Insulin Resistance and Insulin Resistance Syndrome PDF

PREFACE

In 1936, Himsworth (Himsworth, 1936) observed that some diabetic patients require increasing amounts of insulin, and appear to become gradually insensitive to insulin, or "resistant" to the actions of insulin. Today, the term "insulin resistance" is applied to a broad range of biological observations, with an equally wide variety of potential underlying mechanisms. Animal models are being extensively used to examine both the causes of loss of insulin sensitivity, and the potential for reversal of this loss.

Consensus has not yet developed around a specific and quantifiable definition of insulin resistance. Most commonly, the presence of insulin resistance has been inferred when a given amount of endogenous or exogenous insulin has shown less than its expected biological action. In truth, insulin resistance is substantially related to the methods used to seek it, and the methods today differ widely from in vitro cellular methods to whole body euglycemic or hyperglycemic clamps. Over the past twenty years the so-called "gold standard" for measuring in vivo (whole body) insulin resistance has been this "clamp", as developed initially by DeFronzo, Tobin, and Andres (DeFronzo et al., 1979). During the earliest phases in the development of type 2 diabetes, insulin resistance gradually develops, accompanied by increasing fasting hyperinsulinemia and increasing beta cell responsiveness to a glucose stimulus.

Animal models of obesity and diabetes have contributed to understanding the natural history of the development of insulin resistance and to identifying some of the factors underlying this insulin resistance. In the present volume, we have drawn together some of the leaders in the field who provide their perspectives on the mechanisms of insulin resistance, as discerned from various animal models. While the exact mechanism underlying the appearance of resistance to insulin remains unknown, the authors here have examined many of the important factors. The contribution of age, from early perinatal to aged adulthood, has been considered. Insulin resistance is a major feature of the middle-aged onset, obesity-associated Metabolic Syndrome, sometimes referred to as Diabesity (Shafrir, 1993), diabetogenic obesity (Vague, 1956), or syndrome X (Reaven, 1988). This syndrome, described by many clinicians and investigators beginning nearly fifty years ago (Vague, 1956), derives from observation of the frequent interactions of insulin resistance with obesity, dyslipidemia, glucose intolerance, cardiovascular disease, hypertension, and abnormalities in whole body metabolism, as previously reviewed (Hansen, 1999). These clinical features and their possible insulin resistanceassociated pathophysiology, as elucidated by a variety of animal models, are discussed in a series of chapters included here. Finally, many pieces of the complex signaling pathways involved in causing insulin resistance, or emerging as a consequence of insulin resistance have been identified at the molecular level. The human genome revolution has been paralleled by extensive study of the genetics of animal models. New targets for pharmaceutical and other therapeutic interventions, based in part on key observations made in animal models, are being identified, and these genetic and molecular studies are leading to growth in our understanding of insulin sensitivity and insulin resistance.