Continued progression of retinopathy despite spontaneous recovery to normoglycemia in a long-term study of streptozotocin-induced diabetes in rats

Background: This long-term (2.3 years) study determines the temporal relationship between systemic glucose levels and the progression of diabetic retinopathy during the natural course of streptozotocin-induced diabetes in rats. Methods: Of 367 rats, 200 were randomly assigned into a group injected with streptozotocin (50 mg.kg(-1)) and 167 into a control group. Subsets of the rats were killed at 6, 28, 40, 65, 90 and >100 weeks post induction to allow the severity of retinopathy to be assessed quantitatively and qualitatively by trypsin digests of the retinal vasculature. Concurrently blood glucose, body weight and death rate were monitored, Results: Three glycemic phases were observed in the streptozotocin rats. In phase 1 (0 to 36-40 weeks) hyperglycemia was established and maintained. In phase 2 (36-40 to 84-90 weeks) normoglycemia was restored, and maintained during phase 3 (84-90 to 120 weeks). Control rats were normoglycemic throughout. The retinal microangiopathy was marked at 28 weeks during phase 1, developed more slowly in phase 2 and continued to worsen with loss of capillaries in all retinas and saccular microaneurysms present in 50% of retinas in phase 3, Cumulative death rate in streptozotocin rats also followed three phases, with maximum vulnerability occurring between 28 and 40 weeks. Body weight was significantly lower in streptozotocin rats throughout, increasing slowly in phase 1, then more rapidly during and after spontaneous glycemic recovery. Conclusion: The worsening retinopathy, despite sustained recovery to normoglycemia, implies that good glucose control alone does not stop the progression of the retinal microangiopathy at this late stage.