Diabetes Reduces Basal Retinal Insulin Receptor Signaling

Reiter, Chad E.N.; Wu, Xiaohua; Sandirasegarane, Lakshman; Nakamura, Makoto; Gilbert, Kirk A.; Singh, Ravi Shankar; Fort, Patrice E.; Antonetti, David A.; Gardner, Thomas W.

doi:10.2337/diabetes.55.04.06.db05-0744

Cited by 158 publications

(205 citation statements)

References 48 publications

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“…Evidence is now accumulating suggesting that the insulin receptor also provides trophic functions in the brain via the PI 3-kinase/Akt pathway (94). In the retina, insulin stimulates insulin receptor substrate (IRS)-2 tyrosine phosphorylation (89); retinal IRS-2 content is decreased in diabetic rats (90), and IRS-2 deletion leads to degeneration of inner retinal neurons and photoreceptors (95). Hence, it is reasonable to hypothesize that decreased insulin-stimulated prosurvival stimuli, at least in part via loss of PI 3-kinase/Akt-mediated effects, may contribute to retinal cell death.…”

Section: Reduced Insulin Action Leads To Neurodegenerationmentioning

confidence: 99%

Diabetic Retinopathy

et al. 2006

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Diabetic retinopathy remains a frightening prospect to patients and frustrates physicians. Destruction of damaged retina by photocoagulation remains the primary treatment nearly 50 years after its introduction. The diabetes pandemic requires new approaches to understand the pathophysiology and improve the detection, prevention, and treatment of retinopathy. This perspective considers how the unique anatomy and physiology of the retina may predispose it to the metabolic stresses of diabetes. The roles of neural retinal alterations and impaired retinal insulin action in the pathogenesis of early retinopathy and the mechanisms of vision loss are emphasized. Potential means to overcome limitations of current animal models and diagnostic testing are also presented with the goal of accelerating therapies to manage retinopathy in the face of ongoing diabetes. Diabetes 55:2401-2411, 2006 D espite years of clinical and laboratory investigation, diabetic retinopathy remains the leading cause of vision impairment and blindness among working-age adults, yet the fundamental cause(s) remains uncertain. Retinal photocoagulation to reduce neovascularization and macular edema was developed in the 1950s and is still the standard of care (1). The number of people worldwide at risk of developing vision loss from diabetes is predicted to double over the next 30 years (2), so it is imperative to develop better means to identify, prevent, and treat retinopathy in its earliest stages rather than wait for the onset of vision-threatening lesions. Progress in these areas requires a new perspective on the problem that includes the roles of the neural retina, impaired insulin action, and inflammation. In this way, established neurobiological principles can inform us how diabetes impairs vision, and knowledge of metabolism, inflammation, and regenerative medicine may lead to new treatments.This perspective will discuss how the unique anatomy and physiology of the retina may render it vulnerable to the metabolic derangements of diabetes and lead to impaired vision. The intent of this unconventional approach is to encourage consideration of new opportunities for investigations that will advance the field. NORMAL RETINAL STRUCTURE AND PHYSIOLOGY Topographic and cellular organization of the retina.It is instructive to consider the functional organization of the retina (literally a network) to better understand the impact of diabetes (http://webvision.med.utah.edu). The retina is a transparent layer of neural tissue between the retinal pigmented epithelium and the vitreous body. Normal vision depends on intact cell-cell communication among the neuronal, glial, microglial, vascular, and pigmented epithelial cells of the retina. The fundamental functions of the retina are to capture photons, convert the photochemical energy into electrical energy, integrate the resulting action potentials, and transmit them to the occipital lobe of the brain, where they are deciphered and interpreted into recognizable images. The retina is partitioned from the syst...

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Section: Reduced Insulin Action Leads To Neurodegenerationmentioning

confidence: 99%

Diabetic Retinopathy

et al. 2006

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“…IR signaling is also involved in 17␤-estradiolmediated neuroprotection in the retina (4). Recent evidence suggests a down-regulation of IR kinase activity in diabetic retinopathy that is associated with the deregulation of downstream signaling molecules (5). Deletion of several downstream effector molecules of the IR signaling pathway, such as IRS-2 (6), Akt2 (7), and Bcl-xl (8), in the retina resulted in a photoreceptor degeneration phenotype.…”

Section: Insulin Receptor (Ir)mentioning

confidence: 99%

Loss of Neuroprotective Survival Signal in Mice Lacking Insulin Receptor Gene in Rod Photoreceptor Cells

Rajala

Tanito

et al. 2008

Journal of Biological Chemistry

113

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Insulin receptor (IR) signaling provides a trophic signal for transformed retinal neurons in culture, but the role of IR activity in vivo is unknown. We previously reported that light causes increased tyrosine phosphorylation of the IR in vivo, which leads to the downstream activation of the phosphoinositide 3-kinase and Akt pathway in rod photoreceptor cells. The functional role of IR in rod photoreceptor cells is not known. We observed that light stress induced tyrosine phosphorylation of the IR in rod photoreceptor cells, and we hypothesized that IR activation is neuroprotective. To determine whether IR has a neuroprotective role on rod photoreceptor cells, we used the Cre/lox system to specifically inactivate the IR gene in rod photoreceptors. Rodspecific IR knock-out mice have reduced the phosphoinositide 3-kinase and Akt survival signal in rod photoreceptors. The resultant mice exhibited no detectable phenotype when they were raised in dim cyclic light. However, reduced IR expression in rod photoreceptors significantly decreased retinal function and caused the loss of photoreceptors in mice exposed to bright light stress. These results indicate that reduced expression of IR in rod photoreceptor cells increases their susceptibility to lightinduced photoreceptor degeneration. These data suggest that the IR pathway is important for photoreceptor survival and that activation of the IR may be an essential element of photoreceptor neuroprotection. Insulin receptor (IR)2 signaling provides a trophic signal for transformed retinal neurons in culture (1), but the role of the IR in vivo is unknown. IR activation has been shown to rescue retinal neurons from apoptosis through a phosphoinositide 3-kinase (PI3K) cascade (1). We previously reported that light induces tyrosine phosphorylation of the retinal IR and that this activation leads to the binding of PI3K to rod outer segment (ROS) membranes (2). More recently, we demonstrated that IR activation is mediated through the G-protein-coupled receptor rhodopsin (3). IR signaling is also involved in 17␤-estradiolmediated neuroprotection in the retina (4). Recent evidence suggests a down-regulation of IR kinase activity in diabetic retinopathy that is associated with the deregulation of downstream signaling molecules (5). Deletion of several downstream effector molecules of the IR signaling pathway, such as IRS-2 (6), Akt2 (7), and Bcl-xl (8), in the retina resulted in a photoreceptor degeneration phenotype. These studies clearly indicate the importance of the IR signaling pathway in the retina.The IR is highly conserved, and the high degree of IR signaling homology between Caenorhabditis elegans, Drosophila, and humans suggests functional conservation in mammalian retina. The IR regulates neuronal survival in C. elegans (9). In Drosophila, the IR serves an important function to guide retinal photoreceptor axons from the retina to the brain during development (10), and the IR influences the size and number of photoreceptors (11). The lack of IR activation leads to neurod...

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“…Cones are affected indirectly in diseases such as retinitis pigmentosa (RP) 2 and directly in cone and cone-rod dystrophies (23)(24)(25)(26). Selective loss of cones has been reported in diabetic retinopathy (21,22), and retinal IR/PI3K/Akt signaling has been shown to be down-regulated in diabetes (27,28). Insulin/mammalian target of rapamycin (mTOR) pathway has been shown to be essential for cone survival, and activation of this pathway by systemic administration of insulin delays the death of cones in a mouse model of RP (26,29).…”

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confidence: 99%

Insulin Receptor Signaling in Cones

Rajala

Dighe

Agbaga

et al. 2013

Journal of Biological Chemistry

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Background: Insulin receptor (IR)-phosphoinositide 3-kinase (PI3K) signaling pathway provides neuroprotection to cones. Results: Loss of PI3K in cones triggers cone degeneration that is not protected by rod derived cone survival factors. Conclusion: Cones have their own endogenous PI3K-mediated neuroprotective pathway. Significance: The IR-PI3K signaling pathway may be a target for neuroprotective therapeutic intervention.

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Diabetes Reduces Basal Retinal Insulin Receptor Signaling

Cited by 158 publications

References 48 publications

Diabetic Retinopathy

Diabetic Retinopathy

Loss of Neuroprotective Survival Signal in Mice Lacking Insulin Receptor Gene in Rod Photoreceptor Cells

Insulin Receptor Signaling in Cones

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