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Willard M. Freeman, Heather D. VanGuilder Starkey, Georgina V. Bixler, Brian M. Davidson, Wendy Dunton, Sarah K. Bronson; Systems Biology Analysis Of Metabolic Memory In Diabetic Retinopathy. Invest. Ophthalmol. Vis. Sci. 2012;53(14):2408.
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© ARVO (1962-2015); The Authors (2016-present)
Diabetic retinopathy (DR) is a leading cause of blindness in working age adults, and approximately 95% of patients with Type 1 diabetes develop some degree of retinopathy despite normalization of blood glucose by insulin therapy. The goal of this study was to test the hypothesis that a period of hyperglycemia and/or loss of insulin signaling leads to molecular and anatomical retinal alterations that are not normalized with insulin replacement and establishment of normoglycemia.
To investigate the effects of 12 weeks of diabetes and variable insulin replacement on the retina, diabetes was induced in male Sprague Dawley rats by intraperitoneal streptozotocin injection. Following confirmation of hyperglycemia (>250mg/dL), diabetic rats were assigned to one of three insulin-replacement paradigms: 1) uncontrolled (no insulin replacement); 2) good control (insulin replacement initiated after one week of hyperglycemia); or 3) poor control (insulin replacement initiated after six weeks of hyperglycemia). Biochemical and anatomical correlates of retinal neuroinflammation, including mRNA, miRNA, and protein expression, synapse populations, and glial activation, were compared to nondiabetic controls.
Insulin replacement in both the good control and poor control groups normalized blood glucose and glycated hemoglobin levels, which remained significantly elevated in uncontrolled diabetic rats compared to nondiabetic controls. The majority of mRNA, miRNA and proteins dysregulated in uncontrolled diabetics, including markers of acute neuroinflammation and glial activation, were brought to nondiabetic control levels in all insulin-treated rats. Decreased synapse populations and expression of a subset of neuroinflammation-related gene and protein targets remained altered in the poor control diabetic group, suggesting that these changes can be prevented with good control, but are resistant to reversal once established.
These results demonstrate that the majority of diabetes-induced molecular, biochemical, and anatomical retinal alterations are prevented when blood glucose normalization through insulin replacement is initiated soon after diabetes onset, and can be reversed with insulin replacement even after a period of uncontrolled hyperglycemia. Those changes that are not prevented or reversed by insulin therapy, such as synapse loss, may contribute to the metabolic memory phenotype and increase the risk of complications development even after patients undergoing insulin-replacement therapy establish well-controlled diabetes management.
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