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Posted by Claudia on 20:47:49 2004/07/27
Retinopathy: New Research, Unifying Concepts CME/CE
Disclosures
Hans-Peter Hammes, MD, PhD
At this year's American Diabetes Association (ADA) Scientific Sessions, there were 122 presentations related to diabetic retinopathy. While this number indicates the healthy state of research into this important complication, it is, of course, impossible to cover all this information in this report. What follows is a selection of the research presented on retinopathy, and I refer the interested reader to the CD-ROM of all the abstracts presented at the meeting, which is available from the ADA.
A Unifying Concept of Microvascular Complications
The Banting Medal for Scientific Achievement, the most prestigious award of the ADA, was given to Michael Brownlee, MD,[1] Albert Einstein College of Medicine, New York, NY, for his achievements related to the identification of the mechanism that underlies the pathogenesis of vascular complications in diabetes. Dr. Brownlee, who received the ADA Award for Outstanding Scientific Achievement in 1993 for his work on advanced glycation in the pathogenesis of diabetic complications, was also awarded the Claude Bernard medal, the highest scientific prize of the European Association for the Study of Diabetes, in 2003. The crucial progress made by the work of Dr. Brownlee and his coworkers and collaborators is the identification of a unifying concept that ties together the "pieces of the puzzle" of microvascular complications.
For many years, it has been a widely accepted notion that 4 independent pathways, which are all driven by hyperglycemia, play major roles in vascular damage, for example, of the retina:
The polyol pathway converts excess intracellular glucose into sugar alcohols via activity of the enzyme aldose reductase. A concomitant change then occurs in the cell's redox state and in the level of an important intracellular antioxidant system, the glutathione system.
High levels of intracellular glucose activate the enzyme protein kinase C (PKC) by the overflow of glycolytic intermediates into synthesis of diacyl-glycerol, which is a known potent stimulus for PKC. This enzyme system, when activated, plays a major role in the cell's diverse functions, some of which are altered in a way that is found in diabetic retinopathy.
The formation of advanced glycation end products (AGEs) occurs. This particular pathway, which is initiated by the glycolytic intermediate glyceraldehyde-3-phosphate, has been extensively studied by Dr. Brownlee and colleagues. They explained that intracellular rather than extracellular AGEs are important for the cellular changes observed in diabetic tissues, and that their formation is much quicker than previously assumed. Three main consequences have been found in association with AGEs inside cells: (1) functional alterations of intracellular proteins; (2) altered interaction with AGE-receptors; and (3) altered interactions with matrix and other cells.
The hexosamine pathway, which has been found to become activated when glucose levels are high in cells, is used to process an upstream glycolytic intermediate, but with the deleterious consequence of permanent modification of proteins and transcription factors by the product of the pathway, N-acetyl-glucosamine.
Inhibitors of all these pathways have been studied in experimental models of diabetic retinopathy or other microvascular complications, and most of the experiments have demonstrated efficacy. However, not satisfied with the then-fragmented picture, Dr. Brownlee went on to look for a common denominator of these seemingly unrelated pathways, and found that mitochondrial overproduction of reactive oxygen species (ROS), due to increased flux through the glycolytic pathway, activated an enzyme system -- called poly-ADP-ribose polymerase -- which in turn inactivated an enzyme that locates in the glycolytic pathway, thus inhibiting it. The consequence was a shared overflow in the above-mentioned pathways, because all of the intermediates accumulating upstream of the inhibited enzyme were initiators of the 4 biochemical pathways mentioned.
Having identifed the unifying mechanism, Dr. Brownlee and collegues studied new therapies based on these findings. One concept was to shift the toxic intermediates away from toxic into nontoxic pathways, which is possible, for example, by activating the enzyme transketolase by thiamine (vitamin B1). Studies in cell culture and in experimental models of diabetic retinopathy showed that activation of transketolase led to a normalization of the hyperglycemia-induced biochemical abnormality, and, even more importantly, to the prevention of retinal damage. Another approach was to inhibit the ROS-induced enzyme poly (ADP-ribose) polymerase 1 (PARP), and administration of PARP inhibitors to diabetic animals also yielded promising results.
With this new concept, an improved understanding of the underlying pathobiochemistry and cell biology of diabetic angiopathy was achieved; this led to the logical development of new therapeutic strategies, which will be seen in clinical studies.
Other reports of research in retinopathy are available at the link below:
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