Date of this Version
Diabetic retinopathy is the major ocular complication of diabetes, both in terms of incidence and irreversible visual impairment. In spite of modern procedures for strict blood glucose control (DCCT, 1993), laser treatment (ETDRS, 1991f; Aiello, 1994), vitrectomy (Gardner and Blankenship, 1994; Glaser, 1994b), and classical pituitary ablation (Kohner et al., 1976; Speakman et al., 1966; Poulsen, 1953), it is a serious threat to normal vision. It is mainly a vascular disorder, primarily involving microvessels (Garner, 1970). Retinal capillaries undergo multiple, extremely complex structural alterations in response to the unavoidable hyperglycemia of long-term diabetes. Because many of the angiopathies occur on microscopic vessels before retinal changes can be detected clinically, differentiating primary from secondary events in the etiology of diabetic retinopathy has been difficult. Histopathological studies are critical for determining the earliest microscopic changes that may cause the subsequent, clinically discernable, constellation of lesions comprising this disorder. Identification of the primary, triggering factors and the development of an appropriate animal model are necessary for the design and evaluation of therapies to prevent the many debilitating effects of this diabetic complication.
A summary of the salient clinical and histopathological features of diabetic retinopathy is presented first (Sections 2-5) to provide a basis for subsequent discussions of experimental models (Sections 6 and 7), currently available therapeutics (Sections 8-10), possible underlying mechanisms (Sections 11 and 12) and the significance of the galactose-fed rat model (Section 13). There has been a deliberate attempt to keep Sections 2-5 free of any reference to animal data so that the true status of current information on the human condition can be evaluated as accurately and independently as possible before assessing the relevancy of animal models. Emphasis throughout will be placed on the initial pathologies and their possible prevention or delay. There is evidence that the primary triggering event of diabetic retinopathy is the increase in tissue aldose reductase activity, which results from elevated circulating levels of glucose and other hexoses. The reduction of excess glucose results in marked intracellular accumulation of sorbitol and unleashes a cascade of biochemical and structural anomalies. Clear causative relationships have been demonstrated between increased aldose reductase activity and the earliest structural changes of diabetic retinopathy: capillary basement membrane thickening and intramural pericyte loss. These, in turn, are probably causally linked to various subsequent retinal microangiopathies such as endothelial cell proliferation, microaneurysms, dilated channels and overt neovascularization.