS)
  • pharmacy
  • toxicology
  • Farmakologi
  • farmakognosi
  • farmaci
  • toxikologi
  • Endocrinology
  • secreting systems
  • diabetology
  • Endokrinologi
  • sekretion
  • diabetologi


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