Table 2

Effects of Therapies on Development of Diabetic Retinopathy in Rats

Type 2 diabetes

db/db mice develop a type 2 diabetes due to loss of function mutation in the leptin receptor gene. The C57Bl/KsJ db/db has early hyperinsulinemia, obesity, and progressive hyperglycemia. Diabetes in the C57Bl/6J db/db strain is less severe. The KK mouse strain exhibits glucose intolerance and insulin resistance, and becomes obese with aging (89). Introduction of lethal yellow agouti gene (Ay) into KK mice resulted in KKAy mice (90), which are characterized by early onset and prolongation of severe levels of hyperinsulinemia, hyperglycemia, obesity, and yellow coat color (91), accompanied by pathological changes in a variety of tissues (92).

Histopathology and Rate of Development of Retinopathy

Vascular disease

C57B1/6J mice made diabetic with streptozotocin develop retinal vascular pathology characteristic of the early stages of diabetic retinopathy (degenerate, acellular capillaries (AC) and pericyte ghosts (PG); Fig. 2) beginning at about 6 months of diabetes. The degenerate capillaries and pericyte ghosts become more numerous with increasing duration of diabetes (93–95). Ins2Akita mice develop similar retinal vascular pathology with increasing duration of diabetes, becoming also significantly greater than in nondiabetic controls by 6 months of diabetes. J129sv/B16 mice having streptozotocin-induced diabetes of 4 months’ duration have been reported to develop neovascularization (96), but the claimed “neovascularization” has been poorly demonstrated and seems more likely to be only increased retinal vascular density.

The capillary disease that develops in type 2 models of diabetes seems quite similar to that seen in type 1 models. Compared to that in nondiabetic controls, genetically diabetic db/db mice have been observed to develop pericyte loss, strand-like and relatively acellular capillaries, thickening of retinal capillary basement membranes, as well

Fig. 2. Vascular histopathology characteristic of the retinopathy that develops in diabetic rats (8 months diabetes). Lesions visible include a degenerate, acellular capillary (AC) and a pericyte ghost (PG).

as blood-retinal barrier breakdown (97–99). These animals also showed increased density of retinal capillaries in the inner nuclear layer, which was interpreted as vessel proliferation (but not preretinal neovascularization). db/db mice crossed with apolipoprotein E-deficient mice, resulting in both hyperglycemia and hyperlipidemia, exhibited accelerated development of acellular capillaries and pericyte ghosts compared with littermate control diabetic animals, demonstrating hyperlipidemia can accelerate the degeneration of retinal capillaries in diabetes (100).

Pericyte ghosts and acellular capillaries with occasional microaneurysms have been reported between 20 and 64 weeks of age in the KK mouse (101). After 3 months of diabetes, the major changes in the retinal capillaries involved mitochondria, with endothelial cell hyperplasia, basement membrane thickening, and some edema and vacuolar degeneration of capillary cells (102).

Neural disease

Whether or not neurodegeneration occurs in the diabetic C57Bl/6 model is controversial. Some investigators have reported a 20–25% loss of cells in the ganglion cell layer after only 14 weeks of diabetes (103), whereas others have detected no evidence of ganglion cell loss after as long as a year of diabetes (93). Diabetic C57Bl/6 mice have not been found to show Müller glial cell activation (based on GFAP induction) (39, 104), other than a transient increase that disappears soon after induction of diabetes (93). In contrast, heterozygous Ins2Akita male mice developed significant reductions in the thickness of the inner plexiform and inner nuclear layers and in the number of cell bodies in the retinal ganglion cell layer after 22 weeks of hyperglycemia (105). After 1 month of diabetes, the numbers of apoptotic cells in the retinal ganglion cell and inner nuclear layers of diabetic KKAy mice were significantly greater than in nondiabetic controls, and the rate of cell death increased with duration of diabetes (102). Fifteen-month-old db/db mice were reported to