Енергетичний стан сітківки щурів з експериментальним діабетом і осьовою міопією

I.N. Mikheytseva; Асhmed  Амаied; Сергій Коломійчук

doi:10.31288/oftalmolzh202346166

Authors

I.N. Mikheytseva State University "Institute of Eye Diseases and Tissue Therapy named after V.P. Filatov of the National Academy of Sciences of Ukraine"
Асhmed Амаied ДУ «Інститут очних хвороб і тканинної терапії імені В.П. Філатова НАМН України»
Сергій Коломійчук ДУ «Інститут очних хвороб і тканинної терапії імені В.П. Філатова НАМН України»

DOI:

https://doi.org/10.31288/oftalmolzh202346166

Keywords:

діабет, діабетична ретинопатія, міопія, сітківка, гіпоксія, енергетичний обмін, мітохондрії, експеримент

Abstract

Background: Elucidating the pathogenesis of diabetic retinopathy (DR) for further development of methods of treatment and prevention of the disease is an important medical and social task for ophthalmologists. The development of DR in the presence of myopia has some special features. In the presence of myopia, the diabetic complications in the retina are less severe than in emmetropia. The mechanisms of this paradoxical impact of eye myopization on the severity of these complications are, however, still unknown.

Purpose: To examine the state of retinal energy metabolism based on evaluation of biochemical markers of mitochondrial function (lactate, pyruvate, adenosine triphosphate (ATP) and adenosine diphosphate (ADP) levels and succinate dehydrogenase activity) in rats with streptozotocin (STZ)-induced diabetes that developed in the presence of axial myopia, compared to rats with diabetes alone and those with myopia alone.

Material and Methods: High axial myopia was produced in two-week animals by surgically fusing the eyelids of both eyes and maintaining these animals under conditions of reduced illumination for two weeks. A 15 mg/kg intraperitoneal streptozotocin injection for 5 days was used for inducing diabetes mellitus in rats with induced axial myopia and intact rats. Animals in the control group were maintained under conditions of natural illumination. In two months, all rats were euthanized under anesthesia, and their eyes were enucleated. ATP, ADP, lactate, and pyruvate levels were measured in blood and retinal specimens and ATP/ADP ratio and lactate/pyruvate ratio were determined. Succinate dehydrogenase activity was determined in isolated retinal mitochondria. For statistical analysis of biochemical results, Student’s t-test was conducted (Statistica software).

Results: Rats with diabetes alone exhibited lower retinal and plasma energy metabolism characteristics (ATP, ADP, and succinate dehydrogenase activity), and developed retinal hypoxia, with retinal lactate and pyruvate levels being 1.838-fold and 1.455-fold higher, respectively, and their ratio, 26.5% higher, compared to controls. In animals with STZ-induced diabetes in the presence of axial hypoxia, retinal lactate and pyruvate levels were 20.2% and 15.5% lower, respectively, and their ratio was lower (36.5 versus 38.7), compared to rats with diabetes alone, indicating lower hypoxia in the setting of eye myopization. In addition, in rats with diabetes in the presence of axial hypoxia, plasma and retinal ATP levels were 21.8% and 21.2% higher, respectively, and retinal succinate dehydrogenase activity, 20.8% higher, compared to rats with diabetes alone.

Conclusion: In experimental diabetes, an increase in the axial length of the eye (i.e., eye myopization) is accompanied by activation of energy processes and the development of hypoxia adaptation in retinal cells.

References

Miller DJ, Cascio MA, Rosca MG. Diabetic Retinopathy: The Role of Mitochondria in the Neural Retina and Microvascular Disease. Antioxidants (Basel). 2020 Sep 23;9(10):905. doi: 10.3390/antiox9100905.

Gudzenko KA, Mogilevskyy SIu. Predictors of the risk of developing diabetic retinopathy in type 2 diabetes mellitus and primary open-angle glaucoma in the course of a comorbid condition. J Ophthalmol (Ukraine). 2021;1:84-8.

Chen Y, Coorey NJ, Zhang M, et al. Metabolism Dysregulation in Retinal Diseases and Related Therapies. Antioxidants (Basel). 2022 May 11;11(5):942. doi: 10.3390/antiox11050942.

Rykov SO, Mogilevskyy SIu, Lytvynenko SS, Ziablitsev SV. Angiopoietins and prediction of vitreous hemorrhage in type 2 diabetes patients with diabetic retinopathy. J Ophthalmol (Ukraine). 2022;1:3-10.

Thagaard, MS, Vergmann AS, Grauslund J. Topical treatment of diabetic retinopathy: a systematic review. Acta Ophthalmol. 2022; 100:136-147. https://doi.org/10.1111/aos.14912.

Mikheytseva IN, Mohammad A, Putienko AA, et al. Correlation between axial length and anterior chamber depth of the eye and retinal disorders in type 2 diabetic rabbits with myopia. Oftalmol Zh. 2018;6:44-51.

Mohammad A, Mikheytseva IN, Putienko AA, Kolomiichuk SG. On the role of lipid metabolism and lipid peroxidation in the development of retinal disorders in type 2 diabetic rats with myopia. J Ophthalmol (Ukraine). 2019;5:56-63.

Mikheytseva IN, Molchaniuk NI, Mohammad A, et al. Ultrastructural changes in the chorioretinal complex of the rat after inducing form-deprivation axial myopia only, diabetic retinopathy only and diabetic retinopathy in the presence of myopia. J Ophthalmol (Ukraine). 2021;4:72-8.

Lim LS, Lamoureux E, Saw SM, Tay WT, Mitchell P, Wong TY. Are myopic eyes less likely to have diabetic retinopathy? Ophthalmology. 2010;117(3):524–30. http:// dx.doi.org/10.1016/j.ophtha.2009.07.044.

Wang X, Tang L, Gao L, et al. Myopia and diabetic retinopathy: A systematic review and meta-analysis. Diabetes Res Clin Pract. 2016 Jan.; 111:1-9. doi: 10.1016/j.diabres.2015.10.020.

Sultanov MI, Gadzhiev RV. [Features of the course of diabetic retinopathy in myopia]. Vestn Oftalmol. 1990;106(1):49-51. Russian.

Vähätupa M, Järvinen TAH, Uusitalo-Järvinen H. Exploration of Oxygen-Induced Retinopathy Model to Discover New Therapeutic Drug Targets in Retinopathies. Front Pharmacol. 2020 Jun 11;11:873. doi: 10.3389/fphar.2020.00873.

Joyal JS, Sun Y, Gantner ML, et al. Retinal lipid and glucose metabolism dictates angiogenesis through the lipid sensor Ffar1. Nat Med. 2016 Apr;22(4):439-45. doi: 10.1038/nm.4059.

Gunton JE. Hypoxia-inducible factors and diabetes. J Clin Invest. 2020 Oct 1;130(10):5063-5073. doi: 10.1172/JCI137556.

Bhatti JS, Bhatti GK, Reddy PH. Mitochondrial dysfunction and oxidative stress in metabolic disorders-A step towards mitochondria based therapeutic strategies. Biochim Biophys Acta (BBA). Mol Basis Dis. 2017;1863:1066-1077.

Joyal JS, Gantner ML, Smith LEH. Retinal energy demands control vascular supply of the retina in development and disease: The role of neuronal lipid and glucose metabolism. Prog Retin Eye Res. 2018 May; 64:131-156. doi: 10.1016/j.preteyeres.

Palkovits S, Lasta M, Told R, et al. Relation of retinal blood flow and retinal oxygen extraction during stimulation with diffuse luminance flicker. Sci Rep. 2015 Dec 17;5:18291. doi: 10.1038/srep18291.

Bisbach CM, Hass DT, Robbings BM, et al. Succinate Can Shuttle Reducing Power from the Hypoxic Retina to the O2-Rich Pigment Epithelium. Cell Rep. 2020 May 5;31(5):107606. doi: 10.1016/j.celrep.2020.107606.

Bénit P, Goncalves J, El Khoury R, et al. Succinate Dehydrogenase, Succinate, and Superoxides: A Genetic, Epigenetic, Metabolic, Environmental Explosive Crossroad. Biomedicines. 2022;10:1788. https://doi.org/ 10.3390/biomedicines10081788.

Mikheytseva IN, Mohammad А, Putienko AA, et al. Modelling form deprivation myopia in experiment. Journal of Ophthalmology (Ukraine); 2018;2(481):50-5.

Bergmeyer HU. Methods of enzymatic analyses. London: Аcademic Press; 1984. 499 р.

Prokhorova MI. [Methods of biochemical studies (lipid and energy metabolism)]. Leningrad University Press: Leningrad; 1982. Russian.

Parikh S, Goldstein A, Koenig MK, et al. Diagnosis and management of mitochondrial disease: a consensus statement from the Mitochondrial Medicine Society. Genet Med. 2015 Sep;17(9):689-701. doi: 10.1038/gim.2014.177.

Hurley JB, Lindsay KJ, Du J. Glucose, lactate, and shuttling of metabolites in vertebrate retinas. J Neurosci Res. 2015 Jul;93(7):1079-92. doi: 10.1002/jnr.23583.

Li X, Yang Y, Zhang B, et al. Lactate metabolism in human health and disease. Sig Transduct Target Ther. 2022;7:305. https://doi.org/10.1038/s41392-022-01151-3.

Bogan JS. Granular detail of β cell structures for insulin secretion. J Cell Biol. 2021 Feb 1;220(2):e202012082. doi: 10.1083/jcb.202012082.

Gurina AE, Mikaelyan NP, Kulaeva IO, et al. [Association between activity of insulin receptors and blood ATP in the presence of dyslipidemia in children with diabetes mellitus]. Fundamentalnyie issledovaniia. 2013;12 (1):30-4. Russian.

Bakhtiari N, Hosseinkhani S, Larijani B, et al. Red blood cell ATP/ADP & nitric oxide: The best vasodilators in diabetic patients. J Diabetes Metab Disord. 2012 Aug 24;11(1):9. doi: 10.1186/2251-6581-11-9.