Book Review

Insulin Resistance: The metabolic syndrome X

N Engl J Med 1999; 341:1402October 28, 1999

Article

Insulin Resistance: The metabolic syndrome X
(Contemporary Endocrinology.) Edited by Gerald M. Reaven and Ami Laws. 374 pp. Totowa, N.J., Humana Press, 1999. $145. ISBN: 0-89603-588-3

With the discovery of insulin in 1922, the study of diabetes was changed forever. From that time forward, it has been difficult to discuss the pathophysiology of diabetes without in some way referring to this critical metabolic hormone, which is a life-saving treatment in patients who lack it. The role of insulin in diabetes proved to be far more complex than its absence, however. Research over the past 60 years has gradually revealed that disease caused by resistance to insulin (type 2, or non-insulin-dependent, diabetes) is more prevalent than that due to the absence of insulin (type 1 diabetes). This realization, now universally accepted, caused researchers to emphasize the study of insulin-signaling pathways and to initiate efforts to treat the disease with drugs meant to alleviate the resistant state. The thiazolidinediones are a class of drug that fulfill this need; they represent a therapeutic milestone. But the problem of insulin resistance extends far beyond type 2 diabetes, in ways that were totally unanticipated. Gerald Reaven was among the pioneers in this burgeoning field. He identified insulin resistance as a risk factor for and pathophysiologic trigger of disorders as apparently unconnected as hypertension, hyperlipidemia, and polycystic ovary disease. Reaven and Laws have now brought together the diverse elements of this field in a book that will be of broad interest to the medical community.

The book has three parts. The first part contains seven chapters about various aspects of the genetic and environmental factors that affect the action of insulin. The subjects of these chapters include the genetic epidemiology of insulin resistance, the variations in insulin resistance among ethnic groups, and the effects of body-fat distribution, exercise, and smoking. This section is uneven in quality but contains much valuable information that is hard to find in one place.

The second part comprises six chapters concerning insulin resistance. The first chapter reviews the molecular basis of insulin resistance, including evidence of defects at the level of the tyrosine kinase domain of the insulin receptor. Three chapters examine the basis of insulin resistance in the three key target organs for the metabolic action of insulin: liver, skeletal muscle, and fat. It is increasingly recognized that the consequences of insulin resistance, and the mechanisms for insulin resistance, are highly tissue-specific, and these chapters are valuable summaries of what is known about this topic. The chapter on nuclear magnetic resonance as a noninvasive probe of the mechanisms of insulin resistance in humans is the best review of this field that I have encountered.

The real excitement in this field derives from an examination of the important clinical syndromes that are viewed, at least by the authors, as being associated with — and possibly caused by — insulin resistance. In the third part of the book, discussions of cardiovascular disorders predominate; the chapters cover the links between insulin resistance and dyslipidemia, hypertension, microalbuminuria, cardiovascular disease, and fibrinolysis. Much work in this area has been heavily based on associations between insulin resistance, as assessed by hyperinsulinemia or insulin-clamp techniques, and various end points, such as blood pressure. The missing ingredient has been precise mechanistic links allowing investigators to distinguish between noncausal associations and direct causal effects. On the basis of the assessments in these chapters, we still have a way to go in this regard. The ability of insulin to induce expression of the prothrombotic molecule plasminogen-activator inhibitor type 1 is an excellent example of how future studies may evolve. The availability of thiazolidinediones that act directly to reduce insulin resistance may prove the most rapid route to defining unambiguously the role of insulin resistance in the pathophysiology of the diverse disorders to which it has been linked. Recent studies make it clear that reducing insulin resistance and hyperinsulinemia with thiazolidinediones improves hyperandrogenism in women with polycystic ovary disease, as reviewed in the final chapter.

The study of insulin resistance will continue to evolve as new insights into insulin signaling emerge and as better drugs to treat the disorder become available. This book is an excellent and useful compendium of information about this rapidly moving field. It will be an essential addition to the libraries of those interested in any of the disorders linked to this prevalent metabolic state.

Jeffrey S. Flier, M.D.
Beth Israel Deaconess Medical Center, Boston, MA 02215