Differential Roles of Hyperglycemia and Hypoinsulinemia in Diabetes Induced Retinal Cell Death: Evidence for Retinal Insulin Resistance

Abstract

Diabetes pathology derives from the combination of hyperglycemia and hypoinsulinemia or insulin resistance leading to diabetic complications including diabetic neuropathy, nephropathy and retinopathy. Diabetic retinopathy is characterized by numerous retinal defects affecting the vasculature and the neuro-retina, but the relative contributions of the loss of retinal insulin signaling and hyperglycemia have never been directly compared. In this study we tested the hypothesis that increased retinal insulin signaling and glycemic normalization would exert differential effects on retinal cell survival and retinal physiology during diabetes. We have demonstrated in this study that both subconjunctival insulin administration and systemic glycemic reduction using the sodium-glucose linked transporter inhibitor phloridzin affected the regulation of retinal cell survival in diabetic rats. Both treatments partially restored the retinal insulin signaling without increasing plasma insulin levels. Retinal transcriptomic and histological analysis also clearly demonstrated that local administration of insulin and systemic glycemia normalization use different pathways to counteract the effects of diabetes on the retina. While local insulin primarily affected inflammation-associated pathways, systemic glycemic control affected pathways involved in the regulation of cell signaling and metabolism. These results suggest that hyperglycemia induces resistance to growth factor action in the retina and clearly demonstrate that both restoration of glycemic control and retinal insulin signaling can act through different pathways to both normalize diabetes-induced retinal abnormality and prevent vision loss.

Regulated in Development and DNA Damage 1 Is Necessary for Hyperglycemia-induced Vascular Endothelial Growth Factor Expression in the Retina of Diabetic Rodents

“…To specifically evaluate the contribution of diabetes-induced hyperglycemia to these changes, normalization of blood glucose levels by phlorizin was used to achieve glycemic control. As previously observed (20), twicedaily administration of phlorizin reduced serum glucose levels in diabetic rats close to normal levels independently of insulin (145.0 Ϯ 23.0 mg.dL Ϫ1 in control versus 547.3 Ϯ 21.5 mg.dL…”

SIK2 Is Involved in the Negative Modulation of Insulin-Dependent Müller Cell Survival and Implicated in Hyperglycemia-Induced Cell Death

“…20 Enhanced Müller cell apoptosis and decreased Akt activity have been reported in diabetic animal models. 21,22 Consistent with these observations, Müller cell apoptosis via downregulation of Akt activity under hyperglycemic conditions has been observed in vitro. 23 The role of serine phosphorylation of IRS proteins is well established in attenuation or fine-tuning of IR signaling and insulin resistance during diabetes.…”

Transgenic Mice Overexpressing Serum Retinol-Binding Protein Develop Progressive Retinal Degeneration through a Retinoid-Independent Mechanism

“…Retinal insulin resistance contributes to diabetic retinopathy in rodents with streptozotocin (STZ)-induced diabetes, in which insulin receptor signaling is downregulated (81) and systemic or ocular injection of insulin significantly reduced proinflammatory gene expression and neurodegeneration (70,82,83). Intriguingly, disruption of insulin receptor signaling in cone photoreceptors causes disorganized and reduced photoreceptor ribbon synapses (79), similar to the types observed in RBP4-Tg mice.…”