be manifest. As can be seen, the shorter-lived models develop considerably less pathology than is characteristic of diabetic patients, likely due in part to shorter lifespan. Available evidence suggests that the earlier stages of the retinopathy (notably capillary degeneration) can contribute to the later development of later stages of the retinopathy. Since diabetes-induced degeneration of retinal capillaries has been found to occur in all species studied to date, and progressive deterioration of those capillaries can contribute to retinal ischemia and likely neovascularization over long periods of time, the data suggest that even species that develop only the earliest stages of the retinopathy can offer valuable insight regarding events at various points along the spectrum of events that ultimately leads to the advanced stages of the retinopathy.

DIABETIC PRIMATES

Type of Diabetes

Type 1 diabetes. The development of diabetic retinopathy has been studied in rhesus monkeys by alloxan, streptozotocin, or total pancreatectomy.

Type 2 diabetes. Aging primates commonly become obese and develop insulin resistance, and in some cases, also hypertension. The development of retinopathy has been studied in obese rhesus monkeys (Macaca mulatta) and cynomolgus monkeys (Macaca fascicularis) that developed diabetes spontaneously.

Histopathology and Rate of Development of the Retinopathy

Studies to date have revealed a very slowly developing retinopathy in diabetic primates. Retinal microaneurysms were found to develop infrequently in a group of 12 alloxan diabetic rhesus monkeys studied through 10–15 years of chronic glycosuria (1,2). Microaneurysms occurred in only five of the diabetic monkeys, never during the first 7 years of diabetes, and no more than four microaneurysms occurred in any eye. A dot hemorrhage occasionally was encountered ophthalmoscopically, and occurred also in nondiabetic monkeys studied for comparison, and unlike microaneurysms, the red dots showed no fluorescence during angiography and disappeared within a few days. An ischemic retinopathy with macular edema appeared in two of the monkeys, but microaneurysms were few and the relative role of diabetes or vascular hypertension in its development is uncertain (2). Microaneurysms were said to occur in three rhesus monkeys alloxan diabetic 2 to 4 years, but no photographic or other evidence was provided (3). Monkeys studied up to 15 years after induction of diabetes by streptozotocin or pancreatectomy likewise had a relative absence of vascular lesions of diabetic retinopathy, although retinal ischemia and defects in the blood-retinal barrier and macula did appear (4,5).

Retinas from the primates with type 2 diabetes show a retinopathy that seems somewhat different from the picture described for the primates with type 1 diabetes, but the duration of diabetes commonly is unknown in the spontaneous diabetes. These primates developed hemorrhages, large areas of retinal capillary nonperfusion, cotton-wool spots, intraretinal hemorrhages, and hard exudates in the macula. Formation of small IRMAs and microaneurysms was associated with the areas of nonperfusion, and some aged spontaneously diabetic monkeys developed macular edema (6–8).