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 resistance to preventing development of diabetic retinopathy despite achieving good glycemic control.
“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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“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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ResultEpigenetic programming, early life nutrition and the risk of metabolic disease
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“98 This phenomenon of ‘metabolic memory’ was first described in 1987 by Engerman and Kern”
BackgroundOn the Pathogenesis of Diabetic Retinopathy
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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 126 · see citing works
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“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 · see citing works
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“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 · see citing works
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“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
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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 · see citing works
“5 years of poor control does not benefit the development of diabetic retinopathy [15].”
BackgroundBasement membrane abnormalities in diabetes mellitus: Relationship to clinical microangiopathy
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“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 · see citing works
“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 110 · see citing works
“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
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“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 108 · see citing works
“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 · see citing works
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“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 · see citing works
“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…”
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“During intensive blood glucose control in IDDM, retinopathy has been seen to deteriorate initially rather than improve [10-17].”
BackgroundGlycemic memory associated epigenetic changes
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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 · see citing works
“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 103 · see citing works
“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 · see citing works
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 102 · see citing works
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 100 · see citing works
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 · see citing works
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 · see citing works
“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
- 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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