Histopathology and Rate of Development of Retinopathy

Vascular disease

The models in which diabetes has been induced chemically reproducibly develop acellular, degenerate capillaries, pericyte loss and basement membrane thickening. Acellular capillaries in the diabetics have been found to become significantly more numerous than in nondiabetic rats at about 6 months of diabetes. Immunohistochemical methods have demonstrated a significant loss of pericytes after as little as 2 months of diabetes (49), whereas numbers of pericyte ghosts (a different way to assess pericyte loss) have not been significantly increased above normal until about 6 months of diabetes (37, 50–52). More advanced stages of the retinopathy (microaneurysms, IRMA (intraretinal microvascular abnormalities), and hemorrhages) have not been reported to develop reproducibly, although some of these abnormalities have been reported at very long durations of diabetes (53). Vascular abnormalities consistent with possible intraretinal neovascularization also have been reported (53), but have not been observed in the preretinal vitreous.

The retinal vascular disease in spontaneous models of type 1 models seems consistent with that reported in chemically induced diabetes. Diabetic BB rats exhibit retinal lesions similar to those observed in rats having chemically induced diabetes, including pericyte loss, basement membrane thickening, “microinfarctions with areas of nonperfusion” (i.e., capillary degeneration), and an absence of microaneurysms after 8–11 months of diabetes (54–58). Pancreas transplantation inhibited development of the retinal microvascular lesions (59). Studies of vascular histopathology in Torii (SDT) rat retina seem contradictory. Histology and fluorescein angiography reportedly demonstrated nonperfusion and neovascularization in the retina at the extraordinarily short duration of 5–10 weeks of diabetes (60), but another report claimed that Torii rats at age of 50 weeks show proliferative retinopathy without vascular nonperfusion (61). Photomicrographs published demonstrating neovascularization have not been convincing. Degeneration of retinal capillaries and preretinal neovascularization has been claimed also in male WBN/Kob rats at 19 and 24 months of age, respectively (62), but photographic documentation of the new vessels has been equivocal. Retinal degeneration (not typical of diabetes) also occurred in this model (63–65).

Retinal vascular pathology in type 2 models of diabetes has been less well studied. Zucker fatty rats diabetic approximately 5 months had thickening of retinal capillary basement membrane, but the expected capillary degeneration was not apparent (66). In fact, nuclear density of retinal capillary cells was greater than normal in diabetic animals (66, 67). Likewise, mild or no retinal vascular changes were detected in GotoKakizaki (GK) rats; the ratio of retinal capillary endothelial cells to pericytes was greater than normal at 8 months of age (33), but neither pericyte ghosts nor acellular (degenerate) capillaries were detected (33).

Otsuka Long-Evans Tokushima fatty (OLETF) rats had retinal capillary basement membrane thickening at 14 months of age (36), as well as loss of cells from the inner nuclear and photoreceptor layers of the retina, ultrastructural evidence of endothelial degeneration and microaneurysm-like lesions (43). In contrast, other investigators found no pericyte ghosts and no increase in number of degenerate, acellular capillaries in 45-week-old OLETF rats, and those authors concluded that this strain of rat was not a good model of diabetic retinopathy (68).