Resistance of retinal inflammatory mediators to suppress after reinstitution of good glycemic control: novel mechanism for metabolic memory

Diabetic retinopathy resists arrest of its progression after reestablishment of good glycemic control that follows a profound period of poor glycemic control. The objective of this study was to elucidate the role of inflammation in the resistance of retinopathy to arrest after termination of hyperglycemia. Streptozotocin-diabetic rats were (a) maintained either in poor glycemic control [PC group; glycated hemoglobin (GHb)>11%] or in good glycemic control (GC group; GHb<7%) for 12 months or (b) allowed to be in poor glycemic control for 6 months followed by good glycemic control for 6 additional months. At 12 months, retina was analyzed for pro-inflammatory mediators. Twelve months of PC increased retinal interleukin 1 beta (IL-1 beta) mRNA by 2-fold and its protein expression by 25% compared with the values obtained from normal rat retina. Tumor necrosis factor alpha (TNF-alpha) was elevated approximately 3-fold (both mRNA and protein), and the receptors for IL-1 beta and TNF-alpha were increased by 40% each. The concentrations of intercellular cell adhesion molecule 1 and vascular cell adhesion molecule 1 were elevated by 40% and 150%, respectively, and inducible nitric oxide synthase transcripts were elevated by 6-fold. Six months of good glycemic control that followed 6 months of poor glycemic control failed to reverse the elevations in IL-1 beta. TNF receptor type 1, and intercellular cell adhesion molecule 1 but had some beneficial effects on TNF-alpha, inducible nitric oxide synthase, and vascular cell adhesion molecule 1, however these mediators remained significantly elevated. However, the GC group showed no significant change in the retinal pro-inflammatory mediators compared with the normal rats. Failure to reverse retinal inflammatory mediators supports their important role in the resistance of retinopathy to arrest after cessation of hyperglycemia. (C) 2010 Elsevier Inc. All rights reserved.