Histologic and Electroretinographic Evidence of Diabetes-induced Retinal Neurodegeneration
Open Access
- Author:
- Robinson, William Foster
- Graduate Program:
- Anatomy
- Degree:
- Doctor of Philosophy
- Document Type:
- Dissertation
- Date of Defense:
- September 29, 2010
- Committee Members:
- Alistair J Barber, Dissertation Advisor/Co-Advisor
Alistair J Barber, Committee Chair/Co-Chair
Patricia Mclaughlin, Committee Member
Steven Abcouwer, Ph D, Committee Member
Samuel Shaomin Zhang, Committee Member - Keywords:
- diabetes
retinopathy
neurodegeneration
photoreceptor
electroretinography
ERG
immunohistochemistry - Abstract:
- Diabetic retinopathy is a vision-threatening condition, currently affecting more than 5 million Americans. It is the leading cause of new cases of blindness in working-aged adults. The pathogenesis of the disease is poorly understood, but the earliest symptoms include subtle visual disturbances such as color and contrast sensitivity changes, delayed dark adaptation, and difficulty seeing in low-light environments. The earliest clinical signs of diabetic retinopathy are vascular abnormalities such as microaneurysms and edema. There is considerable evidence suggesting that retinal neurodegeneration takes place before the onset of such vascular changes. Previous research in our lab has established that retinal neurodegeneration is an apoptotic event, leading to retinal thinning. Animal models of experimental diabetes have been used to determine that retinal thinning takes place preferentially in the inner retina. The retinal ganglion cells are especially vulnerable, demonstrating the greatest loss in peripheral regions of the retina. The current study seeks to further explore the effects of diabetes on the neuronal components of retinas from human donors and from diabetic mice. The studies compiled here seek to test the hypotheses that early stages of diabetes lead to histologic evidence of neurodegeneration in human donor tissue, and that diabetes in the Ins2Akita mouse leads to alterations in rhodopsin content and electroretinographic output. Donor retinas from humans who had had diabetes for less than 10 years were compared with retinas from age-matched nondiabetic donors. Comparisons were made on the basis of retinal thickness and cell counts. Ins2Akita mice, which spontaneously develop diabetes at 4 weeks of age, were tested after being diabetic for 7 weeks. Electroretinograms were recorded and the following waveforms were analyzed for amplitude and implicit time: scotopic threshold response, a- and b- waves, and oscillatory potentials. Results of the human histopathology study indicate that, while there are no differences between retinal thickness measurements from diabetic vs. nondiabetic donors, the retinas from donors with short-term diabetes had fewer cells in the peripheral regions of the outer nuclear layer. Cell counts from the cone photoreceptors were unchanged, indicating rod loss. Studies of rod photoreceptor protein content demonstrated a decrease in rhodopsin content in diabetic mice, without a change in the protein content of other phototransduction proteins (transducin and phosphodiesterase). ERG results from diabetic mice demonstrate reduced scotopic threshold response and delayed oscillatory potentials, compared to age-matched controls. The findings presented here confirm that neurodegeneration takes place in the peripheral retina early in the progression of diabetes in humans. In contrast to animal models in which the inner retina is implicated, it may be that the photoreceptors of the outer retina are the cells most vulnerable to neurodegeneration in humans with diabetes. Diabetic mice, however, demonstrate loss of rhodopsin without concomitant photoreceptor loss. ERG results in the Ins2Akita diabetic mice show deficits in scotopic vision and changes in oscillatory potentials similar to those seen in humans with diabetes.