Summary
Primary prevention with aminoguanidine — an inhibitor of advanced glycation end product (AGE) formation — has been successfully employed to prevent diabetic retinopathy in the rat. However, it is unknown whether inhibition of AGE formation is still effective in a secondary intervention strategy. The present study addresses this question by comparing secondary intervention with aminoguanidine with syngeneic islet transplantation in the rat model. After 6 months of diabetes, one group was treated with aminoguanidine (50 mg/100 ml drinking water; D-AG) while another group received syngeneic transplantation of collagenase-ficoll isolated islets by intraportal injection (Tx). After an additional 4 months, both groups were compared to a normal (NC 10) and diabetic (DC 10) control group. Retinal autofluorescence was increased 2.5-fold after 6 months and increased 3.7-fold after 10 months of diabetes (p<0.001). Aminoguanidine and islet Tx retarded the further accumulation of autofluorescence equally (p<0.001 vs DC 10), although the values were higher than those observed in DC at 6 months (p<0.001). Diabetes was associated with a 2.7-fold increase in acellular capillaries after 6 months and a 4.1-fold increase after 10 months. Treatment with aminoguanidine or islet Tx reduced but did not completely attenuate the progression of vascular occlusion (p<0.001 vs DC 10; D-AG vs DC 6, p<0.05; Tx vs DC 6, p<0.01). Both treatments reduced endothelial proliferation (22.4% after 10 months; p<0.001) and completely arrested pericyte dropout (40% after 10 months; p<0.001).
These data demonstrate that aminoguanidine is as effective as islet transplantation in retarding the progression of diabetic retinopathy in a secondary prevention setting.
Article PDF
Similar content being viewed by others
Avoid common mistakes on your manuscript.
Abbreviations
- Tx:
-
Islet transplantation
- AGE:
-
advanced glycation end product
- iNOS:
-
inducible form of nitric oxide synthase
References
Klein R, Klein BEK, Moss S et al. (1984) The Wisconsin Epidemiologic Study of Diabetic Retinopathy. II. Prevalence and risk of diabetic retinopathy when age at diagnosis is less than 30 years. Arch Ophthalmol 102: 520–526
Klein R, Klein BEK, Moss S et al. (1984) The Wisconsin Epidemiologic Study of Diabetic Retinopathy. III. Prevalence and risk of diabetic retinopathy when age at diagnosis is 30 or more years. Arch Ophthalmol 102: 527–532
Kohner EM, Porta M, Hyer SL (1991) Pathogenesis of diabetic retinopathy and cataract. In: Pickup J, Williams G (eds) Textbook of diabetes. Blackwell Scientific Publications, Oxford, pp 564–574
Merimee TJ (1990) Diabetic retinopathy. A synthesis of perspectives. New Engl J Med 322:978–983
Engerman R, Bloodworth JMB, Nelson S (1977) Relationship of microvascular disease in diabetes to metabolic control. Diabetes 26: 760–769
DCCT Research Group (1993) 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 329: 977–986
Hammes HP, Martin S, Federlin K et al. (1991) Aminoguanidine treatment inhibits the development of experimental diabetic retinopathy. Proc Nat Acad Sci USA 88:11555–11558
Hammes HP, Brownlee M, Edelstein D et al. (1994) Aminoguanidine inhibits the development of accelerated diabetic retinopathy in the spontaneous hypertensive rat. Diabetologia 37: 32–35
Lacy PE, Kostianovsky YM (1967) Method for the isolation of intact islets of Langerhans from the rat pancreas. Diabetes 16: 35–39
Kuwabara T, Cogan DG (1960) Studies of retinal vascular patterns. I. Normal architecture. Arch Ophthalmol 64: 904–911
Engerman RL, Kern TS (1987) Progression of diabetic retinopathy during good glycemic control. Diabetes 36: 808–812
Beaven MA, Gordon JW, Jacobson S, Sever W (1969) A specific and sensitive assay for aminoguanidine: its application to a study of the disposition of aminoguanidine in animal tissues. J Pharmacol Exp Ther 165: 14–22
Brownlee M (1994) Lilly lecture 1993. Glycation and diabetic complications. Diabetes 43: 836–841
Ruderman NB, Williamson JR, Brownlee M (1992) Glucose and diabetic vascular disease. FASEB J 6:2905–2914
Nicholls K, Mandel TE (1989) Advanced glycosylation end-products in experimental murine diabetic nephropathy: effect of islet isografting and aminoguanidine. Lab Invest 60: 486–493
Fu MX, Wells-Knecht KJ, Blackledge JA et al. (1994) Glycation, glycoxidation, and cross-linking of collagen by glucose. Kinetics, mechanisms, and inhibition of late stages of the Maillard reaction. Diabetes 43: 676–683
Roy S, Sala R, Cagliero E, Lorenzi M (1990) Overexpression of fibronectin induced by diabetes or high glucose: phenomenon with a memory. Proc Nat Acad Sci USA 87: 404–408
Soulis-Liparota T, Cooper M, Jerums G (1993) Effects of early and late aminoguanidine therapy on experimental diabetic nephropathy. 5th Int Symp on Maillard Reaction, Minnesota, USA (Abstract)
Mitsuhashi T, Nakayama H, Itch S, Kuwajima S et al. (1993) Immunochemical detection of advanced glycation end products in renal cortex from STZ induced diabetic rats. Diabetes 42: 826–833
Kumari K, Umar S, Bansal V, Sahib MK (1991) Monoaminoguanidine inhibits aldose reductase. Biochem Pharmacol 41: 1527–1528
Corbett JA, Tilton RG, Chang K et al. (1992) Aminoguanidine, a novel inhibitor of nitric oxide formation, prevents diabetic vascular dysfunction. Diabetes 41: 552–556
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Hammes, H.P., Strödter, D., Weiss, A. et al. Secondary intervention with aminoguanidine retards the progression of diabetic retinopathy in the rat model. Diabetologia 38, 656–660 (1995). https://doi.org/10.1007/BF00401835
Received:
Revised:
Issue Date:
DOI: https://doi.org/10.1007/BF00401835