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Effect of Endothelium-Specific Insulin Resistance on Endothelial Function In Vivo

Effect of Endothelium-Specific Insulin Resistance on Endothelial Function In Vivo

https://devfeature-collection.sl.nsw.gov.au/record/TN_cdi_crossref_primary_10_2337_db07_1111

Effect of Endothelium-Specific Insulin Resistance on Endothelial Function In Vivo

About this item

Full title

Effect of Endothelium-Specific Insulin Resistance on Endothelial Function In Vivo

Publisher

Alexandria, VA: American Diabetes Association

Journal title

Diabetes (New York, N.Y.), 2008-12, Vol.57 (12), p.3307-3314

Language

English

Formats

Publication information

Publisher

Alexandria, VA: American Diabetes Association

More information

Scope and Contents

Contents

Effect of Endothelium-Specific Insulin Resistance on Endothelial Function In Vivo
Edward R. Duncan 1 ,
Paul A. Crossey 1 ,
Simon Walker 1 ,
Narayana Anilkumar 1 ,
Lucilla Poston 3 ,
Gillian Douglas 3 ,
Vivienne A. Ezzat 1 ,
Stephen B. Wheatcroft 1 2 ,
Ajay M. Shah 1 and
Mark I. Kearney 1 2
1 Cardiovascular Division, Department of Cardiology, King's College London, U.K
2 Division of Cardiovascular and Diabetes Research, Multidisciplinary Cardiovascular Research Centre, University of Leeds, Leeds,
U.K
3 Maternal and Fetal Research Unit, Division of Reproduction and Endocrinology, King's College London, London, U.K
Corresponding author: Mark Kearney, m.t.kearney{at}leeds.ac.uk , or Ajay M. Shah, ajay.shah{at}kcl.ac.uk
Abstract
OBJECTIVE— Insulin resistance is an independent risk factor for the development of cardiovascular atherosclerosis. A key step in the
development of atherosclerosis is endothelial dysfunction, manifest by a reduction in bioactivity of nitric oxide (NO). Insulin
resistance is associated with endothelial dysfunction; however, the mechanistic relationship between these abnormalities and
the role of impaired endothelial insulin signaling versus global insulin resistance remains unclear.
RESEARCH DESIGN AND METHODS— To examine the effects of insulin resistance specific to the endothelium, we generated a transgenic mouse with endothelium-targeted
overexpression of a dominant-negative mutant human insulin receptor (ESMIRO). This receptor has a mutation (Ala-Thr 1134 ) in its tyrosine kinase domain that disrupts insulin signaling. Humans with the Thr 1134 mutation are insulin resistant. We performed metabolic and vascular characterization of this model.
RESULTS— ESMIRO mice had preserved glucose homeostasis and were normotensive. They had significant endothelial dysfunction as evidenced
by blunted aortic vasorelaxant responses to acetylcholine (ACh) and calcium ionophore. Furthermore, the vascular action of
insulin was lost in ESMIRO mice, and insulin-induced endothelial NO synthase (eNOS) phosphorylation was blunted. Despite this
phenotype, ESMIRO mice demonstrate similar levels of eNOS mRNA and protein expression to wild type. ACh-induced relaxation
was normalized by the superoxide dismutase mimetic, Mn(III)tetrakis(1-methyl-4-pyridyl) porphyrin pentachloride. Endothelial
cells of ESMIRO mice showed increased superoxide generation and increased mRNA expression of the NADPH oxidase isoforms Nox2
and Nox4.
CONCLUSIONS— Selective endothelial insulin resistance is sufficient to induce a reduction in NO bioavailability and endothelial dysfunction
that is secondary to increased generation of reactive oxygen species. This arises independent of a significant metabolic phenotype.
Footnotes
Published ahead of print at http://diabetes.diabetesjournals.org on 3 October 2008.
P.C. is currently affiliated with the School of Medicine and Medical Science, University College Dublin, Dublin, Ireland.
S.W. and M.K. are currently affiliated with The Leeds Institute for Genetics Health and Therapeutics, Leeds, U.K.
Readers may use this article as long as the work is properly cited, the use is ed...

Alternative Titles

Full title

Effect of Endothelium-Specific Insulin Resistance on Endothelial Function In Vivo

Identifiers

Primary Identifiers

Record Identifier

TN_cdi_crossref_primary_10_2337_db07_1111

Permalink

https://devfeature-collection.sl.nsw.gov.au/record/TN_cdi_crossref_primary_10_2337_db07_1111

Other Identifiers

ISSN

0012-1797

E-ISSN

1939-327X

DOI

10.2337/db07-1111

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