Sex and Gender Factors Affecting Metabolic Homeostasis, Diabetes and Obesity Advances in Experimental Medicine and Biology

Advances in Experimental Medicine and Biology 1043 Franck Mauvais-Jarvis Editor Sex and Gender Factors Affecting Metabolic Homeostasis, Diabetes and Obesity Advances in Experimental Medicine and Biology Volume 1043 Editorial Board IRUN R. COHEN, The Weizmann Institute of Science, Rehovot, Israel ABEL LAJTHA, N.S. Kline Institute for Psychiatric Research, Orangeburg, NY, USA JOHN D. LAMBRIS, University of Pennsylvania, Philadelphia, PA, USA RODOLFO PAOLETTI, University of Milan, Milan, Italy NIMA REZAEI, Tehran University of Medical Sciences, Tehran, Iran More information about this series at http://www.springer.com/series/5584 Franck Mauvais-Jarvis Editor Sex and Gender Factors Affecting Metabolic Homeostasis, Diabetes and Obesity Editor Franck Mauvais-Jarvis Department of Medicine, Section of Endocrinology and Metabolism Tulane University Health Sciences Center, School of Medicine New Orleans, LA, USA ISSN 0065-2598 ISSN 2214-8019 (electronic) Advances in Experimental Medicine and Biology ISBN 978-3-319-70177-6 ISBN 978-3-319-70178-3 (eBook) https://doi.org/10.1007/978-3-319-70178-3 Library of Congress Control Number: 2017961821 © Springer International Publishing AG 2017 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. The publisher, the authors and the editors are safe to assume that the advice and information in this book are believed to be true and accurate at the date of publication. Neither the publisher nor the authors or the editors give a warranty, express or implied, with respect to the material contained herein or for any errors or omissions that may have been made. The publisher remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. Printed on acid-free paper This Springer imprint is published by Springer Nature The registered company is Springer International Publishing AG The registered company address is: Gewerbestrasse 11, 6330 Cham, Switzerland Foreword As children, we were taught to look both ways before crossing the road, as a matter of safety for ourselves and for others. Clearly, looking for traffic in only one direc- tion can be dangerous. Yet in biomedical research, neglecting the larger picture and looking only one way – that is, at male cells and animals in preclinical studies and men in clinical studies – was largely the norm until recently. This biased focus per- sists in some cases, especially in the realm of preclinical research, despite the per- vasiveness of sex differences in human anatomy, physiology, and disease. I first became interested in sex and gender differences in health and disease as a clinician and researcher in ophthalmology, given the female-biased prevalence of many types of ocular diseases and the common roles of sex hormones in those diseases. My interests in sex and gender influences on health and disease, and on sex and gender disparities in research studies, grew from this starting point, eventually leading me to my current role as director of the Office of Research on Women’s Health (ORWH) at the US National Institutes of Health (NIH). As part of NIH’s initiative to enhance reproducibility through rigor and transparency, ORWH has been leading the development of a policy requiring NIH-funded scientists to consider sex as a biological variable in basic, preclinical, translational, and clinical research. While myriad sex and gender differences have been documented across the medical disciplines, they are particularly prominent in certain areas. For example, sex and gender differences appear to be more the rule than the exception when it comes to energy balance, fat distribution, obesity, and metabolic disorders, such as diabetes. Although such sex and gender differences are often well known from a bird’s- eye view, many of the details underscoring the differences still need to be investigated, given the historical overreliance on male cells and animals and the underreporting of sex- and gender-specific results in the medical literature. Fortunately, a promising shift to correct these shortfalls is already underway for research on metabolic homeostasis, obesity, and diabetes. Dr. Franck Mauvais- Jarvis, professor of endocrinology at the Tulane University School of Medicine, has championed a move to include both sexes in preclinical research in these areas of medicine. As editor of this book, Dr. Mauvais-Jarvis brings together leading v vi Foreword colleagues in the field, who cover a comprehensive array of subjects pertaining to metabolic homeostasis and the causes and treatments of diabetes and obesity. These topics include the epidemiology of diabetes and obesity; key sex differences in energy metabolism, diabetes, and obesity; the roles of sex hormones in energy balance, metabolic homeostasis, body fat distribution, muscle function, and feeding behavior; and hormone replacement therapies for men and women. A goal of NIH is for all biomedical research to consider sex and gender (as appropriate) so as to automatically “look both ways” to see the whole picture. Failure to consider both sexes in preclinical research incompletely informs the premise and design of subsequent clinical studies. A focus on only one sex of cells and research animals also results in missed opportunities for discoveries that ulti- mately benefit everyone, for example, “protective effects” of certain factors in one sex, which may have therapeutic relevance for everyone. The foundation of knowledge arising from biomedical research helps answer important questions about disease presentation, clinical care, and the efficacy and safety of therapeutics. Failure of preclinical or clinical research to be inclusive with regard to sex and gender offers a subset of the population with a foundation that lags behind the foundation avail- able to the rest. This book synthesizes an emerging roadmap for considering sex and gender in metabolic homeostasis, diabetes, and obesity. It also exemplifies many important insights that such an approach offers for improved, evidence-based medicine. Publication of the book could not be more timely, owing to the growing global bur- den of obesity and diabetes, which exhibit important sex/gender differences in prevalence, pathophysiology, and consequent risks. National Institutes of Health, Janine Austin Clayton Office of Research on Women’s Health Bethesda, MD, USA 2017 Preface Due to the inherent biological differences between the two sexes, multiple aspects of glucose homeostasis and energy balance are regulated differently in male and female mammals and influence both the development of diabetes and obesity and the response to drugs. In 1993, the National Institutes of Health Revitalization Act mandated the inclusion of women in clinical trials, but many investigators still do not analyze the results by sex. In addition, most researchers avoid studying female rodents due to the added complexity of research plans. The consequence is a genera- tion of data that risks being relevant to only males. NIH director Francis Collins and associate director for research on women’s health Janine Clayton finally asked scientists to consider sex in preclinical research, to ensure that women get the same benefit of medical research as men. The NIH released a notice on new rules to pro- mote the study of animals and cells from both sexes to prevent the overreliance on male animals in preclinical studies. In March 2017, I organized (with the help of Debbie Clegg and Art Arnold) the first Keystone Symposium on “Sex and Gender Factors Affecting Metabolic Homeostasis, Diabetes and Obesity” in Lake Tahoe, CA, to connect interdisciplinary groups of scientists who otherwise would not have an opportunity to meet. Participants came from a wide range of basic and clinical backgrounds but shared a common focus of studying sex differences in metabolic disease. The meeting was a success and generated new knowledge and ideas on the importance of sex and gender biology and medicine, from a molecular standpoint to the population level. This book was conceived as a necessary follow-up to this meeting. Each chapter was written by participants who are experts in their respective fields of sex differences in metabolic homeostasis and disease. New Orleans, LA, USA Franck Mauvais-Jarvis vii Introduction This book is organized to describe major sex differences in metabolic homeostasis and disease as well as the role of estrogens and androgens. In the first chapter, I introduce epidemiological evidence that the incidence and prevalence of both types of diabetes, as well as obesity and metabolic syndrome, exhibit a clear global gender bias. Gender differences affect many aspects of metabolism that are involved in the pathogenesis of dysglycemia and adiposity. The most obvious examples are body composition, as discussed by Miriam Bredella in chapter “Sex Differences

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