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Diabetic Eye Disease: Biochemistry, Ocular Hemodynamics and New Strategies For Prevention A. Paul Chous, M.A., O.D. Chous EyeCare Associates Tacoma, WA practice emphasizing diabetes care and education Type 1 diabetic since 1968 author of Diabetic Eye Disease: Lessons From A Diabetic Eye Doctor – How To Avoid Blindness and Get Great Eye Care (Fairwood Press, 2003) web column writer for Diabetes In Control (www.DiabetesInControl.com) and CNBC’s dLife – Your Diabetes Life (www.dLife.com) I. Introduction Epidemiology of Diabetes Mellitus – A Looming Public Health Crisis Microvascular Complications leading cause of end-stage renal disease – 100k/yr leading cause of non-traumatic amputation – 80k/yr leading cause of new blindness in those <74yo - 12-24k/yr (DRT) third leading cause of blindness overall Macrovascular Complications 5th-7th leading cause of death (100k to 400k/yr) – due to macrovascular disease Hyperglycemia and insulin resistance are associated with dyslipidemia (atherogenic glycation of LDL & hypercoagulability) II. Pathophysiology of Diabetes Complications : Vascular complications of DM are segregated (for convenience) into micro- and macrovascular entities, but share many common pathophysiologic mechanisms Macrovascular Insult (CAD, CVD, PVD) insulin resistance associated with dyslipidemia & endothelial dysfunction elevated triglycerides, LDL cholesterol, CAMs and CRP LDL particles are more atherogenic (smaller and denser) hypercoagulability due to increased plasminogen activator inhibitor 1 (PAI-1) hyperglycemia itself promotes an unfavorable lipid profile hyperinsulinemia increases BP and promotes platelet adhesion glycation of proteins and cells results in atherogenic vascular lesions DRT, AION & retinal vascular occlusion also influenced by these factors Current Therapy: treat any dyslipidemia and HTN; tighter control of blood glucose including carbohydrate restriction/portion control, increased physical activity, and weight loss to decrease visceral adipose tissue (VAT) stores that modulate insulin resistance; anti-platelet therapy Microvascular Insult (retinopathy, nephropathy, neuropathy) Four Biochemical Pathways Identified (see diagram below) polyol pathway increased sorbitol flux with osmotic pressure (as in diabetic cataract) and oxidative stress non-enzymatic glycation of proteins advanced glycation endproducts (AGEs), altered protein function and oxidative stress hyperglycemiaincreased intracellular fructose-6-phosphate via the hexosamine flux pathway alteration in gene expression, primarily through inflammatory cytokeines like PAI-1 and TNF beta-1 tissue sclerosis (as in diabetic nephropathy) and PKC-B increased endothelial glucoseincreased diacyl glycerol (DAG) activates Protein Kinase C- beta (PKC-B) which alters endothelial tight junctions (as in diabetic macular edema) and promotes vascular endothelial growth factor (VEGF), a necessary component for retinal neovascularization (PDR) Anti-Sense GAPDH Blocks Four Pathways of Hyperglycemic Damage Glucose NADPH NADP+ NAD+ Sorbitol NADPH Fructose Polyol Pathway Glucose -6-P Gln Glu Fructose-6-P GFAT Glucosamine -6-P UDP-Glc-NAc + PAI-1 + TNF-B-1 Hexosamine Pathway NAD NADH Glyceraldehyde-3-P DHAP NAD a-Glycerol-PDAGPKC Protein Kinase C Pathway NADH GAPDH O2- (Superoxide) Methylglyoxal AGEs Advanced Glycation Endproduct (AGE) Pathway 1,3 Diphosphoglycerate (useable, harmless glucose metabolite) Adapted Source: Michael A. Brownlee, M.D. “Hyperglycemia, oxidative damage, and protein kinase c” Any increase in glucose or decrease in GAPDH drives accumulation of these injurious glucose metabolites which, in turn, fuels the 4 pathways Each of these pathways is dependant upon underlying mitochondrial over-production of reactive oxygen species (i.e. superoxide) which has been shown to occur when mitochondria are exposed to excess glucose: euglycemia mitochondria ATP hyperglycemia mitochondria ATP +Superoxide Superoxide inhibits the enzyme glyceraldehyde-3- phosphate dehydrogenase (GAPDH) by activating poly(ADP-ribose) polymerase (PARP), leading to a “log jam” in normal glucose metabolism, increasing levels of intra-cellular glucose, glucose-6 phosphate, fructose-6 phosphate and glyceraldehyde-3 phosphate Inhibition of Superoxide (O2-) prevents multiple mechanisms of hyperglycemic damage. Inhibition can be achieved by: tight blood sugar control and less glycemic variability DCCT suggests less DRT and CV events with less fluctuation increasing intracellular superoxide dismutase (SOD): oral SOD not bioavailable, but Cu, Zn and Mn are trace mineral cofactors this gives a biochemical rationale for recommending specific antioxidant supplementation to all patients with diabetes pharmacologic therapies to block individual pathways are being developed and tested (inhibitors of PKC, VEGF, AGE, aldose reductase) Available pharmacologic agents for microvascular complications: Angiotensin II inhibition decreases VEGF (ACE-I or ARB), delays nephropathy and may mitigate retinopathy (DIRECT study) Statins (HMCoA inhibitors) prevent leukocyte adhesion and block AGEReceptor activation, decreasing NFB-mediated endothelial apoptosis Future medical therapies?? catalytic antioxidants that continuously neutralize O 2PARP inhibitors to increase levels of GAPDH Transketolase activators that reduce levels of the injurious glucose metabolites, F-6-P and G-3-P III.Benfotiamine – a transketolase activator synthetic, lipid soluble thiamine (Vitamin B1) used for 12 years in Europe (Germany and Spain) for treatment of painful peripheral neuropathies, including diabetic neuropathy Thiamine is a necessary cofactor for the action of Transketolase Transketolase catalyzes the intracellular breakdown of the dangerous glucose metabolites fructose-6- phosphate and glyceraldehyde-3- phosphate via the “pentose phosphate shunt” diabetics are thiamine deficient due to poor absorption and oxidative depletion, resulting in reduced transketolase activity in the hyperglycemic environment where that activity is needed most thiamine deficiency is particularly notable in vascular endothelium thiamine is water soluble, requiring active transport across the cell membrane, and oral supplementation elevates transketolase activity by 30% ”allithiamins” (lipid soluble thiamine derivatives) are passively absorbed and achieve much higher intracellular concentrations 3 recent studies (Hammes, H. et al, 2003; Ascher, E. et al, 2001; Pomero, F. et al, 2001) have demonstrated that high levels of intercellular thiamine block vascular damage caused by hyperglycemia The recent study published in Nature:Medicine (by an international team of diabetes researchers including, in the US, Dr. Michael Brownlee of the Albert Einstein College of Medicine) showed that: 1. benfotiamine increased transketolase activity by 300-400% 2. benfotiamine reduced activity in the hexosamine pathway 3. benfotiamine reduced production of DAG and PKC 4. benfotiamine reduced production of AGEs 5. benfotiamine reduced expression of NFB These 5 results were demonstrated in cultured endothelial cells In addition: 6. benfotiamine totally prevented both clinically and microscopically detectable evidence of diabetic retinopathy in a well established animal model of the disease (all control animals developed DRT) Questions: safety, efficacy, optimal dosage in humans??? How exactly might benfotiamine prevent diabetic eye disease? IV. The Protein KInase C Pathway- A Closer Look PKC Beta damages retinal vascular endothelium, leading to vessel leakage, capillary closure and recruitment of vascular endothelial growth factor (VEGF) and other vasoproliferative substances which, in turn, further activate PKC-B in a vicious cycle leading to PDR and CSME. PKC-induced ischemia also reduces production of the anti-angiogenic protein, pigment epithelium derived factor (PEDF), promoting PDR Protein Kinase C Beta in Diabetic Retinopathy adapted source: Aaron Vinik, M.D., Ph.D. From “Impact of PKC inhibition on the pathogenesis of diabetic microvascular complications” Hyperglycemia PKC B activation Retinal Vascular Injury Capillary nonperfusion PKC B activation PKC B activation vascular leakage VEGF/VPF production PEDF PKC B activation Neovascularization Macular edema Proliferative retinopathy What other forms of diabetic eye disease might benfotiamine inhibit? V. The AGE Pathway- A Closer Look Advanced Glycation Endproducts form in all mammals with age as a function of the non-enzymatic glycation of proteins. This process is analogous to “carmelization.” Hyperglycemia accelerates the production of AGEs and causes the premature aging of persons with DM. Albumin-bound AGEs activate cellular receptors (RAGE), leading to increased production of superoxide and inflammatory cytokines, including PKC- glucose metabolites bind to the amino groups of proteins (including RBCs, vascular endothelium and collagen) resulting in heterogeneous inter- and intra-molecular cross linking and altered function of those proteins AGE levels are found in higher concentrations with age and hyperglycemia (also implicated in Alzheimer’s, pulmonary fibrosis, male ED and atherosclerosis) Method of food preparation directly affects AGE levels in foods and body tissues AGEs with high temperature, low humidity preparation (baking and broiling) versus lower temperature, high humidity preparation (boiling) AGE receptors (e.g.” RAGE”) have been identified that may promote or inhibit harmful biological effects AGEs and Diabetic Eye Disease Glaucoma High levels of AGE have been found in the optic nerve head of diabetic patients and those with POAG structural changes in the cribriform plates and glial tissues that support/protect optic nerve axons (Amano et al., 2001; Albon et al., 1995) Retinopathy AGEs are found in retinal vascular endothelium of diabetics and are believed to induce pericyte loss (Stitt et al., 1997; Yamagishi et al., 1999) and levels of PKC Keratopathy AGEs are found in Bowman’s Membrane of diabetics and have been implicated in hemidesmosomal weakness and RCE syndrome (Kaji et al., 2000) Cataract Markedly AGEs in diabetic lenses covalent crosslinkings of lens crystallins (premature presbyopia), generation of hydroxyl free radicals and copper-mediated oxidation of ascorbate (cataract). Similar AGE formation seen in smokers (Saxena, et al., 2000) Vitreopathy Vitreous liquefaction and PVD occur prematurely in diabetes, where AGEs cause abnormal crosslinking of collagen fibrils and dissociation from hyaluronin (Stitt, et al., 1998) VI. Ocular Hemodynamics in Diabetes Diabetic eyes have defective vascular autoregulation Hyperglycemia impairs endothelial pericyte contractility Increased flow results in mechanical injury to retinal capillaries, shunting of flow to larger caliber vessels, capillary leakage and non-perfusion Retinal perfusion pressure (RPP) denotes the force of blood flow into the eye via the ophthalmic artery tempered by IOP, and predicts retinal vascular injury in diabetes: RPP is measured directly via ophthaldynamometry (ODM) but may be closely approximated (assuming no asymmetric carotid stenosis) by measurement of blood pressure and intraocular pressure RPP = 2/3 (MAP) – IOP where MAP = mean arterial pressure MAP = (systolic BP – diastolic BP)/3 + diastolic BP Higher IOP effectively lowers RPP, but less so than does lowering blood pressure (examples): Case 1 BP = 120/80 MAP = 93.3 and (a) IOP = 20 or (b) IOP = 10 (a) RPP = 42.2 (b) RPP = 52.2 Case 2 BP = 150/100 and (a) IOP = 20 or (b) IOP = 10 MAP = 116.6 (a) RPP = 57.8 or (b) RPP = 67.8 Conditions that increase retinal blood flow increase the risk and severity of DRT Hyperglycemia Systemic Hypertension Pregnancy Ocular Hypotension Highest Risk of sight-threatening retinopathy (4-6 times RR)* when: RPP > 50.1 mm (Type 1 DM) MAP > 97.1 mm (Type 2 DM) *Source: Sailesh, S. Kallis, C et al. Clinical and Hemodynamic risk factors for the presence of sight threatening retinopathy at presentation to a diabetic retinopathy clinic. International Diabetes Federation, Paris, 2003 Concordant with findings of the UKPDS and WESDR but more predictive of STR Diabetic eyes cannot tolerate elevated blood pressure Beware unnecessarily treating ocular HTN in diabetics with poor glycemic control, uncontrolled systemic HTN and/or longstanding disease Always measure blood pressure in patients with DM VII. New and Old Strategies For Preventing Diabetic Eye Disease Tight glycemic control (HbA1c < 6.5%) and less glycemic variability (mean glucose > 2X the standard deviation) to reduce production of ROS (O 2-) Use of single or multiple pathway inhibitors when they are proven safe and effective consider use of benfotiamine to reduce activity in all 4 harmful pathways food preparation to reduce AGEs (low temperature & high humidity) Targeted antioxidants (Cu, Mn, Zn) to increase SOD and decrease ROS Tight control of any HTN and Dyslipidemia ACE inhibitors or ARBs or both to decrease blood pressure and decrease expression of Angiotensin II and VEGF Statins to decrease leukocyte adhesion and decrease AGE-RAGE signaling Calculate MAP and RPP to gauge and improve risk, with a goal of MAP < 95mm and RPP < 50mm Hg Collaborative patient and physician education, motivation and support Prevention of diabetes The Diabetes Prevention Program (DPP) conducted at 13 US centers showed that “lifestyle modification,” with a goal of 150 minutes moderate physical activity per week and 7% weight loss, reduced the risk of developing type 2 diabetes in prediabetics by 58% - most patients failed to achieve weight targets - exercise was twice as effective as drug (metformin) - walk 30 minutes, five days each week Select References on Biochemical Pathways, including Benfotiamine Ascher, E. et al. Thiamine reduces hyperglycemia-induced dysfunction in cultured endothelial cells. Surgery. 130: 851-8 (2001) Brownlee, M. Biochemistry and molecular cell biology of diabetic complications. Nature. 414: 813-20 (2001) Brownlee, M. The pathobiology of diabetes complications: a unifying mechanism. Diabetes. 2005; 54 (6): 1615-1625. Hammes, H. et al. Benfotiamine blocks three major pathways of hyperglycemic damage and prevents diabetic retinopathy. Nature: Medicine. 9: 294-9 (2003) Pomero, F.et al. Benfotiamine is similar to thiamine in correcting endothelial cell defects induced by high glucose. Acta Diabetol. 38: 135-8 (2001) Select References on AGEs in Ocular Disease Albon, J. et al. Changes in the collagenous matrix in the aging human lamina cribrosa. BJO. 79: 368-75 (1995) Amano, S. et al. Advanced glycation end products in human optic nerve head. BJO. 85: 52-5 (2001) Kaji, Y. et al. Advanced glycation endproducts in diabetic corneas. Invest Ophthalmol Vis Sci. 41: 362-8 (2000) Saxena, P. et al. Transition metal-catalyzed oxidation of ascorbate in human cataract extracts: possible role of advanced glycation end products. Invest Ophthalmol Vis Sci. 41: 1473-81 (2000) Stitt, AW et al. Advanced glycation endproducts (AGEs) colocalise with AGE receptors in the retinal vasculature of diabetic and AGE infused rats. Am J Pathol. 150: 523-32 (1997) Stitt, AW et al. Advanced glycation endproducts in vitreous: structural and functional implications for diabetic vitreopathy. Invest Ophthalmol Vis Sci. 39: 2517-23 (1998) Yamagishi, S.et al. Angiotensin II augments advanced glycation endproduct-induced pericyte apoptosis through RAGE overexpression. FEBS Lett. 2005 Aug 15;579(20):4265-70. Select References on Ocular Hemodynamics in Diabetes Patel, V. et al. Retinal blood flow in diabetic retinopathy. BMJ. 1992 Sep 19;305(6855):678-83. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. Br Med J 1998; 703–13. Sailesh, S. et al. Clinical and Hemodynamic risk factors for the presence of sight threatening retinopathy at presentation to a diabetic retinopathy clinic. International Diabetes Federation, Paris, 2003 Dr. Paul Chous’s Web Site: www.diabeticeyes.com Dr. Chous’s email: [email protected]