DOES "METABOLIC MEMORY" CONTRIBUTE TO INSULIN-THERAPY RESISTANT EPIGENETIC MODIFICATIONS IN DIABETIC RETINOPATHY

investigators

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DOES "METABOLIC MEMORY" CONTRIBUTE TO INSULIN-THERAPY RESISTANT EPIGENETIC MODIFICATIONS IN DIABETIC RETINOPATHY

in summary

Diabetic retinopathy remains the leading cause of blindness in working age adults. Currently, there are no approved and demonstrated treatments for diabetic retinopathy aside from insulin replacement therapy and blood pressure control. Recent longitudinal study reports have demonstrated that despite achieving stable blood glucose levels and HbA1c control, patients formerly under non-intensive insulin therapy continue to have a higher rate of diabetic retinopathy and other complications.

the details

Funded by the National Eye Institute

Overview

Diabetic retinopathy remains the leading cause of blindness in working age adults. Currently, there are no approved and demonstrated treatments for diabetic retinopathy aside from insulin replacement therapy and blood pressure control. Recent longitudinal study reports have demonstrated that despite achieving stable blood glucose levels and HbA1c control, patients formerly under non-intensive insulin therapy continue to have a higher rate of diabetic retinopathy and other complications. This provides the first large-scale clinical evidence for the hypothesis of "metabolic memory", in which a period of poor diabetes management continues to impact development of retinopathy and other complications for years after normal control has been achieved. Understanding the role of metabolic memory in diabetic complications is vitally needed, as the memory phenomenon is obviously not overcome by current treatment regimens. This clinical phenomenon also leads to the question of what molecular events occur during poor control and how do these events persist for years after good glycemic control is established. This series of studies seeks to address this issue through an investigation of the hypothesis that poor control causes epigenomic changes that are not fully reversed with improved diabetes management. In the ongoing studies we will define retinal gene promoter DNA methylation and associated chromatin modifications in the context of diabetes with variable glycemic control. We will then use bioinformatic tools to compare the epigenetic state to retinal gene/protein expression. Epigenetic changes will be confirmed by orthogonal methods and the resulting transcript and protein expression changes will be localized to specific retinal layers and cell types. Lastly the processes that regulate DNA methylation and histone modification will be examined. These studies will serve as the basis for future interventional studies, which seek to maintain or return the normal retina epigenetic state as well as mechanistic studies investigating how specific genes are targeted for epigenetic modifications during hyperglycemia.  

Significance of the research

The significance of our research is that past periods of poor glycemic control can continue to adversely affect health long after normal glycemic control has been restored.  Understanding the epigenetic legacy of these periods of poor glycemic control can provide targets for developing treatments that will either restore the normal epigenetic state or counteract the persistent epigenetic mechanisms.

Innovation

With the advent of new next generation sequencing technologies we have been applying massive amounts of sequencing data to epigenetic questions.  This includes developing a series of new epigenetic methods that allow use to analyze DNA methylation on the genome-wide and gene specific levels.  Combining these new approaches with our rodent models of altered glycemic control provide the opportunity to examine for the first time DNA methylation changes within a relevant biological context.