- •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
50 |
Midena |
diabetes. Moreover, Mehra et al. [28] demonstrated, using CCM, a significant improvement in corneal nerve fiber density and nerve fiber length within 6 months after pancreas transplantation in patients with type 1 diabetes, indicating an early repair process with the restoration of euglycemia. Regeneration of CSNP was demonstrated after refractive surgery [29, 30]. In diabetes, nerve fiber damage is caused by hyperglycemia and oxidative stress [31–33] and not by fiber axotomy, as in refractive surgery [29, 30]. Neurons are obligate glucose users, and whereas some neurons express glucose transporters, glucose may enter the cell solely based on concentration gradient [32]. This makes neurons of the peripheral nervous system particularly vulnerable to hyperglycemia [32]. Vincent et al. [31] reviewed the evidence that indicates that glucose-mediated oxidative stress is an inciting event in the development of diabetic neuropathy. In a pilot study on CSNP regeneration in diabetic patients under topical antioxidant therapy, we observed an increase in NF, NFL, NBe, and nerve sprouting.
CONCLUSION
CCM is currently the key diagnostic technique in evaluating and monitoring CSNP and CDN in vivo. Quantification of CSNP parameters allows a correct, reproducible, and objective in vivo, noninvasive approach to CDN, allowing to characterize peripheral diabetic neuropathy, a potentially highly disabling complication of diabetes, and CCM may represent a valid tool in monitoring CSNP regeneration, which may have important implications for corneal healing and health.
REFERENCES
1. Mokad A, Ford ES, Bowman BA, Nelson DE, Englegau MM, Vinicor F, et al. Diabetes trends in the US: 1990–1998. Diabetes Care. 2000;23:1278–83.
2. Gooch C, Podwall D. The diabetic neuropathies. Neurologist. 2004;10:311–22.
3. Partanen J, Niskanen L, Lehtinen J, Mervaala E, Siiitonen O, Uusitupa M. Natural history of peripheral diabetic neuropathy in patients with non-insulin-dependent diabetes mellitus. N Engl J Med. 1995;333:89–94.
4. Park TS, Park JH, Beak HS. Can diabetic neuropathy be prevented? Diabetes Res Clin Pract. 2004;66:S53–8.
5. Boucek P. Advanced diabetic neuropathy: a point of no return. Rev Diabet Stud. 2006;3: 143–50.
6. Rahman M, Griffin SJ, Rahtmann W, Wareham NJ. How should peripheral neuropathy be assessed in people with diabetes in primary care? A population based comparison of four measures. Diabet Med. 2003;20:368–74.
7. Daube JR. Electrophysiologic testing in diabetic neuropathy. In: Dyck P, Thomas P, editors. Diabetic neuropathy. Philadelphia: WB Saunders; 1999. p. 213–5.
8. Smith AG, Howard JR, Kroll R, Ramachandaran P, Hauer P, Singleton JR, et al. The reliability of skin biopsy with measurement of intraepidermal nerve fiber density. J Neurol Sci. 2005;228:65–9.
9. Umapathi T, Tan WL, Cheong Loke S, Cheow Soon P, Tavintharan S, Huak Chan Y. Intraepidermal nerve fiber density as a marker of early diabetic retinopathy. Muscle Nerve. 2007;35:591–8.
10. Midena E, Cortese M, Miotto S, Gambato C, Cavarzeran F, Ghirlando A. Confocal microscopy of corneal sub-basal nerve plexus: a quantitative and qualitative analysis in healthy and pathologic eyes. J Refract Surg. 2009;25:S125–9.
Corneal Diabetic Neuropathy |
51 |
11. Brugin E, Ghirlando A, Gambato C, Midena E. Central corneal thickness. Z-ring corneal confocal microscopy versus ultrasound pachimetry. Cornea. 2007;26:303–7.
12. Oliveira-Soto L, Efron N. Morphology of corneal nerves using confocal microscopy. Cornea. 2001;20:374–84.
13. Muller LJ, Pels L, Vrensen GFJM. Ultrastructural organization of human corneal nerves. Invest Ophthalmol Vis Sci. 1996;37:476–88.
14. Muller LJ, Marfurt CF, Kruse F, Tervo TMT. Corneal nerves: structure, contents and function. Exp Eye Res. 2003;76:521–42.
15. Ohashi Y. Diabetic keratopathy. Nippon Ganka Gakkai Zasshi. 1997;101:105–10.
16. Creuzot-Garcher C, Lafontaine PO, Gualino O, D’Athis P, Petit JM, Bron A. Study of ocular surface involvement in diabetic patients. J Fr Ophtalmol. 2005;28:583–8.
17. Rao GN. DR P Siva Reddy Oration. Diabetic keratopathy. Indian J Ophthalmol. 1987;35:16–36. 18. Schultz RO, Peters MA, Sobocinski K, et al. Diabetic corneal neuropathy. Trans Am Oph-
thalmol Soc. 1983;81:107–24.
19. Didenko TN, Smoliakova GP, Sorokin EL, et al. Clinical and pathogenetic features of neurotrophic corneal disorders in diabetes. Vestn Oftalmol. 1999;115:7–11.
20. Tavakoli M, Kallinikos PA, Efron E, Boulton AJM, Malik RAM. Corneal sensitivity is reduced and relates to the severity of neuropathy in patients with diabetes. Diabetes Care. 2007;30:1895–7.
21. Midena E, Brugin E, Ghirlando A, Sommavilla M, Avogaro A. Corneal diabetic neuropathy: a confocal microscopy study. J Refract Surg. 2006;22:S1047–52.
22. Rosenberg ME, Tervo TMT, Immonen IJ, Muller LJ, Gronhagen-Riska C, Vesaluoma H. Corneal structure and sensitivity in type 1 diabetes mellitus. Invest Ophthalmol Vis Sci. 2000;41:2915–21.
23. Boulton AJ, Vinik AI, Arezzo JC, et al. Diabetic neuropathies: a statement by the American Diabetes Association. Diabetes Care. 2005;28:956–62.
24. Chang PY, Carrel H, Huang JS, et al. Decreased density of corneal basal epithelium and subbasal corneal nerve bundle changes in patients with diabetic retinopathy. Am J Ophthalmol. 2006;142:488–90.
25. Kallinikos P, Berhanu M, O’Donnel C, Boulton AJM, Efron N, Malik RA. Corneal nerve tortuosity in diabetic patients with neuropathy. Invest Ophthalmol Vis Sci. 2004;45:418–22.
26. Malik RA, Kallinikos P, Abbott CA, et al. Corneal confocal microscopy: a non-invasive surrogate of nerve fibre damage and repair in diabetic patients. Diabetologia. 2003;46:683–8.
27. Quattrini C, Tavakoli M, Jeziorska M, et al. Surrogate markers of small fiber damage in human diabetic neuropathy. Diabetes. 2007;56:2148–54.
28. Mehra S, Tavakoli M, Kallinikos PA, et al. Corneal confocal microscopy detects early nerve regeneration after pancreas transplantation in patients with type 1 diabetes. Diabetes Care. 2007;30:2608–12.
29. Cavillo MP, McLaren JW, Hodge DO, Bourne WM. Corneal reinnervation after LASIK. Prospective 3-year longitudinal study. Invest Ophthalmol Vis Sci. 2004;45:3991–6.
30. Erie J, McLaren JW, Hodge DO, Bourne WM. Recovery of corneal subbasal nerve density after PRK and LASIK. Am J Ophthalmol. 2005;140:1059–64.
31. Vincent AM, Russel JW, Low P, Feldman EL. Oxidative stress in the pathogenesis of diabetic neuropathy. Endocr Rev. 2003;25:612–8.
32. Sullivan KA, Feldman EL. New developments in diabetic neuropathy. Curr Opin Neurol. 2005;18:586–90.
33. McHugh JM, McHugh WB. Diabetes and peripheral sensory neurons: what we don’t know and how it can hurt us. AACN Clin Issues. 2004;15:136–49.