Hansen / Bray The Metabolic Syndrome:

Epidemiology, Clinical Treatment, and Underlying Mechanisms
1. Auflage 2010
ISBN: 978-1-60327-116-5
Verlag: Humana Press
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 402 Seiten

Reihe: Contemporary Endocrinology

This book covers the most important clinical and bench science aspects of metabolic syndrome. It will be of value to all of those seeking a comprehensive update on the metabolic syndrome. Furthermore, it will provide a broad basis for advancing research in the multiple intersecting disciplines encompassed by the metabolic syndrome.

Autoren/Hrsg.

Hansen, Barbara C.

Bray, George A.

Leseproben

"II ENDOTHELIAL FUNCTION, INFLAMMATION, AND DYSLIPIDEMIA (p. 107-108)

7 Insulin Action and Endothelial Function

INTRODUCTION

The endothelium is a diaphanous cellular monolayer lining the lumen of the vasculature throughout the body and weighs approximately 1.8 kg in a 70 kg man. In addition to its well-recognized passive barrier and transport functions, the endothelium actively participates in processes related to local vascular and tissue health. These include active control of vascular tone (1,2), regulation of blood fluidity (3), and modulation of monocyte adhesion (4,5), inflammation (6,7), and lipid peroxidation (8-10), to name but a few processes.

More recently, the endothelium has been recognized as an endocrine organ. Indeed, the endothelium produces a variety of hormones acting in a paracrine fashion to regulate vascular tone as well as growth and remodeling of the vascular wall (11-14). The endothelium also possesses receptors for humoral ligands. These receptors, whose predominant role was initially thought to be transendothelial transfer of hormones, are now known to directly activate signaling cascades and physiological responses.

This chapter discusses the evidence and functional implications of the endothelium as a target tissue for insulin action and the pathophysiological consequences of insulin resistance. We present evidence from in vitro and in vivo studies demonstrating that the vascular endothelium responds to insulin by increasing the release of nitric oxide (the dominant endothelium-derived vasodilator and anti-atherosclerotic factor), and that this action is impaired in states of insulin resistance.

More recent data implicating insulin and other metabolic factors in the regulation of endothelin (the primary endotheliumderived vasoconstrictor and pro-atherosclerotic agent) are also reviewed. Pathophysiological implications relevant to cardiovascular disease in insulin resistance and the opportunities for novel treatment approaches are discussed.

MOLECULAR MECHANISMS OF INSULIN SIGNALING IN THE VASCULATURE

Insulin Signaling Pathways Regulating Production ofNO One important biological action of insulin in vascular endothelium is to directly stimulate production of nitric oxide (NO), a potent vasodilator (15,16). Classical vasodilators such as acetylcholine bind and activate specific G-protein-coupled receptors on the surface of endothelial cells, leading to generation of inositol trisphosphate (lP3) and subsequent increases in intracellular Ca2+ levels.

Ca2+/calmodulin complexes bind to a specific region on eNOS that promotes dissociation of eNOS from caveolin-l and enhances activation of eNOS (Fig. 7.1) (17,18). Signaling pathways leading from the insulin receptor to activation of eNOS are distinct and separable from the classical signaling pathways linking G-protein-coupled receptors to eNOS (19). Studies of endothelial cells in primary culture have elucidated a complete biochemical signaling pathway leading from the insulin receptor to activation of eNOS (19-22)."