Partial Rescue of Retinal Function in Chronically Hypoglycemic Mice

Abstract

PURPOSE.Mice rendered hypoglycemic by a null mutation in the glucagon receptor gene Gcgr display late-onset retinal degeneration and loss of retinal sensitivity. Acute hyperglycemia induced by dextrose ingestion does not restore their retinal function, which is consistent with irreversible loss of vision. The goal of this study was to establish whether long-term administration of high dietary glucose rescues retinal function and circuit connectivity in aged Gcgr Ϫ/Ϫ mice. METHODS.Gcgr Ϫ/Ϫ mice were administered a carbohydraterich diet starting at 12 months of age. After 1 month of treatment, retinal function and structure were evaluated using electroretinographic (ERG) recordings and immunohistochemistry. RESULTS. Treatment with a carbohydrate-rich diet raised blood glucose levels and improved retinal function in Gcgr Ϫ/Ϫ mice. Blood glucose increased from moderate hypoglycemia to euglycemic levels, whereas ERG b-wave sensitivity improved approximately 10-fold. Because the b-wave reflects the electrical activity of second-order cells, we examined for changes in rod-to-bipolar cell synapses. Gcgr Ϫ/Ϫ retinas have 20% fewer synaptic pairings than Gcgr ϩ/Ϫ retinas. Remarkably, most of the lost synapses were located farthest from the bipolar cell body, near the distal boundary of the outer plexiform layer (OPL), suggesting that apical synapses are most vulnerable to chronic hypoglycemia. Although treatment with the carbohydrate-rich diet restored retinal function, it did not restore these synaptic contacts. CONCLUSIONS. Prolonged exposure to diet-induced euglycemia improves retinal function but does not reestablish synaptic contacts lost by chronic hypoglycemia. These results suggest that retinal neurons have a homeostatic mechanism that integrates energetic status over prolonged periods of time and allows them to recover functionality despite synaptic loss. T he retina is among the most metabolically active tissues in the body, requiring a constant supply of blood glucose to sustain glycolysis, oxidative metabolism, and retinal function.1-6 The sensitivity of the retina to glucose is underscored by the observations that acute hypoglycemia decreases rod 7 and cone vision, 8 -10 blurs central vision, and produces temporary central scotomas.10,11 Dietary hyperglycemia can rapidly counteract these effects of acute hypoglycemia and restore retinal function. 12The consequence of sustained hypoglycemia on retinal function is less clear. Hypoglycemia is a common condition caused by poor nutrition, 13 inborn errors of metabolism, 14 and pancreatic tumors, 15 and it is a frequent complication of diabetes medications. 16 Our goal in this study was to understand the effects of sustained hypoglycemia on retinal and visual function. To this purpose we examined mice rendered chronically hypoglycemic by a null mutation in the glucagon receptor gene, Gcgr.17 Gcgr Ϫ/Ϫ mice are moderately hypoglycemic and experience late-onset retinal degeneration with loss of vision.18 Their retinal function (as assessed by the electroretinographic ...

Cellular responses following retinal injuries and therapeutic approaches for neurodegenerative diseases

“…Similar results were found in transgenic mice overexpressing the guanylate cyclase activating protein 2 (GCAP2) in rods leading to a shortening of synaptic ribbons, and to a higher than normal percentage of club-shaped and spherical ribbon morphologies (Lopez-del Hoyo et al, 2012). Mice with chronic hypoglycemia by a null mutation in the glucagon receptor gene Gcgr also showed a loss of synaptic ribbon in the OPL (Umino et al, 2012). Besides, it has also been demonstrated that null mice in the insulin-like growth factor-I (Igf1À/À) suffered important structural modifications in retinal synapses (Rodriguez-de la Rosa et al, 2012).…”

HbA1c level as a risk factor for retinopathy and nephropathy in children and adults with type 1 diabetes: Swedish population based cohort study

“…In this study, preproliferative diabetic retinopathy or worse occurred in seven participants with a mean HbA 1c level of <6.5% (<48 mmol/mol), which was associated with an increased risk of borderline significance (P=0.05) versus an HbA 1c level of 6.5-6.9% (48-52 mmol/mol), and seven participants developed macroalbuminuria. It seems unlikely that low HbA 1c levels indicating glucose levels close to normal should be harmful in themselves; however, preclinical studies have indicated that microvascular complications might be promoted by frequent hypoglycaemia, as is possibly the case with rapid glucose fluctuations that can be related to hypoglycaemia 2526 Moreover, we observed an increased risk of severe hypoglycaemia with HbA 1c levels <6.5% (<48 mmol/mol) compared with 6.5-6.9% (48-52 mmol/mol).…”

Extracellular superoxide dismutase (SOD3) regulates oxidative stress at the vitreoretinal interface

“…Additionally, previous studies have shown that glucose is able to reduce ROS in cultured rat retinal cells by acting on both the glycolytic and pentose phosphate pathways [30], and that enhancing glycolysis in the photoreceptor cells and releasing retained glucose from the RPE to starving photoreceptors provide short-term rescue effects to models of retinitis pigmentosa [31]. Even a high carbohydrate diet, raising blood glucose levels, improved retinal function in disease systems, but was unable to restore the synaptic contacts at the retinal ganglion cell layer [32]. SOD3 has been shown to increase glucose metabolism [33] as an additional mechanism of reducing ROS levels.…”