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Progression of Incipient Diabetic Retinopathy During Good Glycemic Control
Abstract
To assess the extent to which the progression of diabetic retinopathy can be arrested by improved glycemic control, 35 normal dogs were randomly divided into a nondiabetic and three alloxan-induced diabetic groups prospectively identified according to glycemic control: poor control for 5 yr (PC), good control for 5 yr (GC), and poor control for 2.5 yr followed by good control for 2.5 yr (PGC). To achieve good control, insulin was given twice daily together with a measured diet so that hyperglycemia and glucosuria were mild and infrequent, and HbA1 was comparable to normal. Retinal capillary aneurysms and other lesions developed during 60 mo of poor control (group PC) and were inhibited if good control was begun promptly within 2 mo (group GC). In group PGC, retinopathy was absent or equivocal at 2.5 yr of poor control and, surprisingly, was found to develop subsequently despite good glycemic control. Retinopathy in group PGC was greater at autopsy than at 2.5 yr and was greater than in group GC. The results indicate that retinopathy may be preventable but tends to resist arrest even in its incipient stages, before more than the first few aneurysms have appeared.
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“Hyperglycemic memory was first described in humans as the resistance to preventing the development of diabetic retinopathy despite achieving good glycemic control in patients (189).”
From A Critical Review of the Evidence That Metformin Is a Putative Anti-Aging Drug That Enhances Healthspan and Extends Lifespan (2021) · cites this paper as [189]
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“Indeed, this was previously suggested for diabetic retinopathy more than 20 years ago (169), where elegant studies in dogs showed the progression of retinal disease despite good glycemic control.”
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“The first investigation of such a memory was reported over 20 yr ago by the laboratory of Kern (7) in the retina of diabetic dogs who were switched to good glucose control after either 2 months or 2.”
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“…complications once euglycemia is re-established in dogs has led to the hypothesis that the mechanisms associated with hyperglycemia have an irreversible nature causing the persistence of vascular damage involving the so-called hyperglycemic memory (Engerman and Kern 1987; Roy et al. 1990).”
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Curcumin and Turmeric Delay Streptozotocin-Induced Diabetic Cataract in Rats
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Klein, R. (1994) · Archives of Internal Medicine · doi:10.1001/archinte.1994.00420190068008 · Cited by 310
The role of epigenetics in the pathology of diabetic complications
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“Early pioneering studies in dogs found that there was a continuation of retinal complications even after reversal of hyperglycemia (38).”
BackgroundZheng, Z., Chen, H., Li, J., Li, T., Zheng, B., Zheng, Y., Jin, H., He, Y., Gu, Q., & Xu, X. (2012) · Diabetes · doi:10.2337/db11-0416 · Cited by 282
“After being first reported by Engerman and Kern (5), the metabolic memory phenomenon was explored in isolated human umbilical vein endothelial cells, where it was shown that glucose-induced overexpression of fibronectin in cells preexposed to high glucose was not readily reversible after exposure to normal glucose (6).”
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“Studies with diabetic animals have demonstrated that good glycemic control can prevent the development of diabetic retinopathy if the good glycemic control is initiated within a few weeks after the onset of diabetes, but that intervention with good glycemic control after many months of poor control is much less effect…”
BackgroundPharmacological Inhibition of Diabetic Retinopathy
Kern, T. S., & Engerman, R. L. (2001) · Diabetes · doi:10.2337/diabetes.50.7.1636 · Cited by 277
“Trypsin digests of retinal vessels were stained with periodic acid Schiff and hematoxylin for evaluation of retinopathy (1,6,27).”
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“Animal models A study in dogs with alloxan-induced diabetes mellitus has shown that animals subjected to poor glycemic control for 5 years developed diabetic retinopathy”
BackgroundWhite, N. H., Sun, W., Cleary, P. A., Tamborlane, W. V., Danis, R. P., Hainsworth, D. P., & Davis, M. D. (2010) · Diabetes · doi:10.2337/db09-1216 · Cited by 235
“It should be noted that the persistent adverse effects of hyperglycemia and the long-term beneficial effects of lowering glycemia on the development and progression of complications have also been shown in animal models of diabetes (19), in which it has also been termed metabolic memory.”
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Schmetterer, L. F., & Wolzt, M. (1999) · Diabetologia · doi:10.1007/s001250051171 · Cited by 230
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MethodCellular and molecular mechanisms of endothelial dysfunction in diabetes
Roberts, A., & Porter, K. E. (2013) · Diabetes and Vascular Disease Research · doi:10.1177/1479164113500680 · Cited by 234
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“This “metabolic memory” has also been reported in diabetes complications verified in dogs in which retinopathy continues to progress even after hyperglycemia is corrected [4,16].”
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Ihnat, M. A., Thorpe, J. E., Kamat, C. D., Szabó, C., Green, D. E., Warnke, L. A., Lacza, Z., Cselenyák, A., Ross, K., Shakir, S. F., et al. (2007) · Diabetologia · doi:10.1007/s00125-007-0684-2 · Cited by 227
“These data are consistent with findings that retinopathy progression can persist in dogs even after the normalisation of glycaemic control [12].”
ResultEarly Retinal Damage in Experimental Diabetes: Electroretinographical and Morphological Observations
Li, Q., Zemel, E., Miller, B. T., et al. (2002) · Experimental Eye Research · doi:10.1006/exer.2002.1170 · Cited by 220
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Epigenetic mechanisms in diabetic vascular complications
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“retinal complications persisted even after the reversal of hyperglycaemia in dogs.(23) Islet transplantation in diabetic rats, 6 weeks after the onset of diabetes, led to reduced rates of retinopathy, but islet transplantation 12 weeks post-diabetes could not prevent retinopathy.”
BackgroundAdvanced products of nonenzymatic glycosylation and the pathogenesis of diabetic vascular disease
Brownlee, M., Cerami, A., & Vlassara, H. (1988) · Diabetes/Metabolism Reviews · doi:10.1002/dmr.5610040503 · Cited by 187
Glucose and glucosamine regulate growth factor gene expression in vascular smooth muscle cells.
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Two Phases of Nitrergic Neuropathy in Streptozotocin-Induced Diabetic Rats
Cellek, S., Foxwell, N., & Moncada, S. (2003) · Diabetes · doi:10.2337/diabetes.52.9.2353 · Cited by 180
Advances in our understanding of diabetic retinopathy
Stitt, A. W., Lois, N., Medina, R. J., Adamson, P., & Curtis, T. M. (2013) · Clinical Science · doi:10.1042/cs20120588 · Cited by 182
Heritability of Proliferative Diabetic Retinopathy
Hietala, K., Forsblom, C. M., Summanen, P. A., Groop, P., & on behalf of the FinnDiane Study Group (2008) · Diabetes · doi:10.2337/db07-1495 · Cited by 181
“Diabetic retinopathy continues to progress even after improvement of glycemic control (5,15).”
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The emerging challenge in diabetes: The “metabolic memory”
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“The “metabolicmemory” phenomenon has also been reported in animal models of diabetic complications: retinopathy continued to progress for a considerable period even after hyperglycemia was corrected in dogs (Engerman and Kern, 1987), and islet transplantation after several months of diabetes in rats arrested the progr…”
Role of nitrosative stress in the pathogenesis of diabetic vascular dysfunction
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“These data were consistent with findings from studies in dogs that retinopathy progression can persist even after the normalization of glycaemic control (Engerman and Kern, 1987).”
ResultOcular perfusion abnormalities in diabetes
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Metabolic memory: mechanisms and diseases
Dong, H., Sun, Y., Nie, L., Cui, A., Zhao, P., Leung, W. K., & Wang, Q. (2024) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-024-01755-x · Cited by 186
“81 The results demonstrated that the incidence of retinopathy in dogs with good glycemic control after poor glycemic control was similar to that in the poor glycemic control group and higher than that in the good control group.”
BackgroundMetabolic memory and diabetic nephropathy: potential role for epigenetic mechanisms
Tonna, S. J., El‐Osta, A., Cooper, M. E., & Tikellis, C. (2010) · Nature Reviews Nephrology · doi:10.1038/nrneph.2010.55 · Cited by 151
“Models of 'metabolic memory' To complement the findings of the various clinical trials that may have exhibited 'metabolic memory', investigators have been developing in vitro and preclinical models of this phenomenon”
BackgroundAdvanced glycation end products and diabetic complications
Stitt, A. W., Jenkins, A. J., & Cooper, M. E. (2002) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.11.9.1205 · Cited by 152
Retinopathy in animal models of diabetes
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Self-citationDiabetic-like retinopathy in rats prevented with an aldose reductase inhibitor.
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Epigenetic Changes in Diabetes and Cardiovascular Risk
Keating, S. T., Plutzky, J., & El-Osta, A. (2016) · Circulation Research · doi:10.1161/circresaha.116.306819 · Cited by 139
“5 years of insulin therapy and effective glycemic control.(11) Similarly”
Modes of Retinal Cell Death in Diabetic Retinopathy
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“Endothelial cell death and pericyte loss have long been assumed to play an important role in the loss of proper blood-retinal barrier function [4,9,24,25].”
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Lessons From the Diabetes Control and Complications Trial
Santiago, J. V. (1993) · Diabetes · doi:10.2337/diab.42.11.1549 · Cited by 134
“The DCCT results confirm and extend the results of earlier clinical trials on reduction of albuminuria with reduction of hyperglycemia (10-14).”
ResultEpigenetic programming, early life nutrition and the risk of metabolic disease
Block, T., & El-Osta, A. (2017) · Atherosclerosis · doi:10.1016/j.atherosclerosis.2017.09.003 · Cited by 130
Beyond genetics: epigenetic code in chronic kidney disease
Dwivedi, R. S., Herman, J. G., McCaffrey, T. A., & Raj, D. S. (2010) · Kidney International · doi:10.1038/ki.2010.335 · Cited by 136
“98 This phenomenon of ‘metabolic memory’ was first described in 1987 by Engerman and Kern”
BackgroundOn the Pathogenesis of Diabetic Retinopathy
Frank, R. N. (1991) · Ophthalmology · doi:10.1016/s0161-6420(91)32253-x · Cited by 131
Beltramo, E., Berrone, E., Tarallo, S., & Porta, M. (2008) · Acta Diabetologica · doi:10.1007/s00592-008-0042-y · Cited by 133
Epigenetics: deciphering its role in diabetes and its chronic complications
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“Early studies in dogs found a continuation of retinal complications, even after reversing hyperglycaemia.(20) Islet transplantation in rats after 12 weeks of”
BackgroundTewari, S., Zhong, Q. P. W., dos Santos, J. M., & Kowluru, R. A. (2012) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.12-9732 · Cited by 130
Yang, T., Feng, Q., Guo, F., Shao, M., Song, Y., Ren, G., Zhao, L., Qin, G., & Zhao, Y. (2024) · Molecular Medicine · doi:10.1186/s10020-024-00824-9 · Cited by 151
“1A, in 1987, Engerman et al. (Engerman and Kern 1987) first described the phenomenon of metabolic memory that decreased hyperglycemia to normal levels after 2.5 years of exposure in diabetic dogs, and the incidence of DR was still high (Engerman and Kern 1987).”
BackgroundMethodInfluentialVascular lesions in diabetes are distributed non-uniformly within the retina
Kern, T. S., & Engerman, R. L. (1995) · Experimental Eye Research · doi:10.1016/s0014-4835(05)80069-7 · Cited by 125
Self-citationHammes, H. P., Brownlee, M., Edelstein, D., Saleck, M., Martin, S., & Federlin, K. (1994) · Diabetologia · doi:10.1007/bf00428774 · Cited by 128
“Acellular capillaries were quantitated by a modification of the method of Engerman and Kern [13].”
MethodSIRT1, p66Shc, and Set7/9 in Vascular Hyperglycemic Memory
Paneni, F., Volpe, M., Lüscher, T. F., & Cosentino, F. (2013) · Diabetes · doi:10.2337/db12-1648 · Cited by 118
Mishra, M., Zhong, Q. P. W., & Kowluru, R. A. (2014) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.14-15193 · Cited by 121
Ding, H., & Triggle, C. R. (2005) · Vascular Health and Risk Management · doi:10.2147/vhrm.1.1.55.58939 · Cited by 118
“Another concern for the global impact of type 2 diabetes is an apparent association between the use of certain drugs for the treatment of AIDS and an increase in the incidence of diabetes in people with AIDS.”
BackgroundIntraretinal Leakage and Oxidation of LDL in Diabetic Retinopathy
Wu, M., Chen, Y., Wilson, K., et al. (2008) · Investigative Ophthalmology & Visual Science · doi:10.1167/iovs.07-1440 · Cited by 115
Metabolic Memory Phenomenon and Accumulation of Peroxynitrite in Retinal Capillaries
Kowluru, R. A., Kanwar, M., & Kennedy, A. (2007) · Journal of Diabetes Research · doi:10.1155/2007/21976 · Cited by 114
“5 years of poor control does not benefit the development of diabetic retinopathy [15].”
BackgroundBasement membrane abnormalities in diabetes mellitus: Relationship to clinical microangiopathy
Williamson, J. R., Tilton, R. G., Chang, K. C., et al. (1988) · Diabetes/Metabolism Reviews · doi:10.1002/dmr.5610040404 · Cited by 114
Rudberg, S. L., Ullman, E., & Dahlquist, G. G. (1993) · Diabetologia · doi:10.1007/bf00400811 · Cited by 113
“These hypotheses are in agreement with findings that microangiopathy may develop despite restored euglycaemia [31, 32].”
ResultNerve conduction and aldose reductase inhibition during 5 years of diabetes or galactosaemia in dogs
Engerman, R. L., Kern, T. S., & Larson, M. E. (1994) · Diabetologia · doi:10.1007/s001250050084 · Cited by 111
“control was intended to be appreciably less severe than the "poor" glycaemic control that we described previously [2,10,11], and was intended to avoid possibly overwhelming potentially beneficial effects of the aldose reductase inhibitor.”
Self-citationDiabetic Retinopathy, Superoxide Damage and Antioxidants
dos Santos, J. M., Mohammad, G., Zhong, Q. P. W., & Kowluru, R. A. (2011) · Current Pharmaceutical Biotechnology · doi:10.2174/138920111794480507 · Cited by 109
“phenomenon associated with the continued progression of diabetic retinopathy is also observed in the animal models of diabetic retinopathy-studies using chemically-induced diabetic dogs and rodents have demonstrated that diabetic retinopathy resists arrest after hyperglycemic insult is terminated [16, 17, 21, 108].”
BackgroundAldose reductase inhibitors and diabetic complications
Tomlinson, D. R., Willars, G. B., & Carrington, A. L. (1992) · Pharmacology & Therapeutics · doi:10.1016/0163-7258(92)90031-t · Cited by 110
Mishra, M., Zhong, Q. P. W., & Kowluru, R. A. (2014) · Free Radical Biology and Medicine · doi:10.1016/j.freeradbiomed.2014.07.001 · Cited by 108
“Seminal epidemiological studies have clearly demonstrated that despite long-term good glycemic control, prior poor glycemic control remains a risk factor for vascular complications, including retinopathy (27), and similar phenomenon is well documented in both animal and cell models (24, 25, 28, 29, 34, 38, 47).”
BackgroundKanwar, M., & Kowluru, R. A. (2008) · Diabetes · doi:10.2337/db08-1025 · Cited by 110
“Metabolic memory phenomenon is observed also in animal models of diabetic retinopathy (21-26), the formation of acellular capillaries, characteristic of early signs of diabetic retinopathy, does not stop for at least six months when GC is initiated six months after induction of diabetes in rats, and nitrotyrosine leve…”
BackgroundRoth, T., Podestà, F., Stepp, M. A., Boeri, D., & Lorenzi, M. (1993) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.90.20.9640 · Cited by 108
Cellek, S., Qu, W., Schmidt, A. M., & Moncada, S. (2004) · Diabetologia · doi:10.1007/s00125-003-1298-y · Cited by 107
“It is also likely that accumulation of AGEs in tissues explains the progression of hyperglycaemia-induced alterations during normal glucose homeostasis [26, 27].”
BackgroundClinical Evidence for the Earlier Initiation of Insulin Therapy in Type 2 Diabetes
Owens, D. R. (2013) · Diabetes Technology & Therapeutics · doi:10.1089/dia.2013.0081 · Cited by 108
“The group with good control throughout did not experience retinopathy, showing that earlier intensive treatment to maintain good glycemic control is beneficial.(23) Overall, these early results clearly demonstrate that intensive insulin therapy in people with poorly controlled T2DM provides multiple benefits beyond gl…”
Li, W., Liu, X., Yanoff, M., Cohen, S., & Ye, X. (1996) · Diabetologia · doi:10.1007/bf00403300 · Cited by 107
“During intensive blood glucose control in IDDM, retinopathy has been seen to deteriorate initially rather than improve [10-17].”
BackgroundGlycemic memory associated epigenetic changes
Siebel, A. L., Fernández, A. Z., & El‐Osta, A. (2010) · Biochemical Pharmacology · doi:10.1016/j.bcp.2010.06.005 · Cited by 102
Metabolic memory in diabetes-focus on insulin
LeRoith, D., Fonseca, V. A., & Vinik, A. I. (2005) · Diabetes/Metabolism Research and Reviews · doi:10.1002/dmrr.530 · Cited by 102
“Animal studies have demonstrated the need for early initiation of intensive glycemic control to arrest the progression of complications [6].”
BackgroundMaione, A. G., Brudno, Y., Stojadinović, O., Park, L. K., Smith, A., Tellechea, A., Leal, E. C., Kearney, C. J., Veves, A., Tomic‐Canic, M., et al. (2014) · Tissue Engineering Part C Methods · doi:10.1089/ten.tec.2014.0414 · Cited by 110
“31,32 Although metabolic memory has primarily been demonstrated in vascular cells, 33 there is some evidence that fibroblasts retain functional changes, such as altered ECM production, after exposure to high glucose.”
A Mouse Model of Diabetic Retinopathy
Kern, T. S. (1996) · Archives of Ophthalmology · doi:10.1001/archopht.1996.01100140194013 · Cited by 101
Self-citationEpigenetic Modifications in the Pathogenesis of Diabetic Nephropathy
Reddy, M. A., Park, J. T., & Natarajan, R. D. (2013) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2013.05.006 · Cited by 100
A review of endothelial dysfunction in diabetes: a focus on the contribution of a dysfunctional eNOS
Triggle, C. R., & Ding, H. (2010) · Journal of the American Society of Hypertension · doi:10.1016/j.jash.2010.02.004 · Cited by 103
Matsubara, Y., Murata, M., Maruyama, T., Handa, M., Yamagata, N., Watanabe, G., Saruta, T., & Ikeda, Y. (2000) · Blood · doi:10.1182/blood.v95.5.1560.005k43_1560_1564 · Cited by 99
Therapeutic potential of anti-oxidants and diabetic retinopathy
Kowluru, R., & Kennedy, A. (2001) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.10.9.1665 · Cited by 96
“Drugs (2001) 10(9) 1667 many months of poor control is much less effective in inhibiting the retinopathy [12,13] and the extent of pre-existing damage at the time of intervention is a primary factor in determining the outcome of a therapy [14].”
Background
Metadata
- Authors
- Engerman, R. L., & Kern, T. S.
- Affiliations
- University of Wisconsin–Madison (US)
- ORCID
- Kern, Timothy S
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 1987-07-01
- Volume
- 36
- Issue
- 7
- Pages
- 808-812
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2104738423
- Cited by
- 490
- References
- 0
- Citations by year
- 2026: 7 · 2025: 10 · 2024: 15 · 2023: 13 · 2022: 12 · 2021: 13 · 2020: 13 · 2019: 16 · 2018: 11 · 2017: 16 · 2016: 14 · 2015: 25 · 2014: 26 · 2013: 22 · 2012: 17
- FWCI
- 13.21
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Eye Institute (EY00 300)
- Topics
- Health Sciences › Medicine › Ophthalmology › Retinal Diseases and Treatments
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Clinical Biochemistry › Advanced Glycation End Products research
- Keywords
- diabetic retinopathy, disease progression, glycemic control, alloxan-induced diabetes, insulin therapy, HbA1c, glycosuria, retinopathy prevention, dogs
- MeSH terms
- Aneurysm, Animals, Autopsy, Blood Glucose, Capillaries, Diabetic Retinopathy, Dogs, Female, Hyperglycemia, Insulin, Male, Retina
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