cover

Contents

Cover

Title Page

Copyright

Introduction

Contributors

Part One: The Physiology of Metabolic Tissues Under Normal and Disease States

Chapter 1: Gut as an Endocrine Organ: the Role of Nutrient Sensing in Energy Metabolism

Introduction

Food Intake and Nutrient-Sensing Systems in the GI Tract

Molecular Mechanisms of Nutrient Sensing

Regulation of Incretin Secretion

Disorders in Incretin Response in Type 2 Diabetes

Other GI Peptide Hormones or Neurotransmitters

The Physiological Importance of the Gut: Lessons Learned from Gastric Bypass

Summary

References

Chapter 2: Central Glucose Sensing and Control of Food Intake and Energy Homeostasis

Introduction

Brain Glucose Sensing

Physiological Functions Modulated by Central Glucodetection

Multiplicity of Sensing Mechanisms

Conclusion

References

Chapter 3: Abnormalities in Insulin Secretion in Type 2 Diabetes Mellitus

Introduction

Normal Glucose Homeostasis

Insulin Secretion and Effects on Target Tissues

Measuring Insulin Secretion and β-Cell Function

Alterations in Insulin Secretion Kinetics in T2DM

Quantitative and Qualitative Alterations in Insulin Secretion

Progression of Abnormalities of Insulin Secretion

Mechanisms of β-Cell Failure

Reduction in β-Cell Mass in T2DM

Linkage of Reduced β-Cell Mass and Dysfunction

The Compensation of Insulin Resistance by β-Cells

Origin of β-Cell Dysfunction

Conclusions

References

Chapter 4: Adipokine Production by Adipose Tissue: A Novel Target for Treating Metabolic Syndrome and its Sequelae

Introduction

MetS and Obesity

MetS and Adipose Tissue

MetS and the Liver: Nonalcoholic Fatty Liver Disease

MetS and the Pancreas

MetS and the Brain

MetS and the Cardiovascular System

Therapeutic Interventions

Summary

References

Chapter 5: Hepatic Metabolic Dysfunctions in Type 2 Diabetes: Insulin Resistance and Impaired Glucose Production and Lipid Synthesis

Introduction

Balancing Hepatic Glucose Disposal and Production By Glucose-6-Phosphate System

Regulation of Hepatic Glucose Metabolism By Insulin

Insulin-Signaling Pathway

Insulin Regulates Glycogen Synthesis and Breakdown

Effect of Insulin on Gluconeogenesis

Hepatic Lipid Metabolism and Insulin Resistance

Targeting Hepatic Insulin Resistance for the Treatment of T2DM

Summary

References

Chapter 6: Energy Metabolism in Skeletal Muscle and its Link to Insulin Resistance

Introduction

Glucose Metabolism in Skeletal Muscle: The Importance of Glucose Uptake

Insulin Signaling and Mechanisms of Insulin Resistance in Skeletal Muscle

Key Pathways that Impact Muscle Metabolism

Muscle Types and Associated Metabolic Differences

Effects of Muscle Insulin Resistance on Other Tissues

Summary

References

Part Two: Metabolic Diseases and Current Therapies

Chapter 7: Mechanisms and Complications of Metabolic Syndrome

Introduction

The Definition of Metabolic Syndrome

Obesity and Insulin Resistance

Hepatic Insulin Resistance and Dyslipidemia

Development of Hypertension

Mechanisms of Insulin Resistance

Development of Type 2 Diabetes

Mechanisms of Increased Cardiovascular Risk in T2DM

Ethnic Variations in the Development of Metabolic Abnormalities

Genetic Mutations as a Risk Factor

Summary

References

Chapter 8: Emerging Therapeutic Approaches for Dyslipidemias Associated with High LDL and Low HDL

Introduction

Lipoprotein Metabolism

The Role of Lipoproteins in Atherogenesis

Etiology and Classification of Dyslipidemias

Epidemiology

Current Treatment Guidelines for Dyslipidemias

Currently Available Drugs for the Treatment of Dyslipidemias

Emerging Therapies for Lowering LDL-C

Emerging Therapies Targeting HDL

Summary and Outlook

References

Chapter 9: Mechanism of Action of Niacin: Implications for Atherosclerosis and Drug Discovery

Introduction

Mechanisms of Action

Multiple Tissue/Cellular Target Sites of Action of Niacin

Clinical Utilization of Niacin

Clinical Outcome Trials with Niacin

Adverse Effects of Niacin

Use of Niacin in Diabetes Mellitus

Summary

Acknowledgments

References

Chapter 10: Current Antidiabetic Therapies and Mechanisms

Introduction

Antidiabetic Treatments

Weight Loss Drugs

Treatment of Diabetic Complications

Future Strategies of Antidiabetic Therapies

Summary

References

Part Three: Drug Targets for Antidiabetic Therapies

Chapter 11: GLP-1 Biology, Signaling Mechanisms, Physiology, and Clinical Studies

Introduction

Origin of the Incretin Concept

From the Proglucagon Gene to Protein and Secretion

The GLP-1 Receptor

Physiological Role of GLP-1

Ectopic Effects of GLP-1

Central Effects of GLP-1

The GLP-1 Dependent Gut-to-Brain-to-Periphery Axis

Cardiovascular Effects

Effects on Dyslipidemia

Secretion

Clinical Studies

Conclusions

References

Chapter 12: Dipeptidyl Peptidase IV Inhibitors for Treatment of Diabetes

Introduction

The Incretin Concept and Discovery of Incretin Hormones

Incretin Metabolism

DPP-4: Distribution, Substrate Specificity, and Structure

Chemical Classes of Inhibitors and Structures

DPP-4 Inhibitors as Therapeutics for Diabetes

DPP-4 Inhibitors in Type 2 Diabetes

Mode of Action of DPP-4 Inhibitors in Type 2 Diabetes

DPP-4 Inhibitors in Type 1 Diabetes

Future Trends

Acknowledgments

References

Chapter 13: Sodium Glucose Cotransporter 2 Inhibitors

Introduction

Kidney Physiology

Glucose Transporters

Pathophysiology of Diabetes

SGLT Inhibition

Phlorizin

T-1095

Sergliflozin

Dapagliflozin

Remogliflozin

Safety

Summary

References

Chapter 14: Fibroblast Growth Factor 21 as a Novel Metabolic Regulator

Introduction

FGF21 Expression

FGF21 In Vitro Effects

FGF21 in Normal Physiology

FGF21 in Pathophysiology of Metabolic Disease

FGF21 In Vivo Pharmacology

Conclusions

References

Chapter 15: Sirtuins as Potential Drug Targets for Metabolic Diseases

Introduction

Caloric Restriction and Sirtuin Family of Genes

The Catalytic Actions of Sirtuins

The NAD+ Synthesis Pathways

SIRT1

SIRT2

The Mitochondrial Sirtuins (SIRT3, SIRT4, and SIRT5)

SIRT6 and SIRT7

Sirtuin Modulating Compounds and Their Metabolic Actions

Summary

References

Chapter 16: 11β-Hydroxysteroid Dehydrogenase Type 1 as a Therapeutic Target for Type 2 Diabetes

Introduction

Biological Role of 11β-HSD1

11β-HSD1 Mouse Genetics

Role of 11β-HSD1 in Disease Physiology

Small-Molecule Therapeutics

Summary

References

Chapter 17: Monoclonal Antibodies for the Treatment of Type 2 Diabetes: A Case Study with Glucagon Receptor Blockade

Introduction

GCGR Immunogen Generation

Immunization and Hybridoma Generation

Identification of GCGR Binders

Identification of GCGR mAbs with Antagonizing Activity

In Vivo Efficacy Studies of GCGR-Antagonizing mAbs

Conclusions

References

Part Four: Lessons Learned and Future Outlook

Chapter 18: Drug Development for Metabolic Diseases: Past, Present and Future

Introduction

A Historical Perspective with Metabolic Drug Discovery

Lessons Learned from Successful Stories

Lessons Learned from Failures

Issues with Existing Therapies and Unmet Medical Needs

Current Approaches and Challenges

New Insights from Clinical Research

Regulatory Challenges and Future Opportunities

Summary

References

Index

Title Page

Introduction

It has been more than 20 years since Reaven first introduced the concept of syndrome X or insulin resistance syndrome to describe the clustering of several cardiovascular risk factors. The concept has evolved over the years and is now commonly referred to as metabolic syndrome, which covers the individual metabolic abnormalities of obesity, insulin resistance, hyperglycemia, dyslipidemia (high triglycerides and low HDL), and hypertension. Patients with metabolic syndrome have increased risk of developing cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). Despite the debates surrounding the existence and definition of metabolic syndrome, the concept has been useful in understanding the interconnections of the various risk factors that are common in a large population of patients and thereby managing the overall disease risk. From the drug discovery standpoint, all the components of metabolic syndrome are therapeutic targets for the treatment of CVD and T2DM to reduce comorbidities and overall mortality.

While there is a wealth of information concerning the clinical features and mechanisms of metabolic syndrome, putting them in the physiological context relevant to the development of therapeutics is essential for drug discovery. The goal of this book is to provide comprehensive understanding of the molecular and physiological abnormalities associated with metabolic syndrome and the therapeutic strategies for drug development. Part One is devoted to gaining an integrated understanding of the metabolic abnormalities at the tissue and pathway levels that are associated with disease states. In Part Two, metabolic syndrome is discussed at the physiological level and current therapies are summarized. These sections help lay the foundation to identify pathways and molecular targets for the development of antidiabetic therapies in Part Three. Since more than 80% type 2 diabetic patients have metabolic syndrome, a large portion of this book is devoted to antidiabetic therapies. Finally, the successes and failures in developing antidiabetic and cardiovascular drugs and lessons learned are discussed in Part Four. Although the chapters are contributed by different authors, the organization and the content of the book have been carefully designed so that the information is presented systematically. In the meantime, each chapter independently covers a subarea of metabolic or drug discovery topics, the reader has the flexibility to gain information on a specific tissue, pathway, or target in a time-efficient manner. Despite the exciting advances that have been made in developing antidiabetic and CVD therapies in the past several decades, drug discovery in these areas continues to be a challenge. I hope this book will help the reader better understand the exciting science behind metabolic drug discovery and development and develop a greater appreciation of the complexity of metabolic syndrome as well as the treatment strategies.

Contributors

Remy Burcelin, Rangueil Institute of Molecular Medicine, INSERM U858, Toulouse, France

Cendrine Cabou, Rangueil Institute of Molecular Medicine, INSERM U858, Toulouse, France

Vanessa DeClercq, Department of Human Nutritional Sciences, University of

Manitoba, Winnipeg, Canada; Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, Canada

H.-U. Demuth, Probiodrug AG, Biocenter, Halle (Saale), Germany

James D. Dunbar, BioTechnology Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, USA

Shobha H. Ganji, Department of Veterans Affairs Healthcare System, Atherosclerosis

Research Center, Long Beach, CA, USA; Department of Medicine, University of California, Irvine, CA, USA

Pierre Gourdy, Rangueil Institute of Molecular Medicine, INSERM U858, Toulouse, France

Wei Gu, Department of Metabolic Disorders, Amgen, Inc., Thousand Oaks, CA, USA

Pierre-Jean Guillausseau, APHP, Department of Internal Medicine B, Hôpital Lariboisière, Paris, France; Université Paris 7, Paris, France

Clarence Hale, Department of Metabolic Disorders, Amgen, Inc., Thousand Oaks, CA, USA

U. Heiser, Probiodrug AG, Biocenter, Halle (Saale), Germany

Ryan Hunt, Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, Canada; Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, Canada

Serge A. Jabbour, Division of Endocrinology, Diabetes, and Metabolic Diseases, Department of Medicine, JeffersonMedical College, Thomas Jefferson University, Philadelphia, PA, USA

Vaijinath S. Kamanna, Department of Veterans Affairs Healthcare System, Atherosclerosis Research Center, Long Beach, CA, USA; Department of Medicine, University of California, Irvine, CA, USA

Moti L. Kashyap, Department of Veterans Affairs Healthcare System, Atherosclerosis Research Center, Long Beach, CA, USA; Department of Medicine, University of California, Irvine, CA, USA

Alexei Kharitonenkov, BioTechnology Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, USA

Jae B. Kim, Global Development, Amgen, Inc., Thousand Oaks, CA, USA

S.-J. Kim, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, Canada; Diabetes Research Group, Life Sciences Institute, University of British Columbia, Vancouver, Canada

Christophe Magnan, INSERM U858, Toulouse, France; University Paris Diderot, CNRS, Paris, France

C.H.S. McIntosh, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, Canada; Diabetes Research Group, Life Sciences Institute, University of British Columbia, Vancouver, Canada

Devan Marar, Department of Veterans Affairs Healthcare System, Atherosclerosis Research Center, Long Beach, CA, USA; Department of Medicine, University of California, Irvine, CA, USA

Radmila Micanovic, BioTechnology Discovery Research, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, USA

Taly Meas, APHP, Department of Internal Medicine B, Hôpital Lariboisière, Paris, France; Université Paris 7, Paris, France

Lourdes Mounien, Department of Physiology, University of Lausanne, Lausanne, Switzerland; Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland

R.A. Pederson, Department of Cellular and Physiological Sciences, Life Sciences Institute, University of British Columbia, Vancouver, Canada; Diabetes Research Group, Life Sciences Institute, University of British Columbia, Vancouver, Canada

Margaret Ryan, Division of Endocrinology, Diabetes, and Metabolic Diseases, Department of Medicine, JeffersonMedical College, Thomas Jefferson University, Philadelphia, PA, USA

Margrit Schwarz, Department of Metabolic Disorders, Amgen, Inc., South San Francisco, CA, USA

David J. St. Jean, Jr., Department of Medicinal Chemistry, Amgen, Inc., Thousand Oaks, CA, USA

Danielle Stringer, Department of Human Nutritional Sciences, University of

Manitoba, Winnipeg, Canada; Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, Canada

Carla G. Taylor, Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, Canada; Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, Canada

Bernard Thorens, Department of Physiology, University of Lausanne, Lausanne, Switzerland; Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland

Qiang Tong, USDA/ARS Children's Nutrition Research Center, Baylor College of Medicine, Houston, TX, USA; Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA; Department of Medicine, Baylor College of Medicine, Houston, TX, USA; Department of Molecular Physiology and Biophysics, Baylor College of Medicine, Houston, TX, USA

Murielle Veniant-Ellison, Department of Metabolic Disorders, Amgen, Inc., Thousand Oaks, CA, USA

Minghan Wang, Metabolic Disorders Research, Amgen, Inc., Thousand Oaks, CA, USA

Hai Yan, Department of Protein Science, Amgen, Inc., Thousand Oaks, CA, USA

Ruojing Yang, Department of Metabolic Disorders – Diabetes, Merck Research Laboratories, Rahway, NJ, USA

Peter Zahradka, Department of Physiology, University of Manitoba, Winnipeg, Canada; Department of Human Nutritional Sciences, University of Manitoba, Winnipeg, Canada; Canadian Centre for Agri-Food Research in Health and Medicine, St. Boniface Hospital Research Centre, Winnipeg, Canada

Part One

The Physiology of Metabolic Tissues Under Normal and Disease States