Pathophysiology Section

• Preventing Ocular Complications Of Diabetes
  • Etiology of Diabetic Retinopathy in Humans and Rat Model
  • Prevention of Diabetic-like Retinopathy in Rat Model
  • Prevention of Diabetic-like Cataracts
  • Prevention of Diabetic-like Loss of Corneal Sensitivity
• Significance Of Research
  

Preventing Ocular Complications Of Diabetes

The primary cause of ocular complications of diabetes is an elevated level of plasma glucose. The excess glucose causes flux through the polyol pathway, which results in a marked increase in aldose reductase (AR) activity and the accumulation of sorbitol, the polyol of glucose, in all tissues that do not require insulin for glucose uptake. Polyol accumulation is a common denominator between the hyperglycemia of diabetes and galactosemia. High dietary galactose (30% to 62%) results in more AR activity and a greater accumulation of polyol (galactitol) than does diabetes (Figure 1), probably due to the almost fourfold higher affinity of AR for galactose than for glucose and because galactitol, unlike sorbitol, is not metabolized (Figure 2). Evidence that polyol accumulation is a critical factor is supported by the observation that the galactose-fed rat develops retinal vascular lesions that appear to be indistinguishable from those observed in human diabetic retinopathy. Thus, the galactose-fed rat makes a very reliable and convenient model of diabetic retinopathy and other ocular complications for testing pharmacological compounds as possible therapeutic agents.

Figure 1A. Rapid Polyol Accumulation in Lens Epithelium:
Sorbitol in rats rendered diabetic by streptozotocin injection [- - - - - - - - - - - - nondiabetic (n = 3); diabetic (n = 6); diabetic plus the aldose reductase inhibitor AL-1576 (n = 6); ————————— nondiabetic plus AL-1576 (n = 1)].

Figure 1B. Rapid Polyol Accumulation in Lens Epithelium: Galactitol in rats fed a 30% galactose diet nongalactosemic (n = 3); galactosemic (n = 6); galactosemic plus AL-1576 (n = 6); and —— —— —— nongalactosemic plus AL-1576 (n = 1)]. The ARI, AL-1576 (4 mg/kg/day), was administered every 24 hr by gavage. (Robison, W.G., Jr., Laver, N.M. and Lou, M.F.: The role of aldose reductase in diabetic retinopathy: prevention and intervention studies. p. 593-640. In Osborne, N.N. and Chader, G.J. (Eds.): Progress in Retinal and Eye Research v. 14, Oxford, Pergamon, 1995).

Figure 2. Polyol Pathway: There is a greater accumulation of polyol by the reduction of galactose than glucose owing to the higher affinity of aldose reductase for galactose than for glucose and the fact that there is no subsequent metabolism of galactitol. (Robison, W.G., Jr. and Laver, N.: Ocular lesions in animal models of human diabetes. p. 145-163. In Shafrir, E. (Ed.): Frontiers in Diabetes Research, Lessons from Animal Diabetes IV. London, Smith-Gordon and Company Limited, 1993).

In the galactose-fed rat model of diabetic ocular complications, diabetic-like cataracts develop within 2 to 3 weeks; corneal sensitivity is significantly decreased by 4 weeks; both diabetic-like thickening of retinal capillary basement membranes and degeneration of intramural pericytes occur by 16 to 24 weeks. Severe non-proliferative to proliferative retinopathy develops by 96 weeks. Included at these stages are capillary dilations, microaneurysms, intraretinal microvascular abnormalities (IRMA), and some intra- and extraretinal neovascularization. All these lesions, which appear to be indistinguishable from those that occur in human diabetic retinopathy, are prevented in the galactose-fed rat model by treatment with an aldose reductase inhibitor (ARI). These findings are illustrated and summarized in the following brief comments, figures, and legends.