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Jillian Schneider, Ted Han, Sharee Kuny, Yves Sauve, Helene Lemieux; Retina mitochondrial dysfunction precedes Type 2 diabetes-induced hyperglycemia. Invest. Ophthalmol. Vis. Sci. 2016;57(12):5444.
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© ARVO (1962-2015); The Authors (2016-present)
Controversy exists on the pathological events initiating retinal complications in response to prolonged hyperglycemia. High blood sugar causes an increase in glycated hemoglobin, which compromises oxygen supply to the tissues. Due to the high metabolic activity of the outer retina, and its sensitivity to acute changes in oxygen and energy flux, mitochondrial dysfunction has been proposed as a potential early indicator of diabetic retinopathy. We hypothesize that mitochondrial abnormalities will be detected in the retina prior to hyperglycemia onset in the Nile grass rat model of spontaneous slow progressing Type 2 diabetes.
Nile grass rats were fed standard rodent chow (Prolab 2000) or a high fibre low fat diet (Mazuri Chinchilla). Retina and retinal pigment epithelium (RPE) were studied at 2, 6, and 18 months. Following euthanasia and enucleation, tissues from individual animals were isolated, weighed, and homogenized. Function of the distinct respiratory system complexes was assessed with the gold standard, high resolution respirometry, OROBOROS Oxygraph-2k: leak state (ADP-free), oxidative phosphorylation state (ADP-rich), with substrates feeding electrons into Complexes I, II or IV of the electron transport system. Citrate synthase activity and indicators of oxidative stress were also measured.
Hyperglycemia developed by 6 months of age in in chow fed animals and was preceded by hyperinsulinemia starting at 2 months. Presence of respirometric stimulation via addition of exogenous cytochrome c, only released from apoptotic mitochondria, was observed in chow fed Nile rats, already by 2 months of age. In addition, integrated mitochondrial function (in well-coupled mitochondria) could be measured in retina and RPE from single animals, which allowed assessment of the effect of age, diet, sex and glycemic status on specific electron transport system complexes. Specific changes were already seen at 2 months in chow fed animals.
Mitochondrial fragility in the retina can be detected using high resolution respirometry, prior to hyperglycemia onset. These findings provide experimental evidence that retinal mitochondrial dysfunction is upstream to hyperglycemia induced diabetic retinopathy, and as such represents both a novel precocious screening tool and preventative therapeutic target.
This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.
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