Following 50 years of glucocorticoid use in a clinical setting, an international body of expert scientists and physicians presents the most expansive survey of glucocorticoid pharmacology to date. This work traces the history of glucocorticoid biology from the seminal description of glucocorticoid insufficiency by Thomas Addison in the mid-19th century, up to current advances in elucidating the molecular basis of glucocorticoid action. Important discoveries are presented, as well as milestones in drug development, a survey of current clinical practice, and prospects for novel glucocorticoid-based therapeutics. Scientists and clinicians will appreciate the scope of this work, which is of special interest to workers in the fields of endocrinology, inflammation and autoimmune disease.

JIMD Reports publishes case and short research reports in the area of inherited metabolic disorders. Case reports highlight some unusual or previously unrecorded feature relevant to the disorder, or serve as an important reminder of clinical or biochemical features of a Mendelian disorder.

During the past decade many review papers and books have been devoted to descriptions and analyses of biological rhythms (chronobiology) in plants and animals. These contributed greatly to demonstrating the impor tance of bioperiodicities in living beings in general. However, the practi cal aspects of chronobiology with regard to human health and improving the treatment of disease have not yet been a major focus of publication. One of our aims is to establish the relevance of biological rhythms to the practice of medicine. Another is to organize and convey in a simple fashion information pertinent to health- and life-science professionals so that students, researchers, and practitioners can achieve a clear and pre cise understanding of chronobiology. We have limited scientific jargon to unavoidable basic and well-defined terms and we have emphasized illus trative examples of facts and concepts rather than theories or hypotheti cal mechanisms. This volume is divided into seven chapters, each of which is compre hensive in its treatment and includes an extensive bibliography. The book is organized to serve as a textbook and/or reference handbook of modem applied chronobiology. Chapter 1 describes the historical development of chronobiology and reviews why, when, and how major concepts were introduced, accepted, and transformed."

It is fourteen years since insulin was last reviewed in The Handbook of Ex perimental Pharmacology, in volume 32. The present endeavor is more modest in scope. Volume 32 appeared in two separate parts, each having its own subeditors, and together the two parts covered nearly all areas of insulin pharmacology. Such comprehensiveness seemed impractical in a new volume. The amount of in formation related to insulin that is now available simply would not fit in a reasonable amount of space. Furthermore, for better or worse, scientists have be come so specialized that a volume providing such broad coverage seemed likely in its totality to be of interest or value to very few individuals. We therefore decided to limit the present volume to the following areas: insulin chemistry and structure, insulin biosynthesis and secretion, insulin receptor, and insulin action at the cellular level. We felt these areas formed a coherent unit. We also felt, perhaps as much because of our own interests and perspectives as any objective reality, that these were the areas in which recent progress has been most dramatic, and yet, paradoxically and tantalizingly, these were the areas in which most has yet to be learned. Even with this limited scope, there are some major gaps in coverage. Regrettably, two important areas, the beta cell ATP-sensitive potassium channel and the glucose transporter, were among these. Nevertheless, the authors who con tributed have done an excellent job, and we would like to thank them for their diligence.

Endocrinology and Metabolism: Progress in Research and Clinical Prac tice is a new series that has been designed to present timely, critical reviews of constantly evolving fields; to provide practical and up-to-date guidance in the solution of pertinent clinical problems; to offer an alterna tive to the laborious search of the literature (and the often frustrating reading of highly technical articles); and to translate the language of the laboratory into that of the practice of medicine. We think that this volume and those to come will prove useful to physi cians (and to physicians in training), as well as to investigators in a wide variety of specialties; in short, to anyone who seeks answers to questions in endocrinology and metabolism. The first chapter of this volume could well serve as a general introduc tion to the entire series. It points out how our growing understanding of the molecular basis of biologic communication has led to the discovery of a growing number of clinical syndromes, as well as to the realization that phenotypically similar diseases may have radically different pathogenetic mechanisms and thus may require radically different therapeutic strata gems."

The findings of immunogenetic linkages, autoantibodies including autoislet cell and autoinsulin antibodies-and viruses in diabetes has attracted increasing interest among immunologists, virologists, geneticists and clinicians. To gather together the recent avalanche ef new and exciting information emerging in this area, Current Topics in Microbiology and Immunology has put together two volumes on this subject. The first volume, CTMI 156, (see page VI for contents) provided data on the animal models and experimental approaches currently employed to evaluate both the autoimmune and virologic factors contributing to the causation and patho genesis of diabetes. The second is this current volume. It is edited by Drs. BAEKKESKOV and HANSEN and focuses on current knowledge in human diabetes. This volume on human diabetes contains ten chapters from leading researchers. The book is arranged in two components. The first part critically analyzes the genes in man that playa role in susceptibility to insulin dependent diabetes mellitus (IDDM). The second segment analyzes the role(s) that various environ mental factors play in IDDM and provides data on the autoantigens, aberrant immune responses, and the role of cytokines and free radicals in the pathogenesis of diabetes. La Jolla, California MICHAEL B. A. OLDSTONE, M.D. This collection of studies was conceived as part of a two-volume review of the immunology of diabetes. The contents of Volume 156, which forms part 1, are listed below."

One person in four in the industrialized countries suffers from hyperuricemia and is therefore at risk of developing gouty arthritis, nephrolithiasis, or any of the other consequences of urate deposition. At present, far too little is known about urate deposition and the mechanisms by which it occurs, as well as about its clinical consequences, which include formation of toph; over the helix of the ear or in bones close to joints that have never exhibited an attack, development of bursitis, chronic tendovaginitis leading to carpal tunnel syndrome, and gouty paraplegia. Information on these matters is needed to estimate the risks of hyperuricemia and to determine when therapeutic intervention is indicated. The contributions and discussions in this book, resulting from an international symposium held in December 1990 in the Medizinische Poliklinik in Munich, provide an up-to-date source of current knowledge about hyperuricemia in man and its clinical consequences.

JIMD Reports publishes case and short research reports in the area of inherited metabolic disorders. Case reports highlight some unusual or previously unrecorded feature relevant to the disorder, or serve as an important reminder of clinical or biochemical features of a Mendelian disorder.

Alcohol abuse, alcohol intolerance, alcohol dependence and other alcohol-related disabilities are some of the most challenging public health problems facing our modern-day society. The purpose of this comprehensive monograph is to review the available knowledge concerning the pharmacogenetic basis of alcohol sensitivity and its physiolgical implications and to synthesize the bulk of existing knowledge regarding metabolic features and biomedical disturbances related to alcoholism. The chapters cover a broad array of disciplines including an overview of historical and epidemiological aspects, biochemistry and molecular genetics of enzymes involved in alcohol metabolism, biochemical and neuropsychopharmacological effects of alcohol. Major emphasis is placed on the role of genetic factors in alcoholism. The experimental details are summarized and a comprehensive bibliography is included.

This book is based on the Symposium "Metabolic Regulation and Functional Activity in the Central Nervous System" which was held on September 16 and 17, 1972, at Saint Vincent (Aosta)/Italy, and was sponsored by the Accademia di Medicina di Torino with the scientific cooperation of the Istituto di Farmacologia, Universita di Torino, and the Pharmakologisches Institut der Freien Universitat Berlin. Its purpose was to give a greater number of scientists from different countries an opportunity to report their latest results under a heading concerning general relationships between metabolism and function. We quite deliberately refrained from pursuing the partly heterogenous subjects into details. Thus, the organizers hoped to be able to interest a greater circle of readers for the manifold subjects from various fields dealing with the investigation of metabolic processes in the central nervous system. The discussion remarks to the lectures could not be considered for printing. The Accademia di Medicina di Torino and all others concerned do not only thank Dr. R. Di Carlo and other members of the Istituto di Farmacologia, Universita di Torino, for the excellent work they performed in preparing this Symposium, but also the Amministrazione Regionale della Valle di Aosta and SIT A V di Saint-Vincent for their generous support and their kind hospitality which made the stay at Saint-Vincent most agreeable for all participants."

Thirty years have elapsed since the first description by S. A. BERSON and R. S. Y ALOW of the basic principles of radioimmunoassay (RIA). During this period of time, RIA methodology has been instrumental to the growth of many areas of biomedical research, including endocrinology, oncology, hematology, and pharmacology. It has done so by providing a relatively simple universal tool allowing, for the first time, the detection of endogenous mediators that are present 12 10 in body fluids at concentrations as low as 10- _10- M. The fundamental nature of this discovery and the wide-ranging fall-out of basic and clinical knowledge derived from its application have been acknowledged by the many honors tributed to its pioneers, including the Nobel Prize awarded to Dr. Y ALOW 10 years ago. Although several excellent books have been published during the past decades covering various aspects of RIA methodology, we felt the need, as pharmacologists, for a comprehensive discussion of the methodological and conceptual issues related to the main classes of mediators of drug action and to drugs themselves. Thus, we gladly accepted the challenge provided by the invitation to edit a volume of the Handbook of Experimental Pharmacology on Radioimmunoassay in Basic and Clinical Pharmacology. We tried to balance the emphasis placed on more general aspects of the RIA methodology and that on specific mediators.

There has been much popular and scientific interest in the fields of nu trition and aging in recent years. As the importance of proper nutrition in children and young adults becomes more fully understood, it is natural to wonder if proper nutrition could playa similar role in later life. Recent research has indicated that nutrition can potentially intervene in the ag ing process in at least two ways. First, studies in animals and humans have shown that nutrition can be used to improve functional status, which, in turn, is related to perceived quality of life. Second, nutritional manipu lation has been used to extend maximal life span in laboratory animals. How these interesting findings apply to the human situation remains to be explored. The purpose of this book is twofold. The first is to present recent ad vances in our basic knowledge of how nutrition and aging interact with each other. The second is to discuss some applications of this knowledge to the care of the elderly patient. The interaction between aging and nutrition is complex because each may act on the other in either a synergistic or antagonistic fashion. Aging may alter the nutritional status of the elderly by affecting the way nu trients are absorbed and utilized by the body. Aging may also influence food intake and, therefore, nutritional status by decreasing the palatabil ity of food. The environment of the elderly may change so they are less likely to eat well-balanced meals."

Since insulin became available for the treatment of diabetes in 1922 a number of major advances have been made, which include the modification of insulin to vary its timing of action, its purification, and latterly, the production of human insulin. Human insulin in quantities sufficiently large for therapy has been made available by two techniques developed in parallel during the late 1970s. These involve either (i) formulation in E. coli bacteria suitably encoded by DNA recombinant methods of the A- and B-chains of human insulin followed by a chain combination reaction ('biosynthetic' human insulin) or (ii) enzymatic conversion (transpeptidation) of porcine insulin brought to react with a threonine ester by porcine trypsin in a mixture of water and organic solvents, yielding human insulin ('semi-synthetic' human insulin). This book includes the first clinical-pharmacological studies of each of the highly purified 'semi-synthetic' human insulin preparations: Actrapid (R) HM; Monotard (R) HM; Protaphane (R) HM; Actraphane (R) HM; and Ultratard (R) HM (Novo Industri A/S, Copenhagen). The preliminary studies established their safety and efficacy relative to their porcine and bovine counterparts emphasising the relevance of species and formulation on the pharmacokinetics and biological responses to insulin. Additional investigations with human insulin demonstrated the influence of insulin concentration, site of administration, the addition of aprotinin to insulin and the mixing of 'short-' and 'intermediate-acting' formulations on insulin 'bioavailability'. Examination of the 'within' and 'between' subject day-to-day variation in absorption and the effect of subcutaneous insulin also demonstrates the dominating influence of insulin responsiveness.

The advances in science and medicine we are now experiencing are unprec edented and exciting. Life expectancy is prolonged, and quality of life is much improved. We learn of fabulous new discoveries made at the bench or the bedside every week. Many diseases have been totally eliminated, others can be significantly improved by new therapeutic formulations. Much of the success can be attributed to a better understanding of disease processes and the specific targeting of new and more effective medications. As is the case in many areas of successful human endeavour, there can be a downside. In the case of drugs and chemicals it is their adverse effects which are of concern. Of course, every effort is made to devise medications that are safe, and the need to elucidate and understand mechanisms are crucial, yet adverse effects remain a problem. They can be unpredictable and diverse. Drugs have been shown to induce virtually the whole gamut of human liver pathology from acute fulminant hepatitis to chronic active hepatitis to cirrho sis and even malignancy. Hence the possibility of adverse drug effects must be considered in the differential diagnosis of many patients with liver disease. This is well recognized and is very important; indeed, removal of the offending agent can often lead to reversal of the adverse effect. This is an area of hepatology where we can really make a difference."

JIMD Reports publishes case and short research reports in the area of inherited metabolic disorders. Case reports highlight some unusual or previously unrecorded feature relevant to the disorder, or serve as an important reminder of clinical or biochemical features of a Mendelian disorder.

This volume provides guidance and answers to frequently asked questions in infectious diseases, thus facilitating improved patient care, prudent and cost effective management and investigation of these disorders. Other more complicated but less common conditions are also reviewed. Uniquely, this volume directly discusses several controversies regarding infectious diseases from the 21st century.

Adipose Tissue and Adipokines in Health and Disease presents a comprehensive survey of adipose tissue, its physiological functions, and its role in disease. This volume spans the entire range of adipose tissue studies, from basic anatomical and physiological research to epidemiology and clinical studies. The authors-distinguished researchers, clinicians and epidemiologists-have incorporated groundbreaking recent studies into traditional models of adipose tissue properties. Chapters on well-known properties of adipokines leptin and adiponectin are complemented by an introduction to a novel view of adipose tissue as a dynamic organ that regulates systemic substrate availability and metabolism, along with a variety of other discrete functions. This novel concept is expanded as the role of adipose tissue in maintaining body homeostasis and the modulation of inflammatory and metabolic responses is discussed. Worldwide trends in obesity are discussed from an evolutionary perspective and causes of the current obesity epidemic are postulated. Additionally, researchers and clinicians examine the association and potential role of adipose tissue in disease mediation and offer epidemiological evidence. This volume concludes with a thoughtful and innovative discussion of various approaches to inducing and sustaining weight loss in obese patients and the health effects of such treatments. Adipose Tissue and Adipokines in Health and Disease provides a broad and substantial foundation for understanding new developments in adipose tissue biology and successfully integrating them into new research endeavors.

In the years since the initial discovery that blood from diabetic patients contains increased amounts of a posttranslationally gluco sylated form of hemoglobin (hemoglobin Ale)' an impressive number of studies have clarified and expanded the use of glycohemoglobin levels to assess disease status. Many other structural proteins have been shown to undergo similar changes, including proteins from tissues most commonly affected in diabetes (e.g., lens, aorta, peripheral nerve, basement membrane). Thus, the nonenzymatic glycosylation of hemoglobin emerges as an invaluable model for the pathogenesis of certain chronic diabetes complications. In addition to reviewing a wealth of investigative possibilities in the area of these chronic complications-including eye, kidney, nerve, and vascular disease-Dr. Cohen indicates how enhanced nonenzymatic glycosylation in uncontrolled diabetes underscores the pressing need for maintenance of long-term euglycemia. Dr. Cohen is an endocrinologist and diabetes specialist whose research activities have largely focused on the chemistry and metabo lism of the basement membrane in diabetes. This superb monograph on nonenzymatic glycosylation clearly shows the major trends of her past and present research and clinical activities. This book is beautifully written and a pleasure to read. It provides great insight into the mechanisms of the pathogenesis of the oom- vii viii Foreword cations of diabetes and should be of immense value not only to basic and clinical investigators, but also to internists, diabetologists, and endocrinologists in clinical practice."

As I read this unique volume on diabetes and pregnancy edited by Lois Jovanovic, I was struck by two themes that run throughout these collected chapters. First, this volume provides an excellent assessment of past problems, present management, and future challenges presented by dia betes in pregnancy. Orury's unique, longitudinal experience with diabetes iIi pregnancy provides the reader with an important overview, as does Coetzee's discussion of gestational diabetes. Current problems-deter mining the etiology and prevention of congenital malformations in infants of diabetic mothers (10M), assessment of antepartum fetal condition, management of pregnant patients with diabetic retinopathy, recognition of thyroid dysfunction in the pregnant diabetic woman, and understanding the multitude of metabolic sequelae observed in the 10M-are thoroughly reviewed. Finally, important considerations for future treatment and ther apy such as the adaptation of the fetal pancreas to the disordered intra uterine environment often seen in maternal diabetes, the use of fetal pan creatic tissue for transplantation, the application of exercise in the management of the pregnant woman with diabetes, and the long-term con sequences for the 10M provide an exciting glimpse into the future. The second important theme that emerges is the critical role the problem of diabetes in pregnancy has played in our understanding of maternal and fetal physiology. Clinical observations supported by basic research have emphasized the role of fetal fuels in teratogenesis.

It has been a challenge for us to edit this volume of Endocrinology and Metabo lism: Progress in Research and Clinical Practice. The topic of the pathogenesis of insulin-dependent, type I diabetes mellitus is particularly appropriate for this series, since advances in this area have been made, to a large extent, by applying state-of-the-art laboratory techniques to clinical samples. Over the last several years, a number of lines of evidence have been gathered, suggesting that classic type I diabetes mellitus results from the autoimmune des truction of pancreatic beta-cells in genetically susceptible individuals. This hypothesis is particularly appealing because it offers a rational approach to the prevention of diabetes by immunosuppression. We have tried to present a balanced, authoritative summary of the information currently available to support the autoimmune hypothesis for the pathogenesis of human type I diabetes, to place this information in historical perspective, to include relevant information from animal models of type I diabetes in which more invasive experimentation is ethical, and, finally, to update the reader on the current status of attempts to intervene in the progression of diabetes with immunosuppressive drugs. New York, New York Fredda Ginsberg-Fellner Robert C. McEvoy Contents Preface.. . . .. .. .. . . . . . . . . . . . . ... . . . . . . . . . . . .. . . . . . . .. . . . . v Contributors. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Xl . . . . . . . . . . . . . 1. The Autoimmune Hypothesis of Insulin-Dependent Diabetes: 1965 to the Present . . . . . . . . . . . . ..................... . . . . . .

Glucagon III complements "Glucagon I" and "II" published in 1983 in this series as "Vols. 66/I" and "II." These three volumes truly represent a "glucagon encyclopedia" and as such have no competitors in the scientific literature worldwide. In this volume, the most recent data on glucagon molecular biology are reviewed together with clinically relevant information on the role of glucagon in the pathophysiology of diabetes, the place of glucagon in medical imaging or in emergency medicine. Chapters are devoted to newly identified members of the glucagon family such as glucagon-like peptide-1 (GLP-1) and oxyntomodulin. Glucagon III is a comprehensive review of all information published on this important hormone since 1983 and is "the" reference book on the subject.

JIMD Reports publishes case and short research reports in the area of inherited metabolic disorders. Case reports highlight some unusual or previously unrecorded feature relevant to the disorder, or serve as an important reminder of clinical or biochemical features of a Mendelian disorder.

JIMD Reports publishes case and short research reports in the area of inherited metabolic disorders. Case reports highlight some unusual or previously unrecorded feature relevant to the disorder, or serve as an important reminder of clinical or biochemical features of a Mendelian disorder.

Atherosclerosis leading to coronary heart disease and to cerebrovascular disorders is the number one cause of death in industrialized societies. For the last two decades, great ad vances have been made in understanding the pathogenesis of those disorders. Recent studies have revealed that the earliest event in atherogenesis is the adhesion of circulating leukocytes to the vascular endothelial cells and their migration into the subendothelial space. These cells are known to playa central role in the formation of a fatty streak consist ing of lipid-laden foam cells. As pathological events continue, the lesion is converted to a more fibrous lesion associated with vascular smooth muscle cells. To solve the enigma of this complicated process, intensive studies in molecular biology have disclosed the genes involved in those events. Some of the genes have been verified by creation of novel animal models, which have led to novel therapeutic strategies for subjects with atherosclerosis. This volume contains papers presented at the International Symposium on Lipoprotein Metabolism and Atherogenesis held in Kyoto December 5-8, 1998, supported in part by the Japan Intractable Diseases Research Foundation. The following three topics were the focus of the three-day program: I) The molecular approach to studying risk factors and prevention 2) The creation of novel animal models 3) Lipoprotein disorder as a cause of activation of vascular endothelial cells Thirty distinguished researchers from the United States, the United Kingdom, Austria, Finland, Australia, and Japan were invited."