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Modulation of regional nitric oxide metabolism: Blood glucose control or insulin?

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An Erratum to this article was published on 25 June 2008

An Erratum to this article was published on 24 May 2008

Abstract

Objective

Tight glycaemic control by intensive insulin therapy (IIT) reduces morbidity and mortality in critically ill patients. As potential mechanisms contributing to the clinical benefits we hypothesized that glycaemic control affects regional nitric oxide (NO) bioavailability by changing NO synthases (NOS) activity, NOS transcription, NOS substrate availability or the endogenous NOS inhibitor asymmetric dimethylarginine (ADMA) levels.

Design

Prospective, randomized experimental study.

Setting

University medical laboratory.

Interventions

In a rabbit model of prolonged critical illness we assessed the relative impact of maintaining normal insulin/normoglycaemia (n = 8), high insulin/normoglycaemia (n = 8), normal insulin/hyperglycaemia (n = 9) and high insulin/hyperglycaemia (n = 8) plasma levels over 7 days on activity and gene expression of endothelial and inducible NOS isoforms in muscle, liver and aorta biopsies, and on plasma levels of NO, arginine and ADMA.

Measurements and results

Compared with normoglycaemic groups, both hyperglycaemic groups revealed 53% higher day-3 NO plasma levels (p < 0.05), 40% lower NOS activity in muscle (p < 0.01) and 35% lower endothelium-mediated relaxation of aortic rings (p < 0.01), 515% higher gene expression of iNOS in muscle (p < 0.01) and 99% higher eNOS gene expression in aorta (p < 0.01). Only the hyperglycaemic/hyperinsulinaemic group showed lower arginine plasma levels (53% lower, p < 0.0001). Compared with healthy controls, normoglycaemic animals revealed 33% lower ADMA levels (p < 0.05).

Conclusions

In this animal model of prolonged critical illness, maintaining normoglycaemia, and not glycaemia-independent actions of insulin, prevented excessive systemic NO release on day 3 and appeared to preserve local endothelial function. Factors contributing to this finding may comprise direct endothelial cell damage, direct effects on the enzyme activity, decreased substrate availability or less NO-induced inhibition.

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Acknowledgements

We thank S. Fieuws, Biostatistical Center, School of Public Health, Katholieke Universiteit Leuven, Belgium, for independently reviewing the statistical analysis, and E. Van Herck, S. Vander Perre, S. Derde, E.-J. Ververs, I. Jans, K. Reyniers, M. Mathys, R. Bouillon and P. Wouters for their support. The work was supported by Innovative Medizinische Forschung (EL 610304), B. Braun Stiftung, Germany (B.E.), postdoctoral fellowship of the Fund for Scientific Research (FWO), Belgium (L.L., I.V.), doctoral fellowship FWO, Belgium (Y.D.), FWO, an unrestricted Novo Nordisk grant and the Research Council of the University of Leuven, Belgium. We thank B. Braun, Melsungen, Germany, Tyco Healthcare, Mechelen, Belgium, Fresenius-Kabi, Wilrijk, Belgium, and Baxter, Lessines, Belgium, for technical support.

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Authors and Affiliations

  1. Department of Intensive Care Medicine, Katholieke Universiteit Leuven, 3000, Leuven, Belgium

    Björn Ellger, Lies Langouche, Yves Debaveye, Ilse Vanhorebeek & Greet Van den Berghe

  2. Department of Anesthesiology and Intensive Care Medicine, University Hospital, 48149, Muenster, Germany

    Björn Ellger

  3. Department of Surgery, VU University Medical Center, 1007 MB, Amsterdam, The Netherlands

    Milan Richir & Paul A. Van Leeuwen

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  1. Björn Ellger
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  7. Greet Van den Berghe
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Correspondence to Björn Ellger.

Additional information

An erratum to this article can be found at http://dx.doi.org/10.1007/s00134-008-1185-6

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Ellger, B., Langouche, L., Richir, M. et al. Modulation of regional nitric oxide metabolism: Blood glucose control or insulin?. Intensive Care Med 34, 1525–1533 (2008). https://doi.org/10.1007/s00134-008-1118-4

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