Metabolic memory puzzle and progression of diabetic retinopathy

Abstract

Abstract Purpose Retinopathy is one of the most feared complications of diabetes. Good glycemic control can inhibit its development, but the effects of good glycemic control on the progression of retinopathy are not immediate. Diabetic patients may take years after re‐establishment of good glycemic control to show signs of arrest of its progression. Further, good glycemic control after a profound period of poor glycemic control does not immediately benefit the progression of retinopathy, and the imprinted effects of prior glycemic control produce the long lasting benefits of good glycemic control, thus suggesting a ‘metabolic memory’ phenomenon. Results Animal models of diabetic retinopathy, including dogs and rats, have duplicated this metabolic memory phenomenon. In rats, histopathology associated with diabetic retinopathy does not stop for at least six months when good glycemic control is initiated six months after induction of diabetes. Increase in retinal oxidative stress and peroxynitrite levels and activation of apoptosis execution enzyme‐caspase‐3 resist reversal after re‐institution of good glycemic control. Hyperglycemia‐induced inactivation of retinal glyceraldehyde dehydrogenase that is postulated to activate some of the key pathways associated with the development of diabetic complications remains inactive and covalently modified, and pro‐inflammatory markers elevated. Conclusion This suggests that the process of metabolic memory is complex, and multiple pathways contribute to this resistance of diabetic retinopathy to arrest. Understanding the mechanism responsible for the tendency of diabetic retinopathy to progress after reestablishment of good glycemic control should help reveal targets for therapies to prevent its progression.