Abundant evidence has established that glycemic control, if not started at a very early stage of diabetes, is not enough to completely reduce its chronic complications, including retinopathy. This phenomenon has recently been defined as “metabolic memory”. Diabetic retinopathy (DR) is one of the common complications. This review summarizes the relationship between the “metabolic memory” phenomenon and DR, the molecular mechanisms for propagating this phenomenon, and potential therapeutic agents to reverse “metabolic memory” in DR, contributing to a future strategy in the prevention and treatment of DR.
Nathan DM, Cleary PA, Backlund JY, et al. Intensive diabetes treatment and cardiovascular disease in patients with type 1 diabetes. N Engl J Med,2005,353:2643-53.
[2]
The Diabetes Control and Complications Trial Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med,1993,329:977-986.
[3]
The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med,2000,342:381-389.
[4]
Writing Team for the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA,2002,287:2563-2569.
[5]
White NH, Sun W, Cleary PA, et al. Prolonged effect of intensive therapy on the risk of retinopathy complications in patients with type 1 diabetes mellitus: 10 years after the Diabetes Control and Complications Trial. Arch Ophthalmol,2008,126:1707-1715.
[6]
Holman RR, Paul SK, Bethel MA, et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med,2008,359:1577-1589.
[7]
Engerman RL, Kern TS. Progression of incipient diabetic retinopathy during good glycemic control. Diabetes,1987,36:808-812.
[8]
Hammes HP, Klinzing I, Wiegand S, et al. Islet transplantation inhibits diabetic retinopathy in the sucrose-fed diabetic Cohen rat. Invest Ophthalmol Vis Sci,1993,34:2092-2096.
[9]
Cusick M, Chew EY, Ferris F, 3rd, et al. Effects of aldose reductase inhibitors and galactose withdrawal on fluorescein angiographic lesions in galactose-fed dogs. Arch Ophthalmol,2003,121:1745-1751.
[10]
Kanwar M, Kowluru RA. Role of glyceraldehyde 3-phosphate dehydrogenase in the development and progression of diabetic retinopathy. Diabetes,2009,58:227-234.
[11]
Kowluru RA, Chan PS. Metabolic memory in diabetes-from in vitro oddity to in vivo problem: role of apoptosis. Brain Res Bull,2010,81:297-302.
[12]
Kowluru RA, Koppolu P. Termination of experimental galactosemia in rats, and progression of retinal metabolic abnormalities. Invest Ophthalmol Vis Sci,2002,43:3287-3291.
[13]
Kowluru RA. Effect of reinstitution of good glycemic control on retinal oxidative stress and nitrative stress in diabetic rats. Diabetes,2003,52:818-823.
[14]
Ihnat MA, Thorpe JE, Kamat CD, et al. Reactive oxygen species mediate a cellular ′memory′ of high glucose stress signalling. Diabetologia,2007,50:1523-1531.
[15]
Ceriello A, Ihnat MA, Thorpe JE. Clinical review 2: The “metabolic memory”: is more than just tight glucose control necessary to prevent diabetic complications? J Clin Endocrinol Metab,2009,94:410-415.
[16]
Madsen-Bouterse SA, Mohammad G, Kanwar M, et al. Role of mitochondrial DNA damage in the development of diabetic retinopathy, and the metabolic memory phenomenon associated with its progression. Antioxid Redox Signal,2010,13:797-805.
[17]
Monnier VM, Bautista O, Kenny D, et al. Skin collagen glycation, glycoxidation, and crosslinking are lower in subjects with long-term intensive versus conventional therapy of type 1 diabetes: relevance of glycated collagen products versus HbA1c as markers of diabetic complications. DCCT Skin Collagen Ancillary Study Group. Diabetes Control and Complications Trial. Diabetes,1999,48:870-880.
[18]
Genuth S, Sun W, Cleary P, et al. Glycation and carboxymethyllysine levels in skin collagen predict the risk of future 10-year progression of diabetic retinopathy and nephropathy in the diabetes control and complications trial and epidemiology of diabetes interventions and complications participants with type 1 diabetes. Diabetes,2005,54:3103-3111.
[19]
Takeuchi M, Takino J, Yamagishi S. Involvement of the toxic AGEs (TAGE)-RAGE system in the pathogenesis of diabetic vascular complications: a novel therapeutic strategy. Curr Drug Targets,2010,11:1468-1482.
[20]
Intine RV, Sarras MP, Jr. Metabolic Memory and Chronic Diabetes Complications: Potential Role for Epigenetic Mechanisms. Curr Diab Rep,2012,12:551-559.
[21]
Zhong Q, Kowluru RA. Role of histone acetylation in the development of diabetic retinopathy and the metabolic memory phenomenon. J Cell Biochem,2010,110:1306-1313.
[22]
Zhong Q, Kowluru RA. Epigenetic changes in mitochondrial superoxide dismutase in the retina and the development of diabetic retinopathy. Diabetes,2011,60:1304-1313.
[23]
Zheng Z, Chen H, Li J, et al. Sirtuin 1-mediated cellular metabolic memory of high glucose via the LKB1/AMPK/ROS pathway and therapeutic effects of metformin. Diabetes,2012, 61:217-228.
[24]
Chan PS, Kanwar M, Kowluru RA. Resistance of retinal inflammatory mediators to suppress after reinstitution of good glycemic control: novel mechanism for metabolic memory. J Diabetes Complications,2010,24:55-63.
[25]
Kowluru RA, Zhong Q, Kanwar M. Metabolic memory and diabetic retinopathy: role of inflammatory mediators in retinal pericytes. Exp Eye Res,2010,90:617-623.
[26]
Kowluru RA, Chakrabarti S, Chen S. Re-institution of good metabolic control in diabetic rats and activation of caspase-3 and nuclear transcriptional factor (NF-?资appa B) in the retina. Acta Diabetol,2004,41:194-199.