Bashar Saad · Hilal ZaidSiba Shanak · Sleman Kadan

Anti-diabetes and Anti-obesity Medicinal Plants and PhytochemicalsSafety, E� cacy, and Action Mechanisms

Anti-diabetes and Anti-obesity Medicinal Plants and Phytochemicals

Bashar Saad • Hilal Zaid • Siba Shanak Sleman Kadan

Anti-diabetes and Anti- obesity Medicinal Plants and PhytochemicalsSafety, Efficacy, and Action Mechanisms

ISBN 978-3-319-54101-3 ISBN 978-3-319-54102-0 (eBook)DOI 10.1007/978-3-319-54102-0

Library of Congress Control Number: 2017939932

© Springer International Publishing AG 2017This 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.

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Prof. Bashar Saad, PhDAlQasemi Academic CollegeBaqa Algharbiya, IsraelArab American University- Jenin, Palestine

Siba Shanak, PhDArab American University- Jenin, Palestine

Hilal Zaid, PhDAlQasemi Academic CollegeBaqa Algharbiya, IsraelArab American University- Jenin, Palestine

Sleman KadanAlQasemi Academic CollegeBaqa Algharbiya, Israel

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Foreword

Diabetes and obesity are chronic diseases that have become major public health problems throughout the world because of their high prevalence, causal relationship with serious diseases, adverse effect on the quality of life, and considerable eco-nomic consequences. Our modern lifestyle that requires minimal daily physical activity and provides an abundance of pleasurable foods contributes to an adverse gene–environment interaction with harmful consequences. Because diabetes and obesity are closely linked with the development of serious complications, including cardiovascular disease and several malignancies, their impact from a public health perspective is enormous and continues to increase. As the population ages and becomes more sedentary, the morbidity and mortality associated with obesity and diabetes will continue to escalate. Thus, it is imperative to focus our research efforts on trying to understand the etiology of obesity and diabetes as well as the mecha-nisms underlying the development of the complications associated with these condi-tions. It is also critically important to focus our public health efforts on the prevention and our clinical efforts on the treatment of these disease states. The cornerstone of diabetes and obesity therapy is to alter lifestyle behaviors to consume less energy than expended in order to burn endogenous triglyceride stores for fuel, through phar-macotherapy and via bariatric surgery. The aforementioned strategies represent the current treatment options used to generate a negative energy balance and induce weight loss. Despite the great progress in Western medicine, herbal medicine has continued to be often utilized by people in most developed and developing nations. Furthermore, the popularity of herbal medicine preparations has increased world-wide in the past three decades, probably because of the sustainability of this medi-cine over the years. According to the World Health Organization (WHO), more than 220 million people worldwide were diabetic in 2010, and this number will be dou-bled in 2040. The prevalence of diabetes is the highest in the Middle East, where the number of diabetic subjects reached 15.2 million in 2000 and it will almost be tripled within 30 years (from 15.2 million in 2000 to about 42.6 million in 2030).

Anti-diabetes and Anti-obesity Medicinal Plants and Phytochemicals: Safety, Efficacy, and Action Mechanisms, compiled by Bashar Saad, Hilal Zaid, Sleman Kadan, and Siba Shanak, presents an integrated diabetes and obesity diet and

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herbal- based management approach. It is a fascinating exploration of the richness of the past knowledge, combined with ethnopharmacology of herbal medicine today, safety and pharmacology of medicinal plants, and clinical aspects. In this, it is quite unique, especially because of its coverage of research on the herbs; much of it is carried out in the author’s own labs. This book breaks new ground in opening up a forgotten resource for both drug discovery and new herbal-based medicines.

Prof. Badiaa Lyoussi, PhD. Laboratory Physiology-Pharmacology &

Environmental HealthUniversity of Fez, Fes, Morocco

Foreword

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Preface

Diabetes, obesity, and their related complications are reaching epidemic proportions all over the world in the twenty-first century. A strong relationship exists between diabetes and obesity, with adipose tissue playing an important role in diabetes. The currently observed increase in diabetes, especially in industrialized countries, is correlated with the increase in obesity. For example, in the United States alone, one third of the population is obese, and another third is overweight; more than ten million people have been diagnosed with diabetes mellitus, and another five million remain undiagnosed. Similar prevalence has been reported in other Western nations as well, but it is more prevalent in developing countries. For instance, obesity has reached epidemic proportions in the Arabic-speaking countries, especially those in higher-income, oil-producing countries. Changes in food consumption, socioeco-nomic and demographic factors, physical activity, and multiple pregnancies may be important factors that contribute to the increased prevalence of obesity engulfing the Arabic-speaking countries.

Because diabetes and obesity are closely linked with the development of serious complications, including cardiovascular disease and several malignancies, their impact from a public health perspective is enormous and continues to increase. As the population ages and becomes more sedentary, the morbidity and mortality associated with obesity and diabetes will continue to escalate. Thus, it is imperative to focus our research efforts on trying to understand the etiology of obesity and diabetes as well as the mechanisms underlying the development of the complica-tions associated with these conditions. It is also critically important to focus our public health efforts on the prevention as well as our clinical efforts on the treatment of these disease states.

Despite the great progress in synthetic chemistry, herb-derived compounds still build an important source of new drugs. Herbal-based therapies are still utilized as the main form of drugs by about 80% of the world’s population, and about one quarter of the currently used modern drugs are of herbal origin, containing at least one herb-derived active compound or chemically modified herbal phytochemicals to produce a pharmaceutically active drug.

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Synthetic drugs dominated because of rapid developments in the pharmaceutical industry, though herbal medicine has never ceased. Even today, at least 25% of sold drugs are plant derived. In addition, about 75% of plants that provide active ingredi-ents for prescription drugs came to the attention of researchers because of their use in traditional medicine. Additionally, among the 120 active compounds currently isolated from the higher plants are widely used in modern medicine today; 80% show a positive correlation between their modern therapeutic use and the traditional use of the plants from which they are derived.

Anti-diabetes and Anti-obesity Medicinal Plants and Phytochemicals: Safety, Efficacy, and Action Mechanisms furthers these goals by presenting a comprehensive review of both the research and clinical aspects of obesity and diabetes to scientists and practicing clinicians alike.

Part I (Chaps. 1 and 2) is a review of obesity, diabetes, and medicinal plants including possible action mechanisms. Part II (Chaps. 3, 4, and 5) focuses on medicinal plants and their potential role in the management of obesity and related diseases, reviewing known mechanisms and interactions. Part III (Chaps. 5 and 6) focuses on medicinal plants and phytochemicals and their potential role in the man-agement of diabetes and related complications. Finally, Part IV (Chap. 8) presents state-of-the-art approaches using phytochemicals and polyherbal formulations to prevent/treat obesity and diabetes.

Acknowledgments

In the course of writing this book, we have accumulated many debts of gratitude. We wish to thank first those who read the entire manuscript with great care and made numerous suggestions, namely, Mrs. Zahya Ganayim, Mr. Basheer Abo Farkh, and Dr. Abdalsalam Kmail. We were fortunate in being able to include in this book a number of attractive paintings of Arab and Muslim scholars, and we wish to thank Jamell Anbtawi for permitting their reproduction in this volume.

Prof. Bashar Saad, PhD President of Al-Qasemi Academic College Baga Algharbiya, Israel

Preface

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Contents

Part I Introduction to Diabetes, Obesity and Medicinal Plants

1 Introduction to Diabetes and Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . 31.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31.2 Diabetes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 51.3 Exercise as a Physiological Mechanism Countering

Insulin Resistance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71.4 Distributed Control of Blood Glucose . . . . . . . . . . . . . . . . . . . . . . . 81.5 Signaling Mechanisms Regulating Glucose Uptake . . . . . . . . . . . . 81.6 Antidiabetic Plant-Derived Drugs . . . . . . . . . . . . . . . . . . . . . . . . . . . 91.7 Obesity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 101.8 Diabesity: The Correlation of Obesity and Diabetes . . . . . . . . . . . . 16References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17

2 Introduction to Medicinal Plant Safety and Efficacy . . . . . . . . . . . . . . 212.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 212.2 Historical Aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 232.3 Revival of Interest in Phytomedicine . . . . . . . . . . . . . . . . . . . . . . . . 272.4 The Status of Herbal Medicine in the Mediterranean . . . . . . . . . . . 282.5 Safety of Herbal Medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 292.6 Safety Monitoring and Regulatory Status

of Herbal Medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 312.7 Herbal Active Compounds . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 332.8 Structure and Classification Secondary Metabolites . . . . . . . . . . . . 342.9 Synergistic Actions of Phytomedicines . . . . . . . . . . . . . . . . . . . . . . 382.10 Preparation Techniques and Administration Form

of Herbal Medicines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 392.11 Therapeutic Properties of Herbal-Based Active Compounds . . . . . . 412.12 Examples of Herbal Compounds and Their Pharmacological

Properties . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 49References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 53

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Part II Safety, Efficacy, and Action Mechanisms of Anti-obesity Medicinal Plants

3 Anti-obesity Medicinal Plants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 3.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 59 3.2 Appetite Regulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 60 3.3 Enzymes Inhibition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 63 3.4 Inhibitors of Adipogenesis and Adipogenic Factors . . . . . . . . . . . . . 68 3.5 Stimulators of Thermogenesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 3.6 Increase Satiety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71 3.7 Commonly Used Anti-obesity Medicinal Plants . . . . . . . . . . . . . . . . 73References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 89

4 Prevention and Treatment of Obesity-Related Diseases by Diet and Medicinal Plants . . . . . . . . . . . . . . . . . . . . . . . . . . 95 4.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 95 4.2 Strategy to Prevent Inflammatory Responses in Obese Adipose

Tissues by Medicinal Plants and Phytochemicals . . . . . . . . . . . . . . . 974.2.1 Medicinal Plant Diets That Act Through 

PPARγ- Dependent Pathways . . . . . . . . . . . . . . . . . . . . . . . . . 1014.2.2 Medicinal Plant Diets That Act Through

PPARγ- Independent Pathways . . . . . . . . . . . . . . . . . . . . . . . . 105 4.3 Medicinal Plants and Phytochemical-Based Strategies

to Prevent Obesity-Related Hypertension . . . . . . . . . . . . . . . . . . . . . 114 4.4 The Mediterranean Diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 118References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 124

5 Herbal-Derived Anti-obesity Compounds and Their Action Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 5.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 129 5.2 Phytochemical Compounds Used for the Treatment of Obesity . . . . 132 5.3 Major Basic Anti-obesity Mechanisms . . . . . . . . . . . . . . . . . . . . . . . 133 5.4 Targeting Adipose Tissue . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 136References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 141

Part III Safety, Efficacy, and Action Mechanisms of Anti-diabetes Medicinal Plants

6 Antidiabetic Medicinal Plants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 6.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 147 6.2 Herbal-Based Diabetes Mellitus Remedies . . . . . . . . . . . . . . . . . . . . 148 6.3 Plant Mixtures Used in The Treatment of Diabetes . . . . . . . . . . . . . . 164 6.4 Antidiabetic Phytochemicals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 165References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 167

Contents

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7 Antidiabetic Medicinal Plants and Their Mechanisms of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 7.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 175 7.2 Strategies for the Glycemic Control . . . . . . . . . . . . . . . . . . . . . . . . . . 179 7.3 Antidiabetic Medicinal Plants and Their Mechanisms

of Action . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1827.3.1 Increased Pancreatic Secretion of Insulin: Augmentation

of the Pancreas and Increased Insulin Sensitivity. . . . . . . . . . 1827.3.2 Inhibition of Glucose Production in the Liver . . . . . . . . . . . . 1877.3.3 Enhanced Glucose Uptake in the Muscle

and Adipose Tissues . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1907.3.4 Inhibition of Glucose Absorption . . . . . . . . . . . . . . . . . . . . . . 1957.3.5 Inhibition of Diabetes-Related Complications . . . . . . . . . . . . 199

References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 206

Part IV Polyherbal Formulations Used in the Prevention/Treatment of Obesity and Diabetes

8 Hypoglycemic and Anti-obesity Polyherbal Mixtures . . . . . . . . . . . . . . 217 8.1 Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 217 8.2 The Concept of Synergistic Effects in the Main

Traditional Medical Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 220 8.3 Synergistic Actions of Phytochemicals and Their

Action Mechanisms . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 226 8.4 Clinical and Experimental Studies on Hypoglycemic

and Anti-obesity Effects of Herbal Formulations . . . . . . . . . . . . . . . . 228 8.5 Commonly Used Herbs in Polyherbal Mixtures . . . . . . . . . . . . . . . . 238 8.6 Food Synergy: Diabetes Preventive Components

in the Mediterranean Diet . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 242 8.7 Honey: A Natural Polyherbal Formula . . . . . . . . . . . . . . . . . . . . . . . . 245References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 247

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 253

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Abbreviations

ACP Acid phosphataseALT Alanine transaminaseADH Alcohol dehydrogenasesALP Alkaline phosphataseAMPK AMP-activated protein kinaseACE Angiotensin-converting enzymesAA Arachidonic acidAST Aspartate transaminaseBMI Body mass indexCAT CatalaseTC CholesterolJNK C-Jun amino-terminal kinaseCRP C-reactive proteinCOX CyclooxygenaseDM Diabetes mellitusPGE2 EicosanoidEGCG Epigallocatechin gallateERKs Extracellular signal-regulated kinasesFBG Fasting blood glucoseFAS Fatty acid synthaseGLUT4 Glucose transporter-4G6PD Glucose-6-phosphate dehydrogenaseGSH GlutathioneGPX Glutathione peroxidaseGSK3 Glycogen synthase kinase-3HbA1c Glycosylated hemoglobin A1cHDL High-density lipoproteiniNOs Inducible nitric oxide synthasePKB Insulin-dependent protein kinase BIGF Insulin-like growth factorIL Interleukin

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LDH Lactate dehydrogenaseLTB4 Leukotriene B4LPS LipopolysaccharideLO LipoxygenaseLKB1 Liver kinase B1LDL Low-density lipoproteinsLBP LPS-binding proteinLOX Lysyl oxidaseMDA MalondialdehydeMCH Melanin-concentrating hormoneMEOS Microsomal ethanol-oxidizing systemMCP-1 Monocyte chemoattractant protein-1NF-kb Necrosis factor kappa betaNO Nitric oxideNSAIDs Nonsteroidal anti-inflammatory drugsPON1 Paraoxonase 1PTH Parathyroid hormonePGC Peroxisome proliferator-activated receptor-γ coactivatorPI3K Phosphatidylinositol 3′-kinasePEP PhosphoenolpyruvatePAI-1 Plasminogen activator inhibitor-1PPARγ Proliferator-activated receptor gammaPGE2 Prostaglandin E2PKB Protein kinase BROS Reactive oxygen speciesSACS S-allyl cysteine sulfoxideSGLT-1 Sodium-dependent glucose transporter-1SOD Superoxide dismutaseTXB2 Thromboxane B2

TLRs Toll-like receptorsTGF-β Transforming growth factor-βTG TriglycerideTNF-α Tumor necrosis factor-αVEGF Vascular endothelial growth factorVLDL Very-low-density lipoproteinWHO World Health OrganizationXIAP X-linked inhibitor of apoptosis protein

Abbreviations

Part IIntroduction to Diabetes, Obesity

and Medicinal Plants

3© Springer International Publishing AG 2017 B. Saad et al., Anti-diabetes and Anti-obesity Medicinal Plants and Phytochemicals, DOI 10.1007/978-3-319-54102-0_1

Chapter 1Introduction to Diabetes and Obesity

1.1 Introduction

Obesity, diabetes, and their associated complications are reaching epidemic proportions worldwide in the twenty-first century. Changes in food consumption, socioeco-nomic and demographic factors, and physical activity may be important factors that contribute to the increased prevalence of these diseases. Because diabetes and obesity are closely linked with the development of serious chronic diseases, mainly cardiovascular disease and several malignancies, their impact from a public health perspective is enormous and continues to increase. As the population ages and becomes more sedentary, the morbidity and mortality associated with obesity and diabetes will continue to escalate [1, 2].

Historical background: Diabetes was first documented by the Egyptians and is char-acterized by weight loss and polyuria. However, it was the Greek physician Aretaeus who introduced the term diabetes mellitus. In Greek, diabetes means “to pass through” and mellitus is the Latin word for honey (referring to sweetness). Later on, diabetes was recognized by medieval Greco-Arab physicians, and its main symptoms were known by the increased thirst, frequent urination, and tiredness. Greco-Arab physi-cians and practitioners had used a series of medicinal plants for treating these com-bined symptoms (named Zarab). In addition, several instructions for consumption of specific food and mild exercise were recommended. For example, Avicenna (980–1037 A.D.), a renowned physician of the Golden Ages of the Arab-Islamic civilization, described diabetes in his book The Canon of Medicine and mentioned gangrene and collapse of sexual function as a complication of this disease.

Obesity as a chronic disease with well-defined pathologic consequences is less than a century old. The chronic food shortage and malnutrition throughout most of history had led to connotations that being fat was good and that corpulence and increased flesh were desirable as reflected in the arts, literature, and medical opinion of the times. While overweight was desired, obesity has been recognized since ancient

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times as a disease that needs to be treated. For example, Greco-Arab physicians and practitioners used a series of treatments, such as medicinal plants in addition to several instructions for consumption of specific foods as well as mild exercise. Rhazes (841–926 A.D.) critically assessed, in his An Encyclopedia of Medicine, all the available knowledge on obesity at that time and discussed the opinions of schol-ars who preceded him, such as Hippocrates, Galen, Oribasius, and Paul of Aegina. He highlighted the points on which he had a different view, particularly in relation to the management of excessive overweight (obesity). Galen, for example, believed that prolonged thinking and mental activity would slim the obese, but Rhazes stated prolonged thinking that leads to sadness slims; otherwise prolonged thinking does not slim. Rhazes documented his discussion using clinical case reports of the patients with excessive obesity he successfully treated, describing in detail the treat-ments he used, including diet, drugs, exercises, massage, hydrotherapy, and lifestyle changes. Later on, Avicenna (980–1037) devoted a section of the third volume of his The Canon in Medicine to the “drawbacks of excessive overweight.” Ibn el-Nefis (1207–1288 A.D.) in his The Concise Book of Medicine linked the excessive obesity to cerebrovascular accidents as well as to respiratory and endocrine disorders. He stated: Excessive obesity is a constraint on the human being limiting his freedom of actions and constricting his pneuma (vitality) which may vanish and may also become disordered as air may not be able to reach it. They [excessively obese persons] run the risk of a fatal vessel rupture causing sudden death or bleeding into a body cavity. But bleeding into the brain or the heart will lead to sudden death. And frequently they suffer from dyspnea or palpitation [3].

Current status: The current worldwide epidemic of overweight and obesity, now recognized as a public health crisis, is barely a few decades old. Only after the tech-nological advances of the eighteenth century did a gradual increase in food supply become available. The initial effect of these advances in improved public health and amount, quality, and a variety of food was the increased longevity and body size. Notwithstanding these early favorable outcomes of technological advances, their incremental effect since the Second World War has been an overabundance of easily accessible food, coupled with reduced physical activity that accounts for the recent increased prevalence of obesity.

Concomitant environmental factors, such as poor dietary habits, sedentary lifestyle, socioeconomic influences, and, less frequently, genetic disorders that affect hormone secretion and metabolism, result in weight gain. The World Health Organization (WHO) projects that by 2015, 2.3 billion adults will be overweight, body mass index (BMI) >25 (kg/m2), and more than 700 million will be obese, BMI >30 (kg/m2). Consequently, obesity-related comorbidities including type 2 diabetes (T2D), cardio-vascular disease, and nonalcoholic fatty liver disease (NAFLD) will continue to esca-late. Substantial evidence indicates that obesity is linked to a state of chronic low-grade inflammation. Initially, the pro-inflammatory cytokine tumor necrosis factor alpha (TNF-α) was demonstrated to be expressed in the adipose tissues of obese mice and linked to insulin resistance. Significant advances in understanding the highly complex role of immuno-metabolism in health have since been accomplished.

1 Introduction to Diabetes and Obesity

5

Consequently obesity is linked to pro-inflammatory cytokine secretion, immune cell infiltration, and disrupted function of tissues involved in glucose homeostasis. Dysfunctional lipid metabolism accompanies obesity and can impair insulin signal-ing. Additionally, circulating free fatty acids have a negative effect on insulin target tissues, through the activation of inflammatory pathways, via cell surface pattern recog-nition receptors (PRRs). Furthermore, accumulation of lipid derivatives, such as dia-cylglycerol and ceramides, can negatively regulate insulin action [4–8]. It is important to focus our ongoing and future research efforts on trying to understand the etiology of obesity and diabetes as well as the mechanisms underlying the devel-opment of the complications associated with these diseases. It is also critically important to focus our public health efforts on the prevention and our clinical efforts on the treatment of these disease states. Here, in this introductory chapter, obesity, diabetes, their interactions, involved cell and tissues, and signal transduction pathways will be highlighted.

1.2 Diabetes

Diabetes, also known as diabetes mellitus (DM), is a chronic disorder that can affect carbohydrate, protein, and fat metabolism. It is associated with hyperglycemia over a prolonged period. Diabetes symptoms include increased thirst and hunger as well as frequent urination. Untreated diabetes can cause ultimately several acute compli-cations including, but not limited to, ketoacidosis, stroke, heart disorders, kidney failure, eye damage, foot ulcer, impotence, and death. The prevalence of diabetes is rising among adults over 18 years of age. In 1980, only 4.7% of over 18 adults were diabetic, while in 2014 the percentage raised to 8.5% with equal rates in both women and men. Diabetes at least doubles the person’s risk of early death. From 2012 to 2015, approximately 1.5–5.0 million deaths each year resulted from diabe-tes (WHO). The global economic cost of diabetes in 2014 was estimated to be 612 billion US$ [9].

Diabetes is due to either impaired pancreatic insulin production or improbable insulin target tissue (liver, muscle, and fat) response to the circulating insulin. Three main types of diabetes mellitus are known: gestational diabetes, type 1 DM, and type 2 DM.

Gestational diabetes: The World Health Organization (WHO) classifies hyperglyce-mia first identified in pregnancy as gestational diabetes mellitus (GDM). It is defined by the American Diabetes Association as diabetes diagnosed in the second or third trimester of pregnancy that is not clearly overt diabetes. The prevalence of GDM is increasing worldwide and is the most common metabolic disorder during pregnancy. It occurs in about 2–10% of all pregnancies and may disappear after delivery. GDM resembles type 2 DM in several respects, involving a combination of relatively inad-equate insulin responsiveness and secretion. After delivery, approximately 5–10% of women with GDM are found to have type 2 DM. Gestational diabetes can be fully

1.2 Diabetes

6

treatable, if careful medical supervision throughout the pregnancy was taken. GDM management involves dietary changes and blood glucose monitoring, and if needed, insulin can be injected [11].

Though it may be transient, untreated GDM can damage the health of the mother and fetus. GDM increases the risks for developing diabetes and obesity both for the women and the child. Women with GDM are at a high risk of developing type 2 DM. Untreated GDM is associated with a detrimental intrauterine environment, leading to fetal complications, and an increased risk for the child of developing metabolic disorders and obesity [10]. In addition, untreated gestational diabetes can cause central nervous system and congenital heart and abnormalities as well as high birth weight and skeletal muscle malformation. Moreover, elevated insulin levels in the fetus’s blood might inhibit the fetal surfactant production and thus lead to respiratory distress syndrome. Severe cases can ultimately lead to perinatal death [11].

Diabetes type 2: This type of diabetes is usually diagnosed in children and young adults, and it was thus traditionally termed “juvenile diabetes.” It is also known as “insulin-dependent diabetes mellitus” (IDDM) because it results from the failure of the pancreas to produce enough insulin. Insulin is a hormone secreted from pancre-atic beta cells and triggers some of the body organs (muscle, liver, and fat) to get more glucose from the bloodstream when glucose is elevated (i.e., after a carbohydrate- rich meal). Regrettably, type I DM pancreas does not produce enough insulin. With the help of insulin therapy and other treatments, even young children can learn to manage their conditions and lives. Only 5–10% of diabetic patients have this form of the disease. Yet, in most parts of the world, type 1 DM is the most prevalent chronic disease in persons under 18 years of age [12].

Type 1 DM is partly inherited, with multiple genes, including but not limited to the HLA genotypes. As such, the pathogenesis of this disease is complex and mul-tifactorial. Moreover, the continued increase in the incidence of type 1 DM reflects the modern lifestyle [13]. For instance, imbalanced diet or viral infection can initi-ate this disease. Among dietary factors, vitamin D3 deficiency and a protein present in gluten, namely, gliadin, are thought to be involved in the development of type 1 DM [14]. Several viruses have been implicated in this syndrome, but to date there is no stringent evidence to support this hypothesis in humans [15]. Most probably, the presence of distinct modulating and initiating immune response factors leads to the development of the disease. It is associated with the autoimmune process of the destruction of pancreatic beta cells by autoantibodies leading to insulin deficiency and ultimately organ damage [13]. This book will not deal with type 1 DM in depth. Readers who are interested to learn more about this type of diabetes are directed to excellent reviews in the literature [16–18].

Type 2 diabetes is a complex metabolic disease that results in the development of impaired insulin signaling and β-cell dysfunction, insulin resistance, abnormal glucose and lipid metabolism, subclinical inflammation, and increased oxidative stress. These metabolic complications cause long-term neuropathy, retinopathy,

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nephropathy, micro- and macrovascular complications, and a consequent decrease in quality of life and an increase in the rate of mortality. This type of diabetes occurs when the cells fail to respond to insulin properly, a condition termed insulin resis-tance. As the disease progresses, the circulating blood glucose becomes higher, and the pancreas beta cells secrete more insulin leading to hyperglycemia and hyperin-sulinemia. Ultimately, the pancreas starts to be damaged, and the lack of insulin may develop. In this case, diabetic patients must be treated with insulin. Hence, the old term “noninsulin-dependent diabetes mellitus” (NIDDM) is not valid anymore. Moreover, the term “adult-onset diabetes” is not accurate nowadays since this type of diabetes occurs in young people because of the modern lifestyle and the unhealthy food, excessive body weight, and lack of exercise [8, 19].

Diabetes is a chronic metabolic disease that involves various organs in the body. Ancient physicians and practitioners used a series of medicinal plants for treating diabetes symptoms in addition to several instructions for the consumption of specific food as well as mild exercise. The prevention and treatment of type 2 DM can be achieved via maintaining a normal body weight and a healthy diet, through avoiding tobacco, and via regular physical exercise. Weight loss surgery in obese subjects can be effective in some cases. If the previous treatments are not operative, medications with or without insulin must be applied. In recent decades, a number of epidemio-logical investigations have shown that diet rich in foods with high content of phyto-chemicals and high total antioxidant capacity may be related to lower risk of diabetes and predisposing factors [8, 19].

1.3 Exercise as a Physiological Mechanism Countering Insulin Resistance

Current pharmacological treatments of type 2 DM promote pancreatic insulin release (sulfonylureas), reduce hepatic glucose output (biguanides), and prevent fatty acid release through the emergence of highly insulin-sensitive adipocytes. Although each of these strategies indirectly improves insulin response of glucose uptake into the skeletal muscles, to date no single therapy has targeted this phenomenon directly. Strikingly, a physiological mechanism exists to promote glucose uptake into muscle independently of insulin requirements, i.e., muscle contraction/exer-cise. Intensive and sustained exercise programs along with lifestyle modifications improve metabolic control in diabetic patients [20]. Regrettably, most of the dia-betic people are unable to engage in the required exercise programs that would significantly reduce insulin resistance. As a result, in spite of lifestyle modifications, many patients remain diabetic. Moreover, insulin resistance and its progression to type 2 DM have genetic susceptibilities along the metabolic pathways participating in the regulation of muscle glucose uptake, hepatic glucose output, adipocyte fatty acid release, and pancreatic insulin secretion. Hence, behavioral modification alone is unlikely to reduce markedly the prevalence of the disease.

1.3 Exercise as a Physiological Mechanism Countering Insulin Resistance

8

1.4 Distributed Control of Blood Glucose

Glucose is utilized by all the cells in the body. It is actually the main fuel source for them. Several organs are involved directly or indirectly in balancing blood glucose, especially the brain, pancreas, liver, fat cells, and muscle as well as the digestive sys-tem. Glucagon and insulin that are secreted from the pancreas in appropriate doses prevent hypoglycemia. In case of inadequate pancreas response to the circulating blood glucose concentrations, other controllers (e.g., catecholamines, cortisol, growth hormone, and glucose autoregulation) are in place to prevent hyper-/hypoglycemia. The control at the level of the fat cells, liver, and muscle is defined as a distributed controller between glucose delivery to these organs, membrane transport into the cells, and intracellular glucose phosphorylation. The liver plays a dual role in balanc-ing blood glucose: utilization and storage of glucose if at high levels and the secretion to the bloodstream when blood glucose levels are low [19, 21].

During a meal, glucose is disposed in the skeletal muscle and to a lesser extent in fat and liver tissues. Uptake of glucose into the muscles occurs mainly through the insulin-sensitive glucose transporter, glucose transporter-4 (GLUT4). GLUT4 is largely sequestered inside the cell away from the plasma membrane. Insulin, released to the circulation during a meal, binds to the muscle surface, sending signals that ultimately increase GLUT4 abundance at the membrane [19]. Nowadays, diabetes can be treated through medicinal plants, synthetic drugs, or insulin (Fig.  1.1). However, the health challenges of diabetic people can be minimized by exercise, even if it is just going for a brisk walk every day. Exercise activates protein kinase (AMPK) in the muscle, a mediator for GLUT4 translocation to the plasma mem-brane (like insulin but in a distinct signaling pathway) [22]. This is why exercise is recommended as a part of the normal treatment program for patients with type 2 diabetes. Skeletal muscle is the site where glucose uptake is quantitatively the most important. It is the bulk of insulin-sensitive tissues and the primary site of glucose uptake during exercise. The regulation of muscle glucose uptake has been a subject of intensive research at outstanding laboratories worldwide [19, 23–26].

1.5 Signaling Mechanisms Regulating Glucose Uptake

Insulin is secreted from the pancreases in response to elevated glucose levels in the circulation. It binds to the insulin receptors (IRs) in the muscle, adipose, and liver tissues. This binding impinges on GLUT4 redistribution by increasing the GLUT4 levels at the plasma membrane (PM), thereby accelerating glucose disposal from the blood. The signal transduction is triggered upon insulin binding to IR, leading to tyrosine phosphorylation of its substrates (IRS1–4). IRS1 is the most known to be involved in GLUT4 recruitment to the PM.  Activated IRS1 leads to tyrosine phosphorylation of insulin receptor substrate (IRS) proteins and their recruitment of PI 3-kinase, which catalyzes the conversion of phosphatidylinositol (4,5)P2 to phosphatidylinositol (3,4,5)P3 (denoted PIP3). This leads to the activation of Akt

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and its substrate AS160 and eventually to the translocation of GLUT4 to the PM. GLUT4 is stored in storage vesicles, but upon insulin stimulation, it is translocated to the plasma membrane, inducing glucose uptake [19, 23–26]. Skeletal muscle is the largest site for glucose disposal in the mammalian body, and GLUT4 is the major glucose carrier in muscle mediating most of the glucose influx [19].

Distributed control of blood glucose also extends downstream translocation of GLUT4 and the insulin signaling pathway leading to it. Zaid and colleagues suggested that hexokinase-II and GAPDH (glycolytic enzymes) interact directly with the GLUT4 and regulate its activity. This provides means for linking energy metabolism/storage to glucose flux [27]. The paradigms stated here demonstrate just a part of the complexity of balancing blood glucose. Several other players take pace, including, but not limited to, free fatty acids, insulin and related hormones, insulin receptors, and downstream pathways [19, 28].

1.6 Antidiabetic Plant-Derived Drugs

Plants produce a remarkably diverse array of thousands of secondary metabolites. Unlike primary metabolites, secondary metabolites are generally nonessential for the basic metabolic processes of the plant. Frequently, these molecules play roles in the defense of plants against changing environmental conations, stressing conditions, or pathological infections.

Physical activity Food intake

Drug (Phytochemicals)

Insulin

Circulating Glucose

Fig. 1.1 Blood glucose balance. The relationship between food taken into the body (through food and drink) and energy exposure, insulin, and drug in balancing blood glucose

1.6 Antidiabetic Plant-Derived Drugs

10

Numerous scientific reports have identified the active compounds that are responsible for the therapeutic effect of most antidiabetic plants including the Greco-Arab herbs [29]. These include polysaccharides, flavonoids [30], terpenoids, tannins, and steroids [31]. The main antidiabetic drugs that were derived from plants are metformin and resveratrol (for more details, please refer to Chaps. 6, 7, and 8).

Metformin, the most frequently used antidiabetic drug worldwide, improves peripheral glucose uptake and reduces hepatic glucose in patients with diabetes mellitus. Metformin was derived from the flowering plant, Galega officinalis (goat’s rue or French lilac), which was used to treat polyuria in medieval times [32]. Metformin activates AMP-activated protein kinase (AMPK). AMPK is a regulator of cellular and systemic energy homeostasis. The activation of this enzyme inhibits glucose output from hepatocytes and induces glucose uptake in myocytes. AMPK is activated during exercise and thus leads to lowing blood glucose [33].

Resveratrol (3,5,4′-trihydroxystilbene) is a phytoalexin produced in the grapes peel, peanut, and some other plant species. It acts as an antifungal agent in plants. The addition of resveratrol to the diet of a high-fat-fed mice increased insulin sensi-tivity and the number of mitochondria in the liver, prevented development of fatty liver, and prolonged the life span [34]. Resveratrol prevented diet-induced obesity, reduced insulin resistance, and improved mitochondrial function in muscle tissue in young mice [35]. Resveratrol also increases GLUT4 translocation to the plasma membrane in hepatic, fat, and muscle cells, thus increasing glucose uptake that lowers blood glucose.

1.7 Obesity

Obesity is a main risk factor for diabetes and other chronic diseases. Obesity perva-siveness is consensually increasing, and it became a global epidemic and emerging public health threat. Men, women, and children are affected. The prevalence of obesity and overweight in developing and developed countries is increasing and placing a huge burden not only on health but also in economic resources. In fact, the incidence of obesity has more than doubled since 1980 [36]. Obesity rates increased dramatically during the 20 years between 1980 and 2000; adult rates were doubled and the rates of children more than tripled during that time. Despite the increased recognition of the epidemic and the attempts to reduce obesity, change has been slow and obesity rates remained very high. Over 8% of young children (ages 2–5 years) were obese, and about 17% of children (ages 2–19 years) and more than 30% of adults were found to be obese in national surveys [37]. According to the reports by the World Health Organization (WHO), in 1995, adult mortality that was attributable to overnutrition was estimated to be about one million deaths [38]. The WHO estimated that 1.9 billion adult people were overweight, of whom 600 million were obese in 2014.

The definition and measurement of obesity: Obesity is defined as a condition of excessive or abnormal fat accumulation in adipose tissues, thus leading to health

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impairment. However, since the direct measurement of body fat is challenging, the body mass index (BMI) is commonly used as an indicator of obesity and overweight in adults. BMI is calculated through dividing body weight in kilograms by height in meters squared (BMI,  body mass in kg/height in m2). The WHO developed a graded classification system to identify overweight and obesity. BMI ranges are depicted in Table 1.1. BMI of 30 kg/m2 or above indicates obesity. There is a high likelihood that individuals with a BMI of at least 30 will have excessive body fat. Nonetheless, the health risks associated with obesity and overweight rise progressively with a BMI of at least 25 [39].

Food intake and obesity: The meal type, content, size, and frequency determine the body’s total daily energy intake. On the other hand, body activity and rate of metabo-lism determine the energy consumption. Once food intake exceeds the energy con-sumption, body weight rises. Complex interactions involving genetic, humoral cues, social, learned, environmental, and circadian factors determine the perception of hunger and the decision to initiate a meal and ultimately obesity (Fig. 1.2) [40].

Table 1.1 Obesity and overweight classification according to WHO

Classification BMI (kg/m2) Associated health risks

Underweight Less than 18.5 Low (other clinical problems might occur)Normal 18.5–24.9 AverageOverweightPre-obeseObese class IObese class IIObese class III

25 or higher25–29.930–34.935–39.940 or higher

IncreasedModerately increasedSeverely increasedVery severely increased

.

Diet

Lung diseases

Hyper-tension Diabetes Metabolic

syndromeCardiac

alterations Cancer Dis-lipidemia

Sedentary lifestyle

Leptin and ghrelin Genetics Gut flora Social

factors

Obesity BMI > 28

Fig. 1.2 Obesity causes and complications. Obesity is a global health problem affecting all age groups, leading to many complications such as type 2 diabetes, systemic hypertension, cardiovascu-lar diseases, dyslipidemia, atherosclerosis, and stroke. It arises from metabolic changes at cellular level result in an imbalance between energy intake and energy expenditure, which in turn results in increased fat accumulation in adipose tissue

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As such, the hunger and eating process is individual and quite variable. Although several endogenous peptides have been identified with the ability to stimulate feeding, a unifying, physiological explanation for the experience of hunger and the decision to commence eating is still awaited [41].

Among others, the hormone leptin is a key player in the homeostasis of body energy. Leptin, secreted from adipose tissues and it circulates in the bloodstream, sends signals to the brain of changes in both energy balance and the amount of fuel stored as fat. Leptin acts as a negative feedback regulator (in the brain) of adiposity. It leads to constraining fat mass by supporting energy expenditure and limiting energy intake. As such, decreased leptin signaling leads to increased food intake, positive energy balance, as well as fat accumulation. Although plasma leptin levels reliably reflect body fat mass, leptin levels in the plasma can also change in response to short-term alterations of energy balance [41].

Leptin signaling: As stated above, leptin is an anti-obesity hormone (Fig. 1.3) secreted from adipocytes and which circulates in the bloodstream. There are several splice isoforms of the leptin receptor, e.g., Ob-Ra, Ob-Rb, Ob-Rc, Ob-Rd, Ob-Re, and Ob-Rf. These receptors mainly activate the Janus kinase 2 (JAK2) and signal transducer and activator of transcription 3 (STAT3) pathway (JAK2/STAT3). The Ob-Rb isoform is mainly expressed in the hypothalamus and the brain stem. A mutation in the Ob-Rb receptor in db/db mice led to severe obesity, suggesting that the Ob-Rb receptor is considered to play an important role in the anti-obesity effects of leptin [41].

Leptin

Pancreas

Liver

Pancreas

Muscle Adipose

Energy expenditure

Food intake

Insulin secretionInsulin

action

Insulin action

?

?

Fig. 1.3 Leptin signaling, insulin action, and energy homeostasis

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Gut microbial and obesity: The adult human body contains trillions of microorganisms. Our first time exposure to microbes takes place during birth. Eating and breathing are the main sources of microorganisms. While shifting from breast feeding to solid food, the composition of gut microbiota also changes [42]. Later on, gut microbiota remains relatively unchanged until old age where it changes again. Incredibly, adult human body has more than ten times the number of microbial cells (mainly bacteria, nevertheless, viruses, fungi, and other microorganisms) than the body cells. Although individuals have unique microbiota composition, gut microbiota is mainly members of four phyla: Actinobacteria, Bacteroidetes, Firmicutes, and Proteobacteria. The highest density of bacteria is found in the large intestine (about 1011 bacteria per gram of intestinal content) [43].

The effect of gut microbiota in the development of obesity and diabetes is rela-tively a new field studied in the last two decades and is intensively under research nowadays [44, 45]. Different types of gut microbiota are involved in distinct body physiological processes like autoimmunity, blood circulation, and energy homeo-stasis. Obese humans and mice have different gut microbiota composition com-pared to lean. A decrease in the Bacteroidetes phylum as well as an increase in bacteria from the Firmicutes phylum that is believed to be associated with increased energy absorption from food and increased low-grade inflammation was reported in obese subjects [46–48]. Another example for the role of microbiota in obesity was witnessed with patients undergoing Roux-en-Y gastric bypass. Following Roux- en- Y gastric bypass, patients observed dramatic metabolic improvement that could be neither explained by weight loss nor the caloric restriction alone. Indeed, fecal transplantation from Roux-en-Y gastric bypass-treated mice into germ-free mice led to weight loss and decreased fat mass in mice [49].

Gut microbiota affects energy metabolism through increasing the production of short-chain fatty acids. These fatty acids are produced via the anaerobic breakdown of dietary colonic fiber, fermentation. Short-chain fatty acids are actually bacterial waste products produced by the bacteria to balance the redox state in the gut [43]. Acetate, butyrate, and propionate are the most abundant short-chain fatty acids in this category. Butyrate is produced mainly by the Firmicutes phylum. Acetate and propionate are mostly produced by Bacteroidetes phylum. Acetate, butyrate, and propionate are thought to exert beneficial effects on body weight. They were shown to enhance glucose homeostasis as well as insulin sensitivity in mice possibly through increasing energy expenditure and mitochondrial function [50]. Short- chain fatty acids affect also signaling molecules and transduction pathways, e.g., AMP-activated protein kinase (AMPK) in the muscle and adipose tissues. AMPK transduction pathway enhances the metabolism of glucose, cholesterol, and lipid, mainly through activating peroxisome proliferator-activated receptor gamma (PPARγ), peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), and liver X receptors (LXR) [51]. Moreover, short-chain fatty acids have been also shown to activate glucagon-like peptide-1 (GLP-1) through G-protein- coupled receptor 43 (GPR43, also known as free fatty acid receptor 2 (FFAR2)). Knocked-down GPR43 receptor mice were obese; on the other hand, GPR43 overexpression in adipose tissue exhibited leanness under normal conditions [52].

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These phenotypes might be mediated by gut microbiota producing short-chain fatty acids, as these mice strains did not show the same phenotypes in mice when treated with antibiotics or grown under germ-free conditions. Hence, it is believed that the gut microbiota suppresses insulin-mediated fat accumulation via the short-chain fatty acid receptor GPR43 [53]. Gut microbiota also plays a role in the regulation of bile acids and cholesterol metabolism in mammals. Bile acids act as emulsifying agents in the intestine; as such, they are essential players in the degradation and digestion of triacylglycerol and other complex lipids. Gut microbiota enhances the transcription factors that link it to nutritional-induced inflammation, lipid absorp-tion, and de novo lipogenesis [54].

In conclusion, gut microbiota is a key player affecting essential metabolic pathways like energy homeostasis, metabolism, and inflammation. High food consumption as well as unbalanced gut microbiota contributes more to metabolic diseases.

Diet effects on gut microbial composition: Diet and lifestyle (in addition to other factors like genetics and physiological state) determine body weight and obesity that could promote several other metabolic disorders if not appropriately managed (Fig. 1.4). It is well documented nowadays that gut microbial is an essential player in digestion and metabolism of food as well as in harvesting energy. Gut microbial of obese individuals exhibits aberrant lipids and carbohydrate metabolism [55]. Carbohydrates are essential sources of dietary energy. Nonetheless, humans are not capable of digesting all polysaccharide molecules found in our diet (i.e., plant- derived fibers such as cellulose, inulin, and xylans). These polysaccharides can be degraded by gut microbial and converted into other metabolites such as short-chain fatty acids. These fatty acids enter the blood circulation and affect glucose, lipid, and cholesterol metabolism in different body tissues [43].

Diet type and composit ion

Diseases

Ant ibiot ics

Genet ic background

Gut microbiota composit ion

Fig. 1.4 Gut microbiota effectors

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The human genetics, diet, and different environmental factors influence the gut microbial types. As such, the gut microbial has been recognized as being important to greatly influence the host metabolism. High-fat food (“junk” and fast food) leads to an increase in Firmicutes, especially Mollicutes, and a concurrent reduction of Bacteroidetes [56]. High-fat diets modulate the microbiome composition to increase circulatory lipopolysaccharides coinciding with general inflammation [57]. Accordingly, obese (but not lean) individuals are known to have gut microbiota rich in Firmicutes and lower in Bacteroidetes [58]. Firmicutes are specialized in carbohy-drate catabolism. As such, the digestion by-products and molecules absorbed in the subject circulation are different in lean and obese humans. Moreover, Prevotellaceae, a hydrogen-producing bacteria, as well as archaeal species were abundant in obese individuals. Interestingly, gut microbial imbalance is associated with a high level of plasma inflammation and endotoxin, eventually leading to metabolic disorder. Most telling, an endotoxin-producing bacteria (i.e., Enterobacter), when inoculated into germ-free mice, induced obesity and insulin resistance [59]. Furthermore, gut bacteria, especially Bacillus fragilis, Clostridium scindens, and Clostridium sordellii, have a proven role in the biotransformation of bile acids. As such, aberration in the composition of gut microbial might change the levels of bile acids and can accord-ingly manipulate obesity [57]. Weight management and counseling of overweight as well as dietary guidelines for the public by health professionals carries potential for health benefits and managing obesity.

Gut microbial and diabetes: In addition to obesity, gut microbiota contributes to several other human diseases including diabetes mellitus (DM) type 1 and type 2. As mentioned earlier in this chapter, type 1 DM is an autoimmune disease caused by the destruction of pancreatic β-cells by the immune system. Higher rates of type 1 DM incidence that have been reported in recent years are not explained through genetic factors and have been attributed to changes in the subjects’ lifestyle such as hygiene, diet, and antibiotic usage that can directly affect microbiota. Moreover, the incidence of diabetes in the germ-free nonobese diabetic humans significantly increased. These results are in line with the observation that the rates of type 1 DM are higher in countries with stringent hygiene practices. Similarly, the gut microbiota in children with high genetic risk for type 1 DM and their age-matched healthy controls showed less diverse and less dynamic microbiota in the risk group. More telling, there is an observation that new onset of type 1 DM subjects had a different composition of gut microbiota compared to controls [43, 60].

The link between type 2 DM and gut microbiota is more evident since obesity is known as a direct cause of insulin signaling and type 2 DM as well as inflammation, which also leads to type 2 DM [61, 62]. The secretion of the short fatty acids butyrate and incretins by the gut microbiota leads to type 2 DM. The gut microbial by- products affect essential type 2 DM pathways such as insulin signaling, glucose homeostasis, and inflammation. Moreover, gut microbiota disturbs the production of key insulin signaling molecules such as GLP-1 and PYY (molecules associated with the decreas-ing insulin resistance). Others had also shown potential impact of gut microbiota on the development of type 2 DM [43, 63, 64].

1.7 Obesity