Woo Hyun Han1, Jonathan Gotzmann2, Sharee Kuny1, Hui Huang2, Catherine B Chan3, Hélène Lemieux4, Yves Sauvé5. 1. Department of Ophthalmology and Visual Sciences, University of Alberta, Edmonton, Alberta, Canada. 2. Department of Physiology, University of Alberta, Edmonton, Alberta, Canada. 3. Department of Physiology, University of Alberta, Edmonton, Alberta, Canada 3Agriculture, Food and Nutritional Science, University of Alberta, Edmonton, Alberta, Canada. 4. Faculty Saint-Jean, University of Alberta, Edmonton, Alberta, Canada. 5. Department of Ophthalmology and Visual Sciences, University of Alberta, Edmonton, Alberta, Canada 2Department of Physiology, University of Alberta, Edmonton, Alberta, Canada.
Abstract
Purpose: To characterize retinal mitochondrial respiration associated with type 2 diabetes (T2D) progression in a cone-rich diurnal rodent, the Nile rat (genus Arvicanthis, species niloticus). Methods: Nile rats were fed a standard rodent diet that resulted in rising glucose levels from 6 months. Age-matched control animals were fed a high-fiber diet that prevented diabetes up to 18 months. The functional status of specific retinal mitochondrial components and mitochondrial outer membrane integrity were studied by using high-resolution respirometry. Ocular complications were documented with funduscopy, electroretinography (ERG), and trypsin digestion of retinal vasculature. Results: Mitochondrial functional changes were detected during hyperinsulinemia with maintained normoglycemia (2 months), corresponding to stage 1 of human T2D. Our data showed increased contribution of mitochondrial respiration through the NADH pathway relative to maximal oxidative phosphorylation capacity, with simultaneous electron entry into NADH (Complex I and related dehydrogenases) and succinate (Complex II) pathways. These compensatory events coincided with compromised mitochondrial outer membrane integrity. The first clinical sign of retinopathy (pericyte loss) was only detected at 12 months (after 6 months of sustained hyperglycemia) alongside a common ocular complication of diabetes, cataractogenesis. Further prolongation of hyperglycemia (from 12 to 18 months) led to capillary degeneration and delayed photopic ERG oscillatory potentials. Conclusions: Oxidative phosphorylation compensatory changes in the retina can be detected as early as 2 months, before development of hyperglycemia, and are associated with reduced mitochondrial outer membrane integrity.
Purpose: To characterize retinal mitochondrial respiration associated with type 2 diabetes (T2D) progression in a cone-rich diurnal rodent, the Nile rat (genus Arvicanthis, species niloticus). Methods: Nile rats were fed a standard rodent diet that resulted in rising glucose levels from 6 months. Age-matched control animals were fed a high-fiber diet that prevented diabetes up to 18 months. The functional status of specific retinal mitochondrial components and mitochondrial outer membrane integrity were studied by using high-resolution respirometry. Ocular complications were documented with funduscopy, electroretinography (ERG), and trypsin digestion of retinal vasculature. Results: Mitochondrial functional changes were detected during hyperinsulinemia with maintained normoglycemia (2 months), corresponding to stage 1 of human T2D. Our data showed increased contribution of mitochondrial respiration through the NADH pathway relative to maximal oxidative phosphorylation capacity, with simultaneous electron entry into NADH (Complex I and related dehydrogenases) and succinate (Complex II) pathways. These compensatory events coincided with compromised mitochondrial outer membrane integrity. The first clinical sign of retinopathy (pericyte loss) was only detected at 12 months (after 6 months of sustained hyperglycemia) alongside a common ocular complication of diabetes, cataractogenesis. Further prolongation of hyperglycemia (from 12 to 18 months) led to capillary degeneration and delayed photopic ERG oscillatory potentials. Conclusions: Oxidative phosphorylation compensatory changes in the retina can be detected as early as 2 months, before development of hyperglycemia, and are associated with reduced mitochondrial outer membrane integrity.
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