- •Preface
- •Contents
- •Contributors
- •1: Living with Diabetic Retinopathy: The Patient’s View
- •My Patient Experience
- •Others’ Experiences
- •Photos of the Meaning of Diabetes
- •References
- •2: Diabetic Retinopathy Screening: Progress or Lack of Progress
- •Definitions of Screening for Diabetic Retinopathy
- •Studies Reporting the Prevalence of Diabetic Retinopathy
- •Reports on Blindness and Visual Impairment
- •Is There Evidence That Treatment for Sight-Threatening Diabetic Retinopathy Is Effective and Agreed Universally?
- •The Evidence That Diabetic Retinopathy Can Be Prevented or the Rate of Deterioration Reduced by Improved Control of Blood Glucose, Blood Pressure and Lipid Levels, and by Giving Up Smoking
- •The Evidence that Laser Treatment Is Effective
- •The Evidence That Vitrectomy for More Advanced Disease Is Effective
- •Progress of Lack of Progress in Screening for Diabetic Retinopathy in Different Parts of the World
- •References
- •3: Functional/Neural Mapping Discoveries in the Diabetic Retina: Advancing Clinical Care with the Multifocal ERG
- •Introduction
- •The Diabetes Epidemic
- •Current Treatment Focus
- •Vasculopathy and Neuropathy of the Retina
- •The Early Efforts
- •Some Breakthroughs
- •Predictive Models of Visible Retinopathy Onset at Specific Locations
- •How Is the mfERG Measured and What is it Measuring?
- •Where Are These Neural Signals Generated in the Retina?
- •Some Key Results
- •Adolescents and Adult Diabetes
- •Type 1 vs. Type 2: Differences in Retinal Function
- •References
- •4: Corneal Diabetic Neuropathy
- •Introduction
- •Corneal Confocal Microscopy
- •Corneal Nerves and Diabetes
- •Conclusion
- •References
- •5: Clinical Phenotypes of Diabetic Retinopathy
- •Natural History
- •MA Formation and Disappearance Rates
- •Alteration of the Blood–Retinal Barrier
- •Retinal Capillary Closure
- •Multimodal Macula Mapping
- •Clinical Retinopathy Phenotypes
- •Relevance for Clinical Trial Design
- •Relevance for Clinical Management
- •Targeted Treatments
- •References
- •6: Visual Psychophysics in Diabetic Retinopathy
- •Introduction
- •Visual Acuity
- •Color Vision
- •Contrast Sensitivity
- •Macular Recovery Function (Nyctometry)
- •Perimetry
- •Microperimetry (Fundus-Related Perimetry)
- •Conclusion
- •References
- •7: Mechanisms of Blood–Retinal Barrier Breakdown in Diabetic Retinopathy
- •The Protective Barriers of the Retina
- •The Inner and the Outer BRB
- •Inflammation and BRB Permeability
- •Leukocyte Mediators of Vascular Leakage
- •Other Mediators of Leukocyte Recruitment in DR
- •Structural Compromise of the BRB
- •Vascular Endothelial Growth Factor
- •Anti-VEGF Properties of Natriuretic Peptides
- •Proposed Model of BRB Breakdown in DR
- •Key Role of AZ in VEGF-Induced Leakage
- •Azurocidin Inhibition Prevents Diabetic Retinal Vascular Leakage
- •References
- •8: Molecular Regulation of Endothelial Cell Tight Junctions and the Blood-Retinal Barrier
- •The Blood-Retinal Barrier
- •The Retinal Vascular Barrier
- •The Junctional Complex
- •ZO Proteins
- •Claudins
- •Junctional Adhesion Molecules
- •Occludin and Tricellulin
- •Vascular Permeability in Diabetic Retinopathy
- •VEGF-Induced Regulation of Endothelial Permeability
- •Occludin Phosphorylation and Permeability
- •Protein Kinase C in Regulation of Barrier Properties
- •Conclusions
- •References
- •9: Capillary Degeneration in Diabetic Retinopathy
- •Vascular Nonperfusion in Diabetes: Mechanisms
- •Molecular Causes of Capillary Degeneration
- •Unexplained Aspects of Diabetes-Induced Degeneration of Retinal Capillaries
- •What Is the Relation Between the Retinal Vasculature and Neuronal Retina Structure and Function in Diabetes?
- •Conclusion
- •References
- •10: Proteases in Diabetic Retinopathy
- •Proteases in Retinal Vasculature
- •Extracellular Proteases
- •Urokinase Plasminogen Activator System (uPA/uPAR System)
- •Matrix Metalloproteinases
- •Endogenous Inhibitors of Proteases
- •Tissue Inhibitors of Metalloproteinases (TIMPs)
- •Plasminogen Activator Inhibitors (PAI)
- •Proteases in Retinal Neovascularization
- •Tissue Inhibitor of Matrix Metalloproteinases in Retinal Neovascularization
- •Inhibition of Retinal Angiogenesis by MMP Inhibitors
- •Inhibition of Retinal Angiogenesis by Inhibitors of the uPA/uPAR System
- •Proteases in Diabetic Macular Edema
- •Conclusion
- •References
- •11: Proteomics in the Vitreous of Diabetic Retinopathy Patients
- •Introduction
- •Vitreous Anatomy
- •A Candidate Approach
- •Proteomic Approaches
- •Vitreous Acquisition
- •Sample Pre-Fractionation
- •Mass Spectrometry
- •Spectral Analysis
- •Data Analysis
- •The Vitreous Proteome
- •2-DE-Based Proteomics
- •1-DE-Based Proteomics
- •Summary and Conclusions
- •References
- •12: Neurodegeneration in Diabetic Retinopathy
- •Introduction
- •Histological Evidence
- •Early Pathology Studies
- •Histological Evidence of Apoptosis
- •Gross Morphological Changes in the Retina
- •Reductions in Numbers of Surviving Amacrine Cells
- •Retinal Ganglion Cell Loss
- •Abnormalities in Ganglion Cell Morphology
- •Centrifugal Axon Abnormalities
- •Nerve Fiber Layer Thickness
- •Biochemical Evidence of Neurodegeneration and Cell Death
- •Functional Evidence of Neurodegenerative Changes
- •Electrophysiological Evidence for Neurodegeneration
- •Optic Nerve Retrograde Transport
- •Other Changes in Visual Function
- •Summary and Conclusions
- •References
- •13: Glucose-Induced Cellular Signaling in Diabetic Retinopathy
- •Introduction
- •Cellular Targets in DR
- •Endothelial Cell (EC) Dysfunction
- •Endothelial-Pericyte Interactions
- •Endothelial-Matrix Interactions
- •Signaling Mechanisms in DR
- •Altered Vasoactive Factors
- •Alteration of Metabolic Pathways
- •Polyol Pathway
- •Hexosamine Pathway
- •Protein Kinase C Pathway
- •Activation of Other Protein Kinases
- •Mitogen-Activated Protein Kinase (MAPK)
- •Increased Oxidative Stress
- •Protein Glycation
- •Aberrant Expression of Growth Factors
- •Transcription Factors
- •Transcription Regulators
- •Concluding Remarks
- •References
- •Introduction
- •The Growth-Hormone/Insulin-Like Growth Factor Pathway in Proliferative Retinopathies
- •Proliferative Diabetic Retinopathy (PDR)
- •Retinopathy of Prematurity (ROP)
- •Animal Models of Proliferative Retinopathies
- •IGFBP-3 as a Regulator of the Growth-Hormone/ Insulin-Like Growth Factor Pathway
- •Conclusion
- •References
- •15: Neurotrophic Factors in Diabetic Retinopathy
- •Diabetic Retinopathy
- •Neurotrophic Factors
- •Neurotrophins and Others
- •Nerve Growth Factor
- •Glial-Cell-Derived Neurotrophic Factor
- •Ciliary Neurotrophic Factor
- •Anti-angiogenic Neurotrophic Factors
- •Pigment-Epithelium-Derived Factor
- •SERPINA3K
- •Brain-Derived Neurotrophic Factor
- •Fibroblast Growth Factors
- •Insulin and Insulin-Like Growth Factor 1
- •Erythropoietin
- •Vascular Endothelial Growth Factor
- •Neurotrophic Factors and the Future of DR Research
- •References
- •16: The Role of CTGF in Diabetic Retinopathy
- •Introduction
- •ECM Remodeling and Wound Healing Mechanisms in Diabetic Retinopathy
- •ECM Remodeling in PCDR
- •Wound Healing Mechanisms in PDR
- •CTGF Structure and Function
- •CTGF in the Eye
- •CTGF in Ocular Fibrosis
- •CTGF in Ocular Angiogenesis
- •CTGF in Diabetic Retinopathy
- •CTGF in BL Thickening in PCDR
- •AGEs and CTGF in BL Thickening in PCDR
- •Role of VEGF in BL Thickening
- •BL Thickening in Diabetic CTGF-Knockout Mice
- •CTGF in PDR
- •Role of CTGF and VEGF in the “Angiofibrotic Switch” in PDR
- •Conclusions
- •References
- •17: Ranibizumab and Other VEGF Antagonists for Diabetic Macular Edema
- •Introduction
- •Pathogenesis of DME and Current Standard of Care
- •Ranibizumab for DME
- •Pegaptanib for DME
- •Bevacizumab for DME
- •VEGF Trap-Eye for DME
- •Other Considerations in the Management of DME
- •Combination Treatment for DME
- •DME and Quality of Life
- •Conclusions
- •References
- •18: Neurodegeneration, Neuropeptides, and Diabetic Retinopathy
- •Introduction
- •Neuropeptides Involved in the Pathogenesis of DR
- •Glutamate
- •Angiotensin II
- •Pigment Epithelial-Derived Factor
- •Somatostatin
- •Erythropoietin
- •Docosahexaenoic Acid and Neuroprotectin D1
- •Brain-Derived Neurotrophic Factor
- •Glial Cell Line-Derived Neurotrophic Factor
- •Ciliary Neurotrophic Factor
- •Adrenomedullin
- •Concluding Remarks and Therapeutic Implications
- •References
- •19: Glial Cell–Derived Cytokines and Vascular Integrity in Diabetic Retinopathy
- •Introduction
- •The BRB Functional Unit Composed of Glial and Endothelial Cells
- •Tight Junctions Between Endothelial Cells Are Substantial Barrier of the BRB
- •Major Cytokines Derived from Glial Cells Affecting Tight Junctions of the BRB
- •VEGF
- •GDNF
- •APKAP12
- •A Possible Treatment of the Retinopathy with Retinoic Acid Analogues
- •Conclusion
- •References
- •20: Impact of Islet Cell Transplantation on Diabetic Retinopathy in Type 1 Diabetes
- •Introduction
- •What Are the Benefits and Risks of Reducing Blood Glucose?
- •On Average, 3 Years Was Required to Demonstrate the Beneficial Effect of Intensive Treatment
- •The Earlier in the Course of Diabetes That Intensive Therapy Is Initiated, Even Before the Onset of Retinopathy, the Greater the Long-Term Benefits
- •Risk Reduction in the Primary Prevention Cohort
- •Risk Reduction in the Secondary Prevention Cohort
- •There Was No Glycemic Threshold Regarding Progression of Retinopathy
- •Diabetic Ketoacidosis (DKA)
- •Efforts to Normalize Blood Glucose Are Associated with Weight Gain in People with Type 1 Diabetes
- •Connecting Peptide (C-Peptide) Responders Have Less Risk of Progression of Retinopathy
- •Effects of Improved Control on Retinopathy Were Sustained in the Long-Term
- •Quality of Life Measure
- •“Metabolic Memory”: A Phenomenon Producing a Long-Term Beneficial Influence of Early Metabolic Control on Clinical Outcomes
- •Need for a More Physiologic Glycemic Control Regimen
- •Effect of Intensive Insulin Therapy on Hypoglycemia Counterregulation
- •b Cell Function
- •Whole Pancreas Transplantation
- •Effect of SPK Transplantation on Diabetic Retinopathy
- •Islet Cell Transplantation
- •Adverse Effects of Chronic Immunosuppression
- •Effect of Islet Cell Transplantation on Retinopathy
- •References
- •Index
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degree of angiogenesis than a single isoform and provide prolonged efficacy in accelerating angiogenesis [94]. VEGFA165 is the most commonly studied isoform and displays both neurotrophic and angiogenic properties [92].
Low levels of VEGF secretion are presumed to be responsible for its neurotrophic functions in the eye [9, 95]. However, VEGF is found prominently in the vitreous of patients with proliferative DR, pre-proliferative DR, and nondiabetics with choroidal neovascularization [9]. Under ischemic conditions and the appearance of new vessels, such as those observed in DR, VEGF levels increase [9, 96, 97]. In fact, VEGF expression is noted in Müller cells of the retina before any noticeable neovascularization has occurred in DR [9]. The induction of angiogenesis and vascular leakage that occur in DR are thought to occur when higher levels of VEGF are secreted due to the pathological conditions (e.g., ischemia) observed in DR [9]. VEGF increases vascular permeability [98] and thus has been suggested to play a role in the breakdown of the BRB, perhaps leading to diabetic macular edema [9, 99, 100].
Systemic anti-VEGF therapies have disadvantages when considered as possible therapies for patients with DR. Its dual roles as both a neurotrophic and a proangiogenic factor, though beneficial in some aspects, could prove detrimental in DR patients with systemic vascular problems [8]. Therefore, direct intraocular administration of a VEGF therapy is favorable. Currently, an aptamer consisting of a 28-base oligonucleotide that binds to the VEGF is in clinical trials toward the treatment of age-related macular degeneration, a condition that involves neovascularization of the choroid [101]. Another therapeutic potential is the use of ranibizumab, an antibody with high affinity to inhibit all VEGF isoforms. Clinical trials are underway to determine if this drug would be a useful therapy in the treatment of DR [102]. Regulating the expression of VEGF receptors (VEGFR-1 and 2) may be another therapeutic option. In fact, a drug that blocks VEGFR-2 has undergone initial tests as an angiogenesis inhibitor for the treatment of cancer [103], but it has not been tested as a treatment of DR.
NEUROTROPHIC FACTORS AND THE FUTURE OF DR RESEARCH
There are several additional NFs that are expressed in the retina that have yet to be studied in the diabetic retina. Although these factors may play a role in retinal development or have been shown to be modulated during retinal degeneration, they have not been studied in DR. These factors include, but are not limited to, neurturin [104, 105] and members of the neurotrophin family (NT-3, 4, 5, and 6) [106–108].
It is important to realize that characterization of retinal NFs in both the normal and DR retina would be a useful tool to further the development of therapies in the treatment and/or prevention of DR. As the incidence rates for diabetes increase and the world population’s life expectancy increases, there is an ever-increasing desire to prolong quality of life. This includes delaying the progression or halting the onset of DR. A useful therapeutic tool, such as some that have been mentioned above, to promote neuronal survival through the manipulation of neurotrophic factors in the retina could be a powerful technique in order to halt or reverse the progression of the pathological manifestations of DR.
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