PATHOPHYSIOLOGY OF DIABETIC RETINOPATHY

Researchers are hopeful that findings from metabolic profiling studies will lead to better understanding of the pathophysiology of diabetic retinopathy and thus the development of new and personalised treatment regimens. Speaking at the 12th EURETINA Congress, Milam A Brantley Jr MD, PhD, described the rationale for metabolic profiling, results from proof of concept studies showing that patients with diabetic retinopathy could be discriminated from normal controls based on differences in vitreous and serum metabolic profiles, and the follow-up research programme that is currently under way.

“All ophthalmologists have seen diabetic patients who do not develop diabetic retinopathy despite having a long history of disease and suboptimal blood glucose control as well as those at the other end of the spectrum who present with signs of retinopathy at the time of diabetes diagnosis or with eye disease that is rapidly progressive despite seemingly good glucose control. It is likely that genetics plays some role in these different clinical scenarios, and several genetic polymorphisms have been linked with diabetic retinopathy. However, the identified associations have not been that robust. Therefore, it appears there is more to the story, and environmental factors affecting metabolic pathways are likely the missing piece,†said Dr Brantley, assistant professor of ophthalmology and visual sciences, Vanderbilt University Medical Centre, Nashville, TN.

“We are taking a systems approach using metabolomic analysis to investigate environmental factors impacting diabetic retinopathy. Then we aim to combine information on metabolic and genetic variations to determine profiles associated with disease development and treatment response. We hope this will help us identify patients at risk for diabetic retinopathy and interventions that may be most effective for an individual based on that person’s unique genotype and metabolomic profile.†The metabolome, which represents a snapshot of an individual’s physiological state, is comprised of 3,000-10,000 unique metabolites. The metabolomic analyses of collected serum and vitreous specimens and bioinformatics are being done in collaboration with Dean Jones PhD, and Youngja Park PhD at Emory University, Atlanta, GA.

The proof of concept studies discussed by Dr Brantley compared the metabolomic profiles of archived samples collected at the time of vitreoretinal surgery from patients with proliferative diabetic retinopathy to those from non-diabetic controls. For the serum samples, the metabolites that differed significantly between the two groups matched most commonly with pathways of steroid biosynthesis, primary bile acid biosynthesis, arginine and proline metabolism, and arachidonic acid metabolism. Pathway analysis for the vitreous samples also identified significant differences in arginine and proline metabolism separating the diabetic retinopathy patients and controls along with differences in pentose and glucuronate interconversions and ABC transporters.

“Now we are further examining the highly represented pathways, recognising that separating patients with diabetic retinopathy and controls may not be as simple as identifying a difference in a single metabolite,†Dr Brantley said. Dr Brantley noted that the Metabolomics of Diabetic Retinopathy study under way at the Vanderbilt Eye Institute has entered over 300 patients since it was launched in July, 2011. In addition to comparing patients with diabetic retinopathy and normal controls, work has begun to compare the metabolomics profiles in serum and vitreous samples of diabetic patients with and without retinopathy.