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Advances in Biochemical Mechanisms of Diabetic Retinopathy European Review for Medical and Pharmacological Sciences 2007; 11: 155-163 Advances in biochemical mechanisms of diabetic retinopathy C. GIUSTI, P. GARGIULO* Department of Ophthalmology, University “Campus Bio-Medico” – Rome (Italy) *Department of Internal Medicine, University “La Sapienza” – Rome (Italy) Abstract. – Diabetes mellitus is a major lar subretinal fibrosis or proliferative retinopathy cause of blindness in the working population (PDR) with neovascular glaucoma and tractional of the Western World. Numerous large, retinal detachment (RD). prospective, randomized clinical trials have delineated the current standard prevention and The medical, social and financial impact of treatment protocols including intensive diabetic retinopathy (DR) is substantial: in the glycemic and blood pressure control as well as USA, diabetes affects over eighteen million laser photocoagulation for clinically significant people, being DR present in nearly all persons macular edema and/or proliferative retinopathy with duration of the disease of 20 years or at a high risk for tractional retinal detachment. more. If this complication remains untreated, However, despite all these interventions, vi- about 60% of subjects with PDR are expected sion loss from diabetic retinopathy still occurs at an alarming rate and no data provide an ade- to become blind within five years in one or quate explanation for the serious and rapid in- both eyes. Blindness is estimated to occur year- volvement of the retinal microcirculation that ly in over 10,000 patients affected by diabetes may be observed in the disease despite a good in the USA2-5. metabolic control. In fact, there is now ample Despite the growing concern of DR, its ae- of evidence that the development of diabetic tiopathogenesis is still not completely under- retinopathy is a multifactorial process where genetic, metabolic and growth factors play an stood. Most retinal cells are affected by the important role. Some biochemical mecha- metabolic abnormalities of diabetes, but the nisms, supposed to be involved in the patho- sight-threatening manifestations of DR are ulti- genesis of diabetic retinopathy, have been mately attributable to capillary damage (macu- highlighted in this review. lar edema due to abnormal permeability of bar- rier capillaries, and ischemia with unregulated Key Words: angiogenesis due to capillary closure). There is Biochemical mechanisms, Diabetes, Diabetic no doubt that timely tight glycemic control retinopathy, Retina. with glycosylated hemoglobin (HbA1c) close to the normal range (4.0-6.0%) should lead to a significant decrease in incidence and progres- sion of retinopathy4,5. However, only a minori- ty of diabetics achieve near-normal glycemia soon and on a long-term basis and no data pro- vide an adequate explanation for the serious Introduction and rapid involvement of the retinal microcir- culation that may be observed in the disease Diabetes mellitus is a major cause of blindness despite a good metabolic control. Moreover, in among young adults in economically developed a subgroup of patients, proliferation may per- societies1-5. Its most frequent and potentially sist even after well done full scatter laser ap- blinding complications are represented by exuda- plications (still the first-line treatment of tive maculopathy with clinically significant mac- choice for high risk retinal microangiopathy), ular edema (DME), intravitreal or preretinal he- resulting in a 30-50% risk of severe visual loss morrhages, macular pigmentary changes, macu- within the next 5 years2,3. Corresponding Author: Cristiano Giusti, MD; e-mail: [email protected] 155 C. Giusti, P. Gargiulo Pathogenesis formation of advanced glycation end products (AGEs); increased de-novo synthesis of diacyl- Hyperglycemia glycerol from glucose, causing protein-kinase C At present, the most effective medical treatment (PKC) activation; oxidative-nitrosative stress for DR is represented by glycemic control2-6. Two with overproduction of reactive oxygen species major trials have demonstrated the effect of “in- (ROS)2,3. More recently, it has been established tensive” blood glucose in reducing the incidence that reactive oxygen and nitrogen species trigger and progression of DR. The Diabetes Control activation of mitogen-activated protein kinases and Complications Trial (DCCT) has implicated (MAPKs) and poly(ADP-ribose) polymerase hyperglycemia as a major pathogenetic factor in (PARP), as well as the inflammatorycascade, and type 1 patients and a strong correlation has been these downstream mechanisms are also involved observed between the glycemic control and the in the pathogenesis of diabetes complications. incidence and progression of diabetic microvas- The interactions among various hyperglycemia- cular complications. In particular, the adjusted initiated mechanisms are not completely under- mean risk for development of any retinopathy stood, and the relationship between increased al- was reduced by 76% in the intensive therapy, dose reductase activity and the oxidative-ni- compared with the conventional group. For those trosative stress/PARP activation has recently be- with some retinopathy already, the intensive come a focus of interest. According to several group had a higher incidence of progression dur- studies performed in the diabetic lens, nerve, reti- ing the first year whereas from 3 years onwards, na and high-glucose–exposed endothelial cells, the progression of retinopathy was reduced in the increased aldose reductase activity leads to ox- intensive group by 54%. An adverse effect shown idative stress9. However, it has also been reported by the DCCT is that intensive diabetes therapy that increased aldose reductase activity is a con- reduces plasma levels of LDL cholesterol and sequence rather than a cause of oxidative stress triglycerides but increases the risk of major (in particular, mitochondrial superoxide produc- weight gain, which might adversely affect the tion) and PARP activation in the pathogenesis of risk of cardiovascular disease7. diabetes complications9. Similar results were observed for type 2 dia- As a consequence of all this, beside the opti- betics in the United Kingdom Prospective Dia- mal glycemic control that always needs to be betes Study (UKPDS) group8. In this study, pa- achieved in each patient, pharmacologic inhibi- tients who were assigned to intensive glucose tion of the above indicated pathways might pre- control had a 25% risk reduction in microvascu- vent some of the characteristic lesions of DR, lar endpoints, including the need for retinal pho- such as loss of retinal pericytes and microa- tocoagulation. Both studies showed that neurysm formation, changes in retinal hemody- glycemic control is protective for all levels of namics, and aberrant neovascularization. control: there is no glycemic threshold below which a reduction in microvascular complica- Polyol Accumulation tions is not observed. The current recommenda- Aldose reductase, the first and rate-limiting tion is for maintaining the glucose levels as near enzyme in the polyol pathway, reduces glucose normal as possible. However, because of some to sorbitol using NADPH as a cofactor; sorbitol risks associated to hypoglycemia (such as hospi- is then metabolized to fructose by sorbitol de- talizations and possibly deaths while operating hydrogenase, which uses NAD+ as a cofactor9. motor vehicles), the glycemic control targets The polyol (sorbitol) pathway of glucose me- should be individualized. Therapy should be di- tabolism is activated in many cell types when rected toward achieving the lowest glycemic lev- intracellular glucose concentrations are very el that is the safest in terms of hypoglycemic risk high, and it can generate cellular oxidative for each patient. stress through a variety of biochemical abnor- Hyperglycemia is involved in the pathogenesis malities, including myo-inositol depletion and of diabetic neuropathy, retinopathy, nephropathy, downregulation of Na/K ATP-ase activity, and macrovascular disease via multiple mecha- NAD+/NADH and NADP+/NADPH redox im- nisms, the best studied of which are the follow- balances, changes in fatty acid metabolism, im- ing: increased flow through the aldose-reductase paired neurotrophic support, and upregulation pathway (increased aldose reductase activity); of vascular endothelial growth factor (VEGF)10. nonenzymatic glycation and glycoxidation with The polyol pathway appears to be both a 156 Advances in biochemical mechanisms of diabetic retinopathy “dream” and a “dread” target by devising venting retinal and neural damage in diabetes strategies to prevent DR. The pathway is a have been highlighted, thus justifying further dream target because its activation is immedi- clinical trials of specific, potent, and low-toxic ately linked to hyperglycemia, generates vari- ARI9. ous types of cellular stress, and occurs promi- nently in the tissues that develop complications, AGEs Accumulation thus promising returns beyond retinopathy. In Chronically increased amounts of glucose am- addition, polymorphisms of the aldose reduc- plify the physiological process of nonenzymatic tase gene may help in predicting individual sus- protein glycosylation (glycation). For example, ceptibility to retinopathy and other microvascu- glycated hemoglobin (HbA1c) is an acknowl- lar complications, and the enzymatic function edged indicator of time-integreted glycemia4. of aldose reductase can be specifically inhibit- Glucose forms labile links with the NH2-termi- ed. However,
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