New Therapeutic Strategies for Type 2 Diabetes
`Small Molecule Approaches
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`
`RSC Drug Discovery Series
`
`Editor-in-Chief
`Professor David Thurston, London School of Pharmacy, UK
`
`Series Editors:
`Dr David Fox, Pfizer Global Research and Development, Sandwich, UK
`Professor Salvatore Guccione, University of Catania, Italy
`Professor Ana Martinez, Instituto de Quimica Medica-CSIC, Spain
`Professor David Rotella, Montclair State University, USA
`
`Advisor to the Board:
`Professor Robin Ganellin, University College London, UK
`
`Titles in the Series:
`1: Metabolism, Pharmacokinetics and Toxicity of Functional Groups
`2: Emerging Drugs and Targets for Alzheimer’s Disease; Volume 1
`3: Emerging Drugs and Targets for Alzheimer’s Disease; Volume 2
`4: Accounts in Drug Discovery
`5: New Frontiers in Chemical Biology
`6: Animal Models for Neurodegenerative Disease
`7: Neurodegeneration
`8: G Protein-Coupled Receptors
`9: Pharmaceutical Process Development
`10: Extracellular and Intracellular Signaling
`11: New Synthetic Technologies in Medicinal Chemistry
`12: New Horizons in Predictive Toxicology
`13: Drug Design Strategies: Quantitative Approaches
`14: Neglected Diseases and Drug Discovery
`15: Biomedical Imaging
`16: Pharmaceutical Salts and Cocrystals
`17: Polyamine Drug Discovery
`18: Proteinases as Drug Targets
`19: Kinase Drug Discovery
`20: Drug Design Strategies: Computational Techniques and Applications
`21: Designing Multi-Target Drugs
`22: Nanostructured Biomaterials for Overcoming Biological Barriers
`23: Physico-Chemical and Computational Approaches to Drug Discovery
`24: Biomarkers for Traumatic Brain Injury
`25: Drug Discovery from Natural Products
`26: Anti-Inflammatory Drug Discovery
`27: New Therapeutic Strategies for Type 2 Diabetes: Small Molecule Approaches
`
`How to obtain future titles on publication:
`A standing order plan is available for this series. A standing order will bring
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`

`
`NewTherapeuticStrategiesforType
`2 Diabetes
`Small Molecule Approaches
`
`Edited by
`
`Robert M. Jones
`Arena Pharmaceuticals, San Diego, California, USA
`Email: rjones@arenapharm.com
`
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`

`
`RSC Drug Discovery Series No. 27
`
`ISBN: 978-1-84973-414-1
`ISSN: 2041-3203
`
`A catalogue record for this book is available from the British Library
`
`# The Royal Society of Chemistry 2012
`
`All rights reserved
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`Apart from fair dealing for the purposes of research for non-commercial purposes
`or for private study, criticism or review, as permitted under the Copyright,
`Designs and Patents Act 1988 and the Copyright and Related Rights Regulations
`2003, this publication may not be reproduced, stored or transmitted, in any form
`or by any means, without the prior permission in writing of The Royal Society of
`Chemistry or the copyright owner, or in the case of reproduction in accordance
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`the licences issued by the appropriate
`Reproduction Rights Organization outside the UK. Enquiries concerning
`reproduction outside the terms stated here should be sent to The Royal Society
`of Chemistry at the address printed on this page.
`
`The RSC is not responsible for individual opinions expressed in this work.
`
`Published by The Royal Society of Chemistry,
`Thomas Graham House, Science Park, Milton Road,
`Cambridge CB4 0WF, UK
`
`Registered Charity Number 207890
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`For further information see our web site at www.rsc.org
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`

`
`Contents
`
`Chapter 1 Type 2 Diabetes: Disease Overview
`Daniel M. Kemp
`
`1.1 Type 2 Diabetes
`1.1.1 Societal and Economic Effects
`1.1.2 Epidemiology
`1.1.3 Pathophysiology
`1.1.4 Etiology
`1.2 Treatment of Type 2 Diabetes
`1.2.1 Lifestyle Management
`1.2.2 Surgical Intervention
`1.2.3 Current Drug Therapy Options
`1.2.4 Emerging Mechanisms
`1.2.5 Summary of Oral Diabetes Medications
`References
`
`Chapter 2 Marketed Small Molecule Dipeptidyl Peptidase IV (DPP4)
`Inhibitors as a New Class of Oral Anti-Diabetics
`Zhonghua Pei
`
`Introduction
`2.1
`2.2 Marketed DPP4 Inhibitors
`2.3 Potency and Selectivity of Marketed DPP4 Inhibitors
`2.4 Binding Mode of DPP4 Inhibitors
`2.5 Pharmacokinetics, Efficacy, and Safety of Marketed
`DPP4 Inhibitors
`2.6 Summary
`References
`
`RSC Drug Discovery Series No. 27
`New Therapeutic Strategies for Type 2 Diabetes: Small Molecule Approaches
`Edited by Robert M. Jones
`# The Royal Society of Chemistry 2012
`Published by the Royal Society of Chemistry, www.rsc.org
`
`vii
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`1
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`viii
`
`Contents
`
`Chapter 3 SGLT2 Inhibitors in Development
`William N. Washburn
`
`Introduction
`3.1
`3.2 Renal Recovery of Glucose
`3.3 SGLT2 Inhibitors
`3.3.1 Target Validation
`3.3.2 O-Glucosides
`3.3.3 Biological Assays
`3.3.4 C-Glucosides
`3.3.5 Non-Glycoside Containing SGLT2 inhibitors
`3.4 Clinical Studies with SGLT2 Inhibitors
`3.4.1 Clinical Evaluation of O-Glucosides
`3.4.2 Clinical Evaluation of C-Glucosides
`3.4.3 Antisense Inhibitors of SGLT2
`3.5 Conclusion
`References
`
`Chapter 4 Glucokinase Activators in Development
`Kevin J. Filipski, Benjamin D. Stevens and
`Jeffrey A. Pfefferkorn
`
`Introduction
`4.1
`4.2 The Role of Glucokinase in the Regulation of Glucose
`Homeostasis
`4.3 Genetic Evidence for the Importance of Glucokinase in
`Diabetes
`4.4 Small Molecule Glucokinase Activation: Opportunities
`and Challenges
`4.5 Clinical Development Status of Glucokinase Activators
`4.5.1 Advinus Glucokinase Activators
`4.5.2 Array Biopharma / Amgen Glucokinase
`Activators
`4.5.3 AstraZeneca Glucokinase Activators
`4.5.4 Merck Glucokinase Activators
`4.5.5 OSI Prosidion / Eli Lilly Glucokinase
`Activators
`4.5.6 Pfizer Glucokinase Activators
`4.5.7 Roche Glucokinase Activators
`4.5.8 Takeda Glucokinase Activators
`4.5.9 TransTech Pharma / Novo Nordisk / Forest
`Laboratories Glucokinase Activators
`4.5.10 Zydus Cadila Glucokinase Activators
`References
`
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`30
`31
`31
`32
`34
`35
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`71
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`73
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`Contents
`
`Chapter 5
`
`11b-Hydroxysteroid Dehydrogenase Type 1 (11b-HSD1)
`Inhibitors in Development
`James S. Scott and Jasen Chooramun
`
`ix
`
`109
`
`5.1
`
`109
`109
`110
`
`111
`
`Introduction to 11b-Hydroxysteroid Dehydrogenase
`Type 1 (11b-HSD1)
`5.1.1 Glucocorticoids and the Metabolic Syndrome
`5.1.2 Role, Function, and Structure of 11b-HSD1
`5.1.3 Preclinical evidence for 11b-HSD1 in Treatment
`of the Metabolic Syndrome
`5.1.4 The Hypothalemic-Pituitary-Adrenal (HPA)
`112
`Axis
`112
`5.1.5 Carbenoxolone (CBX)
`5.2 Overview of 11b-HSD1 Inhibitors in Development
`113
`11b-HSD1 Inhibitors by Company
`115
`5.3
`115
`5.3.1 Amgen / Biovitrum
`120
`5.3.2 Merck
`124
`5.3.3 Pfizer
`125
`5.3.4
`Incyte
`126
`5.3.5 AstraZeneca
`5.3.6 Vitae Pharmaceuticals / Boehringer Ingelheim 127
`5.3.7 Wyeth
`129
`5.3.8 Bristol-Myers-Squibb
`130
`5.3.9 Roche
`131
`5.3.10
`Japan Tobacco / Akros Pharma
`131
`5.3.11 Lilly
`131
`5.3.12 Other Companies and Institutions
`132
`5.4 Conclusions
`132
`Acknowledgements
`133
`References
`133
`
`Chapter 6 Recent Advances in PTP1B Inhibitor Development for the
`Treatment of Type 2 Diabetes and Obesity
`Rongjun He, Li-Fan Zeng, Yantao He and Zhong-Yin Zhang
`
`Introduction
`6.1
`6.2 Biochemistry of PTP1B
`6.3 Association of PTP1B with Type 2 Diabetes and
`Obesity
`6.3.1 PTP1B in Insulin Signaling
`6.3.2 PTP1B in Leptin Signaling
`6.4 Development of PTP1B Inhibitors
`6.4.1 Phosphonic Acid and F2PMP Derivatives
`6.4.2 Carboxylic Acids
`6.4.3 Sulfonic Acids
`6.4.4
`Imides
`
`142
`
`142
`143
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`145
`145
`147
`148
`149
`150
`154
`155
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`x
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`Contents
`
`6.4.5 Neutral Molecules
`6.4.6 Natural Products
`6.5 Clinic Development of PTP1B Inhibitors
`6.6 Conclusions and Perspectives
`Acknowledgment
`References
`
`Chapter 7 Recent Advances in the Discovery of GPR119 Agonists
`Unmesh Shah, Scott Edmondson and Jason W. Szewczyk
`
`Introduction
`7.1
`7.2 GPR119: Receptor Expression, Signaling, and
`Deorphanization
`7.3 Prototype Small-Molecule GPR119 Agonists and
`Glucose Homeostasis
`7.4 GPR119 Agonists: Medicinal Chemistry
`7.4.1 Arena Pharmaceuticals
`7.4.2 Prosidion Ltd.
`7.4.3 Metabolex
`7.4.4 GlaxoSmithKline
`7.4.5 Merck and Co.
`7.4.6 Novartis
`7.4.7 Bristol-Myers Squibb
`7.4.8 Boehringer Ingelheim
`7.4.9 Pfizer
`7.4.10 Astellas
`7.4.11 Cadila Healthcare
`7.5 Clinical Status of GPR119 agonists
`7.5.1 APD668 and APD597
`7.5.2 PSN821
`7.5.3 MBX2982
`7.5.4 GSK1292263
`7.6 Summary
`Acknowledgment
`References
`
`Chapter 8 Acyl-CoA:Diacylglycerol Acyltransferase-1 Inhibition as an
`Approach to the Treatment of Type 2 Diabetes
`Robert L. Dow
`
`Introduction
`8.1
`8.2 Characterization of DGAT Enzymes
`8.2.1 DGAT Enzymatic Activity
`8.2.2 Cloning of DGAT Enzymes
`
`157
`160
`165
`166
`167
`167
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`177
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`177
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`178
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`180
`182
`182
`186
`189
`190
`192
`195
`197
`197
`198
`200
`201
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`202
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`207
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`215
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`218
`219
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`
`Contents
`
`8.2.3 Structural Characterization of DGAT-1
`8.3 Role of DGAT-1 in Tissue Physiology and Disease
`States
`8.3.1 Tissue Distribution of DGAT Enzymes
`8.3.2 Role of DGAT-1 in Intestine
`8.3.3 Role of DGAT-1 in Liver
`8.3.4 Role of DGAT-1 in Adipose Tissue
`8.3.5 Role of DGAT-1 in Muscle
`8.3.6 Role of DGAT-1 in Hepatitis C Infectivity
`8.4 DGAT-1 Inhibitors
`8.4.1 Biarylamines
`8.4.2 Ureas
`8.4.3 Amides
`8.4.4 Aminopyrimidines
`8.4.5 Additional Lead Series
`8.5 Human Clinical Trials with DGAT-1 Inhibitors
`8.6 Conclusion
`Acknowledgment
`References
`
`Chapter 9 Stearoyl-CoA Desaturase 1 (SCD1) Inhibitors: Bench to
`Bedside Must Only Go Through Liver
`Gang Liu
`
`xi
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`219
`
`220
`220
`220
`222
`223
`224
`226
`227
`227
`230
`232
`235
`238
`238
`240
`241
`241
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`249
`
`9.1
`
`249
`
`Introduction
`9.1.1 Type 2 Diabetes, Obesity, and Dyslipidemia
`Epidemics
`9.1.2 Stearoyl-CoA Desaturases
`9.2 Target Validation
`9.2.1 Target Validation in Rodents
`9.2.2 Adverse Events Associated with SCD Gene
`Deletion
`9.2.3 Human Correlation
`9.3 First-Generation Systemically Distributed SCD
`254
`Inhibitors
`254
`9.3.1 Novel SCD Inhibitors
`260
`9.3.2 Pharmacology and Adverse Events
`262
`9.4 Second-Generation Liver-Targeted SCD Inhibitors
`262
`9.4.1 Passively Liver Selective Inhibitors
`9.4.2 SCD Inhibitors Actively Transported into Liver 262
`9.4.3 Pharmacological Characterization of Liver-
`Targeted SCD Inhibitors
`9.5 Conclusions
`References
`
`249
`250
`251
`251
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`252
`254
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`264
`264
`265
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`xii
`
`Chapter 10 TGR5 Agonists in Development
`Antonio Macchiarulo, Antimo Gioiello and Roberto
`Pellicciari
`
`Contents
`
`270
`
`Introduction
`10.1
`10.2 TGR5 at a Glance
`10.2.1 Early Pharmacological Characterization
`10.2.2 Sequence, Structure, and Gene Variants
`10.3 Expression and Physiological Functions
`10.3.1 TGR5 in Brown Adipose Tissue (BAT) and
`Skeletal Muscle: Control of Energy
`Homeostasis and Body Weight
`10.3.2 TGR5 in the Intestine: Control of Glucose
`Metabolism and Insulin Sensitivity
`10.3.3 TGR5 in Monocytes and Macrophages:
`Immunosuppressive Properties
`10.3.4 TGR5 Functions in Other Tissues
`10.4 TGR5 Modulation as Therapeutic Opportunity in
`Type 2 Diabetes (T2D)
`10.5 Ligands in Development
`10.5.1 Classification of TGR5 Ligands
`10.5.2 Steroidal and Non-Steroidal TGR5 Ligands in
`the Drug-like Property Space
`10.6 Predictive Models of TGR5 Affinity
`10.7 Conclusions
`10.8 References
`
`Chapter 11 The Discovery and Development of MB07803, a Second-
`Generation Fructose-1,6-bisphosphatase Inhibitor with
`Improved Pharmacokinetic Properties, as a Potential
`Treatment of Type 2 Diabetes
`Qun Dang, Paul D. van Poelje and Mark D. Erion
`
`Introduction
`11.1
`11.2 Discovery of First-Generation FBPase Inhibitor
`11.2.1 Discovery of MB06322, First Oral FBPase
`Inhibitor
`11.2.2 Clinical Studies
`11.2.3 N-Acetylation and Possible Impact of N-
`Acetylated Metabolites on Mitochondrial
`Function
`11.3 Design Strategy for Second-Generation FBPase
`Inhibitors
`11.3.1 SAR Summary for FBPase Inhibition by the
`Thiazole Scaffold
`
`270
`271
`271
`271
`273
`
`273
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`276
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`277
`278
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`280
`281
`281
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`294
`295
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`300
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`310
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`
`Contents
`
`11.3.2 Design Strategies to Reduce or Eliminate N-
`Acetylation
`11.4 Discovery of a Second-Generation FBPase Inhibitor:
`MB07803
`11.4.1
`Investigation of C5 Steric Effects of the
`Thiazole Scaffold on N-Acetylation
`11.4.2 Exploration of C5 Electronic Effects of the
`Thiazole Scaffold: Discovery of MB07729
`11.4.3 Oral Delivery of FBPase Inhibitors with no
`NAT Liability: Prodrug SAR
`11.5 Development of MB07803 (6j)
`11.5.1 Efficacy Studies of MB07803 (6j) in Animal
`Models of T2DM
`11.5.2 Phase I/II Clinical Studies
`11.6 Summary
`References
`
`Chapter 12
`
`Inhibition of Glycogen Phosphorylase as a Strategy for the
`Treatment of Type 2 Diabetes
`Brad R. Henke
`
`12.2.2
`
`Introduction
`12.1
`12.2 Characteristics of Glycogen Phosphorylase
`12.2.1 Structure, Function, and Regulation of
`Glycogen Phosphorylase
`Inhibitor Binding Sites of Glycogen
`Phosphorylase
`12.3 Glycogen Phosphorylase Inhibitors
`12.3.1
`In vitro and in vivo Assessment of GP
`Inhibition
`12.3.2 Catalytic Site Inhibitors
`12.3.3 Glycogen Storage Site Inhibitors
`12.3.4 Purine Nucleoside Site Inhibitors
`12.3.5 AMP Site Inhibitors
`12.3.6
`Indole Site Inhibitors
`Inhibitors of the GP-GL Interaction
`12.3.7
`12.3.8
`Inhibitors with an Unknown Binding Mode
`12.4 GP Inhibitors as Therapeutic Agents for Type 2
`Diabetes
`12.4.1 Clinical Results with GP Inhibitors
`12.4.2 Challenges with GP Inhibitors
`12.4.3 Opportunities for GP Inhibitors
`12.5 Conclusions
`Acknowledgment
`References
`
`xiii
`
`312
`
`314
`
`314
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`315
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`316
`317
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`317
`319
`321
`322
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`324
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`324
`325
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`325
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`327
`329
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`329
`331
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`335
`336
`345
`351
`351
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`354
`355
`358
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`360
`360
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`

`
`xiv
`
`Contents
`
`Chapter 13 SIRT1 Activators in Development
`Robert B. Perni, Vipin Suri, Thomas V. Riera, Joseph Wu,
`Charles A. Blum, George P. Vlasuk and James L. Ellis
`
`366
`
`366
`Introduction
`13.1
`367
`13.2 Role of SIRT1 in Metabolic Regulation
`370
`13.2.1 SIRT1 and Regulation of Energy Balance
`371
`13.2.2 SIRT1 and Carbohydrate Metabolism
`372
`13.2.3 SIRT1 and Lipid Metabolism
`374
`13.2.4 SIRT1 and Insulin Secretion and Sensitivity
`375
`13.2.5 SIRT1 and Other Hormones
`376
`13.3 Biochemistry of SIRT1 Activation
`13.3.1 General Characterization of Enzyme Activation 376
`13.3.2 Demonstration of Direct Activation of SIRT1
`by STACs
`13.4 The Medicinal Chemistry of SIRT1 Activators
`13.4.1 Polyphenols
`13.4.2
`Isoflavones
`13.4.3 Dihydropyridines
`13.4.4 Dihydroquinolones
`13.4.5 Oxazolopyridines and Related Analogs
`13.4.6
`Imidazothiazoles, Thiazaolopyridines, and
`Related Analogs
`13.4.7 Newly Disclosed Activators
`13.5 Preclinical Studies with SIRT1 Activators
`13.5.1 SIRT1 Dependence of SIRT1 Modulators
`13.6 Conclusion
`References
`
`377
`381
`381
`382
`382
`383
`383
`
`385
`386
`390
`392
`394
`395
`
`Chapter 14 Long-Chain Free Fatty Acid Receptor Agonists
`Jonathan B. Houze
`
`403
`
`403
`Introduction: Diabetes and Free Fatty Acids
`14.1
`404
`14.2 Free Fatty Acid Receptors
`404
`14.2.1 Biology of FFA1
`409
`14.2.2 Biology of GPR120
`411
`14.3 FFA1 Receptor Agonists
`412
`14.3.1 Open Chain Carboxylic Acids
`413
`14.3.2 Open Chain Carboxylate Bioisosteres
`14.3.3 Bicyclic Carboxylates and Carboxylate Bioisosteres 415
`14.3.4 Tricyclic Carboxylates and Carboxylate
`Bioisosteres
`14.4 GPR120 Receptor Agonists
`14.4.1 Carboxylic Acids
`14.4.2 Carboxylate Bioisosteres
`14.5 Conclusions
`References
`
`418
`419
`419
`421
`422
`422
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`
`Contents
`
`Chapter 15 Glucagon Receptor Antagonists in Development
`Duane E. DeMong and M. W. Miller
`
`Introduction
`15.1
`15.2 Peptide Glucagon Receptor Antagonists
`15.3 Monoclonal Antibodies
`15.4 Small Molecule Glucagon Receptor Antagonists
`15.4.1 b-Alanine Benzamides and their Isosteres
`15.4.2 Biaryl Glucagon Receptor Antagonists
`15.4.3 Phenol-Based hGCGR Antagonists
`15.4.4 Additional Small Molecule hGCGR
`Antagonists
`15.5 Conclusions
`References
`
`Chapter 16 ACC Inhibitors in Development
`Matthew P. Bourbeau
`
`Introduction
`16.1
`16.2 ACC2 Mouse Knockout Studies
`16.2.1 Wakil’s Studies
`16.2.2 Cooney’s Studies
`16.2.3 Lowell’s Studies
`16.2.4 Summary of ACC2 Knockout Data
`16.3 ACC1 Knockout Studies
`16.3.1 Total ACC1 Knockout
`16.3.2 Tissue-Specific ACC1 Knockout: Wakil
`16.3.3 Tissue-Specific ACC1 Knockout: Kusunoki
`16.3.4 Summary of ACC1 Knockout Data
`16.4 ACC as a Target for Cancer Treatment
`16.5 ACC Inhibitors for the Treatment of Metabolic
`Syndrome
`16.5.1 Pfizer’s ACC Inhibitors
`16.5.2 Abbott’s ACC Inhibitors
`16.5.3 Tashio’s ACC Inhibitors
`16.5.4 Torrent’s ACC Inhibitors
`16.5.5 Cropsolutions’ ACC Inhibitors
`16.5.6 Sanofi-Aventis’ ACC Inhibitors
`16.5.7 Astra Zeneca’s ACC Program
`16.5.8 Other ACC Inhibitors with in vivo Data:
`Soraphen A
`16.5.9 Other ACC Inhibitors of Note
`16.6 Conclusions
`References
`
`Subject Index
`
`xv
`
`429
`
`429
`430
`430
`431
`431
`452
`452
`
`454
`457
`457
`
`464
`
`464
`465
`465
`468
`469
`470
`471
`471
`471
`472
`472
`473
`
`473
`473
`479
`482
`485
`486
`488
`490
`
`493
`495
`495
`496
`
`501
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`CHAPTER 1
`
`Type 2 Diabetes:
`Disease Overview
`
`DANIEL M. KEMP
`
`Diabetes & Endocrinology, Merck Research Laboratories, 126 East Lincoln
`Avenue, Rahway, NJ 07065, USA
`E-mail: daniel.kemp@merck.com
`
`1.1 Type 2 Diabetes
`
`1.1.1 Societal and Economic Effects
`
`Type 2 diabetes is a metabolic disease, and is characterized by elevated
`circulating glucose, otherwise known as hyperglycemia. The specific molecular
`cause of type 2 diabetes remains unknown, though considerable progress has
`been made to define the metabolic characteristics of people who have, or later
`acquire, the disease. What we are certain of is that two essential components
`define the overall metabolic dysfunction in type 2 diabetes; firstly, a relative
`insensitivity of glucose-utilizing tissues to insulin (i.e., skeletal muscle, liver,
`and adipose tissue), subsequently compounded by a relative insufficiency of
`insulin production from the pancreas,
`leading to whole body glucose
`intolerance. This progressive phenotype of insulin resistance and glucose
`intolerance contrasts with that of
`type 1 diabetes, which results from
`autoimmune destruction of insulin-producing b-cells of the pancreas, and
`thus is predominantly characterized by insulin insufficiency alone, and is
`treated specifically by injection of exogenous insulin.
`In adults, type 2 diabetes accounts for about 90–95% of all diagnosed cases
`of diabetes, and develops most often in middle-aged and older adults. Among
`
`RSC Drug Discovery Series No. 27
`New Therapeutic Strategies for Type 2 Diabetes: Small Molecule Approaches
`Edited by Robert M. Jones
`# The Royal Society of Chemistry 2012
`Published by the Royal Society of Chemistry, www.rsc.org
`
`1
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`2
`
`Chapter 1
`
`U.S. residents aged 65 years and older, 10.9 million, or 26.9%, had diabetes in
`2010, according to the NIDDK.1 The total number of cases in the US alone is
`forecast to double from 24 million in 2009 to 44 million in 2034. Not
`surprisingly, in association with the growing diabetic population, spending on
`diabetes and related complications are projected to triple in the same period,
`from $100 billion in 2009 to around $300 billion in 2034. A report published in
`2011 that included a dataset of 2.7 million individuals across the world
`concluded that diabetes prevalence is projected to be in the region of 347
`million people.2 These staggering statistics outline the emerging epidemic of
`type 2 diabetes, and strongly indicate the need for new and better therapies.
`
`1.1.2 Epidemiology
`
`Though still poorly understood, the root cause of type 2 diabetes clearly results
`from interplay between genetic and environmental factors. The importance of
`genetics for the development of type 2 diabetes has long been recognized, both
`at the individual level (family history) and at the population level (ethnic
`background). For example, the most convincing evidence of genetic predis-
`position at the level of the individual comes from twin studies. Concordance
`rates for identical twins range from 70% up to close to 90%, with lifelong
`follow-up, and are higher than non-identical twins, siblings, or other family
`members.3 With respect to population genetics, strong evidence comes from
`studies like the San Antonio Heart Study, which focused on studying
`populations with different genetic backgrounds living in the same environ-
`ment. In that study, the prevalence of type 2 diabetes was higher in Mexican
`Americans than in non-Hispanic whites at each level of obesity.4 Despite the
`overwhelming evidence that susceptibility for type 2 diabetes is inherited, the
`specific susceptibility genes and their mode of inheritance have yet to be
`determined, and this has been an area of intense research over the past decade.
`Though some monogenic traits have been firmly associated with a subset of
`type 2 diabetes patients, annotated as MODY genes (maturity onset diabetes
`of the young), the advent of genome-wide association studies, enabled by the
`human genome project, heralded the potential to identify disease-causing genes
`via the association of specific genetic mutations with incidences of type 2
`diabetes. To date more than 50 genetic loci have been discovered, and these
`loci appear to associate predominantly with genes involved in pancreatic islet
`function, with few if any involved in insulin resistance-related pathways.5
`Though initially surprising to some, this observation makes sense, as the
`primary cause of hyperglycemia is the inability of the pancreas to maintain
`sufficient insulin levels to drive glucose uptake into peripheral tissues. As
`mentioned earlier, although insulin resistance is a primary cause of the disease,
`type 2 diabetes only manifests when the b-cells of the pancreas fail to keep pace
`with demand. Mutations in genes that result in functional impairment of
`pancreatic b-cells are therefore most apparent in population genetics studies
`with hyperglycemia as the primary clinical endpoint. More recent genetic
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`Type 2 Diabetes: Disease Overview
`
`3
`
`studies that focus on markers of insulin resistance are currently ongoing, and
`should identify additional genes involved more specifically in the function of
`insulin action and glucose utilization. It is highly anticipated that the results of
`these genetic studies should identify putative drug targets for the treatment of
`both insulin resistance and type 2 diabetes.
`Environmental factors that influence the prevalence of type 2 diabetes can
`be easily exposed by studies focused on migrant populations. For example,
`Japanese migrants in Hawaii and Los Angeles are two to three times more
`likely to suffer type 2 diabetes than Japanese living in Japan.6 Such a shift in
`environmental
`influences over just one or two generations can impart
`surprisingly rapid changes in prevalence and incidence of type 2 diabetes.
`Factors such as birth weight, in utero exposure to diabetes, diet, obesity, and
`physical activity can expose an underlying genetic susceptibility within specific
`ethnic populations. The Pima Indians of Arizona are particularly notable with
`respect to their genetic predisposition to type 2 diabetes, clearly exposed by
`environmental factors of ‘‘western lifestyle’’.7 All of these specific examples
`speak to the broader context of how exposure to an ever evolving global
`economy and cultural environment has unveiled the apparent fragility of the
`human genome, and underscores how habitat is just as important as evolution
`in defining what species thrive and perish.
`
`1.1.3 Pathophysiology
`
`The ability of insulin to stimulate glucose disposal has been extensively
`studied, and abundant evidence exists to confirm that insulin action is
`markedly decreased in patients with type 2 diabetes. The major route of
`glucose disposal, demonstrated by infusion studies, is uptake into the skeletal
`muscle, and it is reasonable to conclude that the majority of patients with type
`2 diabetes have a defect in insulin-stimulated glucose disposal into muscle.
`However, it is also clear that impaired insulin-dependent glucose uptake per se
`cannot account for the development of hyperglycemia in patients with type 2
`diabetes, because relatively normal fasting plasma glucose levels are often
`observed in individuals who are equally insulin resistant as patients with frank
`diabetes. Indeed, type 2 diabetes will develop only when insulin-resistant
`subjects are incapable of secreting sufficient insulin to compensate for the
`defect in skeletal muscle insulin action. To further elaborate, as fasting
`hyperglycemia develops only when the pancreas fails, the consequence of this
`decline in insulin secretory capacity must be defined further in order to
`understand the pathophysiology of type 2 diabetes. We need to consider the
`involvement of adipose tissue as an important player
`in the overall
`characterization of the disease. This is because resistance to insulin regulation
`at the level of the adipose tissue, or as a result of decreased insulin secretion,
`leads to elevated plasma free fatty acid (FFA) concentrations. Indeed, ambient
`plasma FFA concentrations are elevated in type 2 diabetes, and the greater the
`increase in FFA concentration, the higher the plasma glucose concentration.8
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`4
`
`Chapter 1
`
`Exacerbation of the dysmetabolic state then ensues because elevated FFA
`levels decrease insulin-stimulated glucose uptake, cause lipotoxicity at the level
`of the pancreatic b-cell, and further compromises insulin secretory function.
`Furthermore, elevated FFA levels stimulate gluconeogenesis in the liver,
`decreasing the ability of hyperglycemia to suppress hepatic glucose production,
`further compounding the problem. To summarize, when insulin resistance is
`compensated by hyperinsulinemia, whole body glucose homeostasis can be
`preserved. But, when the insulin secretory response declines to a point where
`circulating plasma FFA levels become significantly elevated, the plasma
`glucose concentration increases precipitously due to unsuppressed hepatic
`glucose output, exacerbation of pancreatic b-cell failure, and impaired insulin-
`dependent glucose disposal into muscle.
`Although far from complete, this high level perspective of the pathophysiol-
`ogy of type 2 diabetes serves to highlight complex interactions between
`carbohydrate and fat metabolism, and between the function of multiple
`metabolically active tissues of the body. This is underscored by the fact that
`many therapeutic approaches, including those discussed in this book, target
`diverse mechanisms within different tissues. The repertoire of drug targets
`presented here aim to regulate glucose metabolism either directly or indirectly
`via various compensatory mechanisms.
`
`1.1.4 Etiology
`
`As inferred already, there are many factors that can potentially give rise to, or
`exacerbate, type 2 diabetes,
`including obesity, hypertension, and elevated
`cholesterol. Others include aging, high-fat diets, and an inactive lifestyle. All of
`these causal factors are to some degree a result of our evolving environment.
`The onset of type 2 diabetes has traditionally been most common in middle age
`and later life, although it is now being more frequently seen in adolescents and
`young adults due primarily to the increase in child obesity and inactivity, and
`this aspect is worth further consideration as a defining component of type 2
`diabetes, along with implications to therapeutic intervention.
`A key etiological factor linking obesity to type 2 diabetes is insulin
`resistance, characterized by an impaired ability of insulin to inhibit glucose
`output from the liver and to promote glucose uptake in fat and muscle. The
`physiological mechanisms connecting obesity to insulin resistance have
`received intense attention in recent years resulting in the emergence of several
`hypotheses to explain this link, such as (1) ectopic lipid accumulation in liver
`and muscle secondary to obesity-associated increase in serum free fatty acids,
`(2) altered production of various adipocyte-derived factors (collectively known
`as adipokines), and (3) low-grade inflammation of white adipose tissue (WAT)
`resulting from chronic activation of the innate immune system.9 However, not
`all obese individuals are insulin resistant, and in fact insulin sensitivity has
`been shown to vary up to six fold in this population, highlighting the
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`
`Type 2 Diabetes: Disease Overview
`
`5
`
`Figure 1.1 Obesity Trends Among U.S. Adults between 1990 and 2010. Source:
`Behavioral Risk Factor Surveillance System, CDC.
`
`importance of identifying genetic and environmental factors that place obese
`individuals at the greatest risk of obesity-related complications.10
`The degree to which obesity is affecting westernized society is worth noting,
`as it underlies the prevalence of type 2 diabetes, and serves as a leading
`indicator for metabolic dysfunction. In 2010, no U.S. state had a prevalence of
`obesity less than 20%. Thirty-six states had a prevalence of 25% or more; 12 of
`these states (Alabama, Arkansas, Kentucky, Louisiana, Michigan, Mississippi,
`Missouri, Oklahoma, South Carolina, Tennessee, Texas, and West Virginia)
`had a prevalence of 30% or more.11 By comparing these statistics with those
`from 1990, the explosion in obesity rate is striking, and is depicted in
`Figure 1.1. The data strongly suggest that prevention (or reversal) of obesity
`would have a profound effect on the prevalence of type 2 diabetes. As such,
`many companies have focused their research on anti-obesity programs as a
`means to treating obesity-related metabolic diseases such as diabetes.
`
`1.2 Treatment of Type 2 Diabetes
`
`1.2.1 Lifestyle Management
`
`Diet and exercise are the most powerful means to lower blood glucose levels in
`type 2 diabetes patients and are the foundation of effective treatment and
`disease management. Patient education and self-care practices are important
`aspects of disease management that help people with diabetes lead normal
`lives. In fact, the Diabetes Prevention Program (DPP), a large prevention study
`of people at high risk for diabetes, showed that lifestyle intervention to lose
`weight and increase physical activity reduced the development of type 2
`diabetes by 58% during a 3-year period.12 The reduction was even greater,
`71%, among adults aged 60 years or older. However, due mainly to socio-
`economic factors that have become a glob