A histological study of STZ-diabetic rat retinas indicated that histaminergic centrifugal axons had several pathological abnormalities including swellings [43], which may indicate potential retrograde transport problems leading to distal accumulation of materials.

Nerve Fiber Layer Thickness

The evidence of histological changes in RGCs in humans is difficult to interpret because of the difficulties in collecting postmortem specimens, and there is currently no way to image ganglion cell structure in vivo. Several studies have, however, used clinical imaging techniques to measure the thickness of the NFL, which is presumably relative to the abundance of ganglion cells. A defect in the thickness of the NFL was found in a population of humans with type II diabetes using red-free fundus photography. It was present in 20% of patients with only mild retinopathy (no microaneurysms) and in 57–78% of patients with more severe vascular abnormalities [44]. Scanning laser polarimetry has also been used in several studies to assess changes in the NFL due to diabetes. In age-matched patients grouped according to their glycosylated hemoglobin levels, the NFL was significantly thinner in patients with diabetes and poor blood glucose control (HbA1c > 8%) and in patients with nonproliferative retinopathy [45]. The NFL thickness in patients in this study who maintained HbA1c < 8%, however, was not different from normal. A similar study identified an asymmetric NFL loss in the superior segment of patients with type I diabetes [46]. A further study on type II patients also indicated that NFL thickness decreased with increasing severity of diabetic retinopathy [47]. Together, these clinical studies suggest a strong link between NFL thinning, glycemic control of diabetes, increasing duration, and degree of retinopathy. Recently, a further study on NFL thickness measured by optical coherence tomography showed that panretinal photocoagulation can exaggerate the thinning of the NFL in diabetes, suggesting that laser surgery may induce further atrophy of RGC axons [48].

Thickness of the NFL in rodents has not been measured; however, one study on cross sections of optic nerve from STZ-diabetic rats indicated a reduction in the density of axons, accompanied by increases in the number of glial cells, suggesting denervation or loss of ganglion cells [49].

BIOCHEMICAL EVIDENCE OF NEURODEGENERATION AND CELL DEATH

The predominant evidence for diabetes-induced neurodegeneration in the retina comes from histological studies; however, other studies present biochemical evidence of apoptosis and neuronal dysfunction. Immunohistochemical studies suggest reductions in Bcl-2, which could be linked to increases in apoptosis [25, 50]. Further evidence includes increased activity of several caspase enzymes. A comprehensive assessment of activity of caspases in rat retinas showed that caspases-1, -2, -6, -8, and -9 become active within 2 months of the onset of diabetes in STZ rats. Similar activities were found in postmortem tissue donated from humans with diabetes. In this study, the executioner caspases-3 and -6 became active later in the course of diabetes corresponding to a period when capillary cells are expected to be lost [51]. Similarly, caspase-3 enzyme