Diabetes and Its Complications: Strategies to Advance Therapy and Optimize R&D

Table of Contents

Chapter 1

• Introduction
• 1.1. Risk Factors for Type 2 Diabetes
  • Preventing Development of Diabetes in Prediabetic Individuals
• 1.2. Growth in Prevalence of Diabetes
  • Worldwide Increase in Obesity
• 1.3. Economic Burden of Diabetes
• 1.4. Market Size for Current Diabetes Drugs
• 1.5. Unmet Medical Needs in Diabetes
  • Type 2 Diabetes
  • Type 1 Diabetes

Chapter 2

• Type 1 Diabetes as an Autoimmune Disease
• 2.1. Genetic and Environmental Determination of Type 1 Diabetes
  • Genetic Determinants
  • Environmental Determinants
• 2.2. Pathogenesis of Type 1 Diabetes
  • Trials of Agents to Prevent or Ameliorate Type 1 Diabetes in Patients with Prediabetes or New-Onset Diabetes
  • ENDIT and DPT-1
  • Anti-CD3 Agents
  • New Approaches to Treatment of Established Type 1 Diabetes

Chapter 3

• Type 2 Diabetes as a Metabolic Disease
• 3.1. Obesity as a Cause of Insulin Resistance and Beta-Cell Dysfunction
  • Adipokines, Obesity, and Insulin Resistance
  • Free Fatty Acids as a Critical Factor in Both Insulin Resistance and Beta-Cell Dysfunction
  • Obesity, Inflammation, and Insulin Resistance
  • Salicylates as Therapeutic Drugs
  • Chemical Chaperones as Therapeutic Agents: PBA and TUDCA
• 3.2. Genetic Factors in Development of Beta-Cell Dysfunction
  • Activating Mutations in the KCNJ11 Gene
  • TCF7L2: A Major Risk Factor for Late-Onset Type 2 Diabetes
  • Type 2 Diabetes Is Caused by a Combination of Genetic Risk Factors

Chapter 4

• Current Diagnosis and Treatment of Diabetes
• 4.1. Diagnosis of Diabetes
• 4.2. Treatment of Diabetes
  • Diet and Exercise
  • Concurrent Treatment of Other Aspects of the Metabolic Syndrome
• 4.3. Insulin Products
  • Insulin Formulations with Different Durations of Action
  • Long-Acting Insulin Glargine
  • Inhaled Insulin
• 4.4. Established Oral Antidiabetics
  • Sulfonylureas
  • Biguanides: Metformin
  • Meglitinides
  • Alpha-glucosidase Inhibitors
  • Thiazolidinediones
• 4.5. Type 2 Diabetes Management Using the Established Oral Antidiabetics and Insulin
  • ADA/EASD Consensus Statement
  • ADA/EASD Panel' s Recommendations versus Traditional Treatments
  • De-emphasis of Newer Drugs in the Panel' s Recommendations
  • Disagreement with the Panel' s Findings

Chapter 5

• Novel and emerging antidiabetic drugs
• 5.1. Approved and Pipeline Drugs Belonging to Drug Classes Introduced into the Market since 2005
  • Amylin Analogs: Pramlintide
  • Incretin Mimetics
  • Exenatide
  • GSK716155
  • Liraglutide
  • Dipeptidyl Peptidase-IV Inhibitors
  • Sitagliptin
  • Vildagliptin
  • Saxagliptin
  • PSN9301
  • Outlook for the Newly Introduced Antidiabetic Drugs
• 5.2. Novel Classes of Antidiabetics in Corporate Pipelines
  • PPARa/PPARg Dual Agonists (Glitazars)
  • PPARg Partial Agonists
  • MBX-102
  • FK614 and PA-082
  • PPARg ,b ,a
  • Cannabinoid-1 Receptor Antagonists
  • RIO-Diabetes Study
  • SERENADE
  • 11 Beta-hydroxysteroid Dehydrogenase Type 1
  • Sodium Glucose Cotransporter-2 Inhibitors
  • Glucokinase Activators

Chapter 6

• Early-Stage Drugs and Novel Therapeutic Strategies for Type 2 Diabetes
• 6.1. Does the Lack of Scientific Knowledge of Type 2 Diabetes Hamper Development of Effective Treatments?
• 6.2. The Inadequacy of Animal Models in Type 2 Diabetes
• 6.3. Strategies for Making Drug Discovery and Development More Effective
  • Dealing with Multiple Molecular "Causes" of Disease by Hitting More than 1 Target
  • Whole-Pathway Approaches
  • Biology-Driven Drug Discovery
  • Biomarkers and Translational Medicine
  • Animal Models and Complex Diseases
• 6.4. The Diabetes Survey and Issues Related to Strategies to Improve the Effectiveness of Drug Discovery and Development
• 6.5. Selected Research-Stage Agents and Novel Therapeutic Strategies for Type 2 Diabetes
  • Small-Molecule GLP-1 Receptor Agonists
  • Boc5
  • Ago-Allosteric Modulators
  • Protein Tyrosine Phosphatase 1B Inhibitors
  • Preclinical Development of Small-Molecule PTP1B Inhibitors
  • Development of Antisense Drugs: ISIS 113715
  • AMP-Activated Protein Kinase Activators
  • CytRx Corporation' s RNAi-Based Drug Discovery Programs in Type 2 Diabetes and Obesity
  • Receptor-Interacting Protein 140
  • MAP4K4
  • Sirtuin Modulators
  • Ghrelin Antagonists (Growth Hormone Secretagog Receptor Antagonists)
  • GPR119 Agonists
• 6.6. Conclusions: Development of Novel Antidiabetics and the CHI Diabetes Survey

Chapter 7

• Diabetic Complications
• 7.1. Microvascular Complications
  • Diabetic Retinopathy
  • Diabetic Neuropathy
  • Diabetic Nephropathy
• 7.2. Prevention of Diabetic Complications
• 7.3. Pathogenesis of Diabetic Complications
  • Four Pathogenic Pathways in Diabetic Complications
  • A Unifying Model for Induction of Microvascular Diabetic Complications
  • Induction of Macrovascular Complications in Insulin-Resistant and Diabetic Individuals
• 7.4. Novel Drugs and Therapeutic Strategies for Diabetic Complications
  • Drugs for Diabetic Complications in Clinical Trials
  • Ranirestat
  • Ranibizumab and Pegaptanib
  • Ruboxistaurin
  • Alagebrium
  • Pyridoxamine
  • Sulodexide
• 7.5. Novel Therapeutic Strategies for Diabetic Complications
  • Therapeutic Strategies Based on Brownlee' s Unified Diabetic Complications Model
  • Development of Transketolase Activators
  • Development of PARP Inhibitors
  • Development of Catalytic Antioxidants
  • A Novel Therapeutic Strategy for Diabetic Retinopathy Based on Targeting Extracellular Carbonic Anhydrase and Kallikrein

Chapter 8

• Outlook
• 8.1. A Disease of Progress
• 8.2. Where to Go from Here
• 8.3. Addressing Unmet Needs
• 8.4. Aiming for Multiple Targets

Appendix

References

Company Index with Web addresses