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Nitric oxide (NO) and carbon monoxide (CO): A novel class of messenger molecules regulating insulin and glucagon secretion

Henningsson, Ragnar LU (1999)
Abstract (Swedish)
Popular Abstract in Swedish

Kväveoxid (NO) och framför allt kolmonoxid (CO) tillhör de giftigaste gaserna man känner till. Vem har inte läst i kriminalromaner om hur människor stängts in i garage och gasats ihjäl med kolmonoxid från arbetande bilmotorers avgasutsläpp. Under det senaste årtiondet har man kunnat visa att dessa gaser i själva verket bildas i vår egen kropp och att de utgör signalmolekyler i många livsviktiga kroppsfunktioner bland annat i vår hjärna. Vi har under de senaste åren intensivt undersökt huruvida dessa gaser möjligen kan bildas inte bara i hjärnan utan också i hormonbildande (endokrina) celler som till exempel i de insulinproducerande b-cellerna i de så kallade Langerhanska öarna, som ligger... (More)
Popular Abstract in Swedish

Kväveoxid (NO) och framför allt kolmonoxid (CO) tillhör de giftigaste gaserna man känner till. Vem har inte läst i kriminalromaner om hur människor stängts in i garage och gasats ihjäl med kolmonoxid från arbetande bilmotorers avgasutsläpp. Under det senaste årtiondet har man kunnat visa att dessa gaser i själva verket bildas i vår egen kropp och att de utgör signalmolekyler i många livsviktiga kroppsfunktioner bland annat i vår hjärna. Vi har under de senaste åren intensivt undersökt huruvida dessa gaser möjligen kan bildas inte bara i hjärnan utan också i hormonbildande (endokrina) celler som till exempel i de insulinproducerande b-cellerna i de så kallade Langerhanska öarna, som ligger insprängda som just "öar" i vår bukspottkörtel (pankreas). Vi och andra har härvid funnit att NO bildas i öarnas b-celler och vi har också, som första forskargrupp, kunnat visa att CO kan bildas i jämförelsevis stora mängder i b-cellerna. Vi har gjort omfattande studier för att kartlägga hur NO och CO påverkar insulinsekretionen och vi har erhållit ganska starka evidens för att båda gaserna är av betydelse i detta hänseende och således också kan vara av betydelse för uppkomsten av vissa former av diabetessjukdomen.



Från aminosyran L-arginin bildas under inverkan av enzymet NO-syntas en annan aminosyra L-citrullin och samtidigt utvecklas ekvivalenta (lika) mängder av gasen NO. Genom att mäta mängden bildat L-citrullin kan vi således uppskatta mängden NO, som utvecklas i olika vävnader. Att mäta NO "i gasform" är nämligen mycket svårt eftersom NO-molekylen är mycket reaktiv och reagerar nästan så fort den bildas med praktiskt taget "vad som helst". Denna hyperreaktiva egenskap hos NO gör att den reagerar med och förstör livsviktiga DNA-segment, enzymer och andra proteiner i de insulinproducerande b-cellerna, vilka till slut kan duka under och dö. Denna kväveoxidens roll under utvecklandet av ungdomsdiabetes (typ1) är idag accepterad som en av troligen flera orsaker till denna typ av diabetes. Kolmonoxidmolekylen delar många viktiga egenskaper med NO, men den skiljer sig på en viktig punkt: den är inte lika reaktiv. Detta gör att den kan transporteras längre sträckor i kroppen. Den har inte heller samma cytotoxiska (cellförstörande) effekter som NO. CO bildas från blodfärgämnet heme, vilket frigörs från hemoglobin i blodet när de röda blodkropparna dör. Den största mängden CO bildas därför i de organ i kroppen där de röda blodkropparna bryts ned nämligen i levern och mjälten. Vi har visat att bukspottkörtelns endokrina del, de Langerhanska öarna innehåller stora mängder av det CO-bildande enzymet heme oxygenase. CO-produktionen i öarna är ca 10 ggr större än NO produktionen. Men varför finns det ett CO-bildande enzym i de insulin- och glukagon- bildande cellerna i bukspottkörteln? De har ju ingenting med destruktionen av de röda blodkropparna att göra. Att kunna besvara denna fråga är ett av våra viktigaste projekt just nu. Vi har hittills funnit att CO bildad i de Langerhanska öarna stimulerar sekretionen av både insulin och glukagon troligen via ökning av den intracellulära "budbäraren" cykliskt GMP. En annan kanske viktigare egenskap hos den bildade kolmonoxiden är att den kan binda till NO-syntas enzymet och hämma bildningen av b-cell toxiskt NO. Det verkar alltså som om heme oxygenase-CO systemet motverkar effekterna av den farliga kväveoxiden i de Langerhanska öarna. Teoretiskt skulle man därför kunna tänka sig att en framtida behandling som kan öka öarnas CO-utveckling skulle kunna förhindra utvecklingen av vissa former av diabetes eller i varje fall försena insjuknandet. (Less)
Abstract
During the last decade it has been shown that nitric oxide (NO) and carbon monoxide (CO) are produced in our own body, and that they constitute a novel class of messenger molecules. In 1992 a constitutive NO-producing NO-synthase (cNOS) was found in the islets of Langerhans, and in 1997 we could show for the first time that the islets also contained a CO-producing constitutive heme oxygenase (HO-2). The aim of this thesis was to elucidate the role of NO and CO in the regulation of islet hormone release. Glucagon secretion and glucose-stimulated insulin secretion was stimulated by CO produced from the HO-2 enzyme, which we found to reside in all four endocrine cell types of the islets. The effects of CO in transduction signalling was found... (More)
During the last decade it has been shown that nitric oxide (NO) and carbon monoxide (CO) are produced in our own body, and that they constitute a novel class of messenger molecules. In 1992 a constitutive NO-producing NO-synthase (cNOS) was found in the islets of Langerhans, and in 1997 we could show for the first time that the islets also contained a CO-producing constitutive heme oxygenase (HO-2). The aim of this thesis was to elucidate the role of NO and CO in the regulation of islet hormone release. Glucagon secretion and glucose-stimulated insulin secretion was stimulated by CO produced from the HO-2 enzyme, which we found to reside in all four endocrine cell types of the islets. The effects of CO in transduction signalling was found to include cyclic GMP (cGMP) production as well as NOS inhibition. Islet CO-production was found to be stimulated by glucose. The inducible HO-1 enzyme was induced in vivo by LPS (lipopolysaccharide), concomitant with inducible NOS (iNOS), and might be part of an islet defence against the oxidative stress exerted by NO. L-arginine- and glucose-stimulated insulin secretion was inhibited by cNOS-derived-NO in parallel with islet NO-production and independent of membrane depolarisation events. In contrast, glucagon secretion was stimulated by NO. By measuring both cNOS and iNOS activity in the islets we could show that the NOS-inhibitor NG-mono-methyl-L-arginine (L-NMMA) in low concentrations stimulated islet cNOS-derived-NO-production, and that NG-nitro-L-arginine methyl ester (L-NAME) during long-term oral administration did inhibit islet cNOS activity, but that the total islet NO-production was paradoxically increased because of a compensatory induction of iNOS. Islet iNOS, which by immunocytochemistry and confocal microscopy was found in most b-cells, and a small percentage of a- and PP-cells after in vivo LPS treatment, was also rapidly induced by hyperglycaemia as well as after starvation. In animal models of NIDDM insulin hypersecretion was correlated to low cNOS and iNOS activity, while failing insulin secretion was correlated to high NO-production within the islets. In situations of excessive NO-production the islet adenylate cyclase-cyclic AMP system was upregulated, similar to the HO-system, probably as a counterbalance to the NO-induced suppression of insulin secretion. Glucagon, as well as CO, was found to inhibit islet NOS activity. It seems as if a functional NO system is essential in the islets by stimulating glucagon secretion and inhibiting excessive insulin secretion, constituting a fail-safe instrument to finely tune the influence of insulin secretion on the blood glucose level. (Less)
Please use this url to cite or link to this publication:
author
opponent
  • Professor Gylfe, Erik, Institute of Cell Biology, University of Uppsala Sweden
organization
publishing date
type
Thesis
publication status
published
subject
keywords
carbon monoxide (CO), nitric oxide (NO), Nitric oxide synthase (NOS), Insulin and glucagon secretion, cyclic nucleotides, Endocrinology, secreting systems, diabetology, Endokrinologi, sekretion, diabetologi, Heme oxygenase (HO)
pages
210 pages
publisher
Department of Pharmacology, Lund University
defense location
Lecture Hall Department of Pharmacology Sölvegatan 10
defense date
1999-11-04 09:15
external identifiers
  • other:ISRN: LUMEDW/MEFA--1039--SE
language
English
LU publication?
yes
id
2bf688e5-ee2a-4da8-bea3-8afe3fd2fcbf (old id 39946)
date added to LUP
2007-06-21 09:06:51
date last changed
2016-09-19 08:45:11
@phdthesis{2bf688e5-ee2a-4da8-bea3-8afe3fd2fcbf,
  abstract     = {During the last decade it has been shown that nitric oxide (NO) and carbon monoxide (CO) are produced in our own body, and that they constitute a novel class of messenger molecules. In 1992 a constitutive NO-producing NO-synthase (cNOS) was found in the islets of Langerhans, and in 1997 we could show for the first time that the islets also contained a CO-producing constitutive heme oxygenase (HO-2). The aim of this thesis was to elucidate the role of NO and CO in the regulation of islet hormone release. Glucagon secretion and glucose-stimulated insulin secretion was stimulated by CO produced from the HO-2 enzyme, which we found to reside in all four endocrine cell types of the islets. The effects of CO in transduction signalling was found to include cyclic GMP (cGMP) production as well as NOS inhibition. Islet CO-production was found to be stimulated by glucose. The inducible HO-1 enzyme was induced in vivo by LPS (lipopolysaccharide), concomitant with inducible NOS (iNOS), and might be part of an islet defence against the oxidative stress exerted by NO. L-arginine- and glucose-stimulated insulin secretion was inhibited by cNOS-derived-NO in parallel with islet NO-production and independent of membrane depolarisation events. In contrast, glucagon secretion was stimulated by NO. By measuring both cNOS and iNOS activity in the islets we could show that the NOS-inhibitor NG-mono-methyl-L-arginine (L-NMMA) in low concentrations stimulated islet cNOS-derived-NO-production, and that NG-nitro-L-arginine methyl ester (L-NAME) during long-term oral administration did inhibit islet cNOS activity, but that the total islet NO-production was paradoxically increased because of a compensatory induction of iNOS. Islet iNOS, which by immunocytochemistry and confocal microscopy was found in most b-cells, and a small percentage of a- and PP-cells after in vivo LPS treatment, was also rapidly induced by hyperglycaemia as well as after starvation. In animal models of NIDDM insulin hypersecretion was correlated to low cNOS and iNOS activity, while failing insulin secretion was correlated to high NO-production within the islets. In situations of excessive NO-production the islet adenylate cyclase-cyclic AMP system was upregulated, similar to the HO-system, probably as a counterbalance to the NO-induced suppression of insulin secretion. Glucagon, as well as CO, was found to inhibit islet NOS activity. It seems as if a functional NO system is essential in the islets by stimulating glucagon secretion and inhibiting excessive insulin secretion, constituting a fail-safe instrument to finely tune the influence of insulin secretion on the blood glucose level.},
  author       = {Henningsson, Ragnar},
  keyword      = {carbon monoxide (CO),nitric oxide (NO),Nitric oxide synthase (NOS),Insulin and glucagon secretion,cyclic nucleotides,Endocrinology,secreting systems,diabetology,Endokrinologi,sekretion,diabetologi,Heme oxygenase (HO)},
  language     = {eng},
  pages        = {210},
  publisher    = {Department of Pharmacology, Lund University},
  school       = {Lund University},
  title        = {Nitric oxide (NO) and carbon monoxide (CO): A novel class of messenger molecules regulating insulin and glucagon secretion},
  year         = {1999},
}