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Yumiko Umino, Nicolas Cuenca, Drew Everhart, Laura Fernandez-Sanchez, Robert Barlow, Eduardo Solessio; Metabolic Stress and Loss of Vision in Chronically Hypoglycemic Mice. Invest. Ophthalmol. Vis. Sci. 2012;53(14):1210.
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Mice rendered hypoglycemic by a null mutation in the glucagon receptor gene, Gcgr, display late-onset retinal degeneration and loss of retinal sensitivity. Our goals were: 1) To establish if long-term administration of high dietary glucose rescues retinal function and circuit connectivity in aged Gcgr-/- mice, 2) To determine if loss of vision is associated with systemic and/ or retinal stress.
Gcgr-/- mice were administered a carbohydrate-rich diet starting at 12 months of age. Following one month of treatment retinal function and structure were evaluated using electroretinographic recordings (ERGs) and immunohistochemistry. Visual function was assessed with by monitoring the optomotor response to moving gratings. Plasma levels of corticosterone and growth hormone were determined by radioimmunoassay.
Gcgr-/- retinas have 20% fewer synaptic pairings than Gcgr+/- retinas. Remarkably, most of the lost synapses were located farthest from the bipolar cell body, near the distal boundary of the outer plexiform layer, suggesting that apical synapses are most vulnerable to chronic hypoglycemia. Loss of retinal and visual functions was closely associated with increased plasma levels of the stress hormones corticosterone and growth factor, as well as activation of AMPK in the retina. AMPK is a metabolic sensor that regulates the distribution of energetic resources in cells. While treatment with the carbohydrate-rich diet raised blood glucose levels, restored retinal function and reduced stress, it did not restore the synaptic contacts lost between rods and bipolar cells.
Prolonged exposure to diet-induced euglycemia rescues retinal function but cannot reestablish synaptic contacts lost by chronic hypoglycemia. Our results suggest that retinal neurons possess a homeostatic mechanism that integrates energetic status over prolonged periods of time and allows them to recover functionality despite synaptic loss.
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