The Metabolic Syndrome: (eBook)

Part I: Epidemiology and Clinical Treatment: Issues in defining and treating the metabolic syndrome Chapter 1 Metabolic Syndrome: to be or not to be? Gerald M. Reaven Chapter 2 The Role of Obesity in Insulin Resistance: Epidemiological and metabolic aspects James B. Meigs Chapter 3 Treatment of the Metabolic Syndrome with Weight Loss, Exercise, Hormones, and Surgery George A. Bray Chapter 4 Insulin Resistance, Metabolic Syndrome, and Cardiovascular Disease: an epidemiological perspective Earl Ford and Simin Liu Chapter 5 The Sympatho-Adrenal System in Metabolic Syndrome Lewis Landsberg Part II: Endothelial Function, Inflammation, and Dyslipidemia Chapter 6 Insulin Action and Endothelial Function Kieren J. Mather, Alain Baron, and Michael J. Quon Chapter 7 Macro and Micro Vascular Disease in an Insulin Resistant - Pre-diabetic Animal Model (the JCR:LA-cp Rat) James C. Russell and Spencer D. Proctor: Chapter 8 High Sensitivity C-reactive protein (Hs-CRP) in Metabolic Syndrome Yiqing Song, Simin Liu, and JoAnn Manson Chapter 9 Insulin Signaling in Adipocytes and the Role of Inflammation Christian X. Andersson, Ann Hammarstedt, Per-Anders Jansson and Ulf Smith Chapter 10 Insulin Resistance and Dyslipidemia Tina J. Cahil, Gissette Reyes, and Henry N. Ginsberg Part III: Insulin — Secretion and Action: Underlying mechanisms of the metabolic syndrome Chapter 11 Pancreatic Islet Pathophysiology and Pathology in Obesity Anne Clark, Jenni Moffitt, Leanne van de Laar, Katherine Pinnick, Farhina Sayyed Chapter 12 Glucagon Peptides and Insulin Sensitivity Jens Juul Holst and Filip Krag Knop Chapter 13 The Relationship between the Insulin Receptor Substrates and Metabolic Disease Morris F. White Chapter 14 Insulin Resistance and Inhibitors of the Insulin Receptor Tyrosine Kinase Jack F. Youngren Chapter 15 Fat Feeding and Muscle Fat Deposition Eliciting Insulin Resistance: an update E.W. Kraegen, G.J. Cooney, J.M. Ye, and S.M. Furler: Chapter 16 Alternations in Atypical Protein Kinase-C (APK-C) Activation in Insulin Resistance Syndrome Robert V. Faresse Chapter 17 The Liver’s Role in Insulin Action and Resistance

"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)."