Insulin and β-adrenergic Receptors Inhibit Retinal Endothelial Cell Apoptosis Through Independent Pathways

Abstract

Diabetic retinopathy results from altered insulin receptor signaling. Based on previous studies demonstrating an interaction between β-adrenergic receptors and insulin signaling in hyperglycemic conditions, we hypothesized that β-adrenergic receptor stimulation and insulin stimulation would act synergistically to inhibit one of the hallmarks of diabetic retinopathy, namely retinal endothelial cell apoptosis. To test this hypothesis, human retinal endothelial cells were grown in high glucose (25 mM) medium and treated with a β-1-adrenergic receptor agonist (xamoterol, 10 μM) alone, insulin alone (10 nM) or xamoterol + insulin. We then assessed changes in the levels of insulin receptor, insulin-like growth factor (IGF-1) receptor, and Akt phosphorylation, as well as cleaved caspase 3. Xamoterol alone significantly decreased insulin receptor, IGF-1 receptor and Akt phosphorylation, whereas insulin alone increased insulin receptor, IGF-1 receptor, and Akt phosphorylation. Xamoterol significantly decreased apoptosis of retinal endothelial cells. This data suggests that both β-adrenergic receptors and insulin can inhibit retinal endothelial cell apoptosis in hyperglycemic conditions, but inhibition occurs through independent pathways. These findings have implications for treatments of diabetic retinopathy.

TNFα and SOCS3 regulate IRS-1 to increase retinal endothelial cell apoptosis

“…After the appropriate treatment, cells were collected into lysis buffer and processed for Western blotting as we have done in the past [32,33]. Briefly, following cell lysis, protein concentrations are obtained using the Bradford assay.…”

Beta-2-Adrenergic Receptor Regulates Insulin Signaling to Reduce Cell Death in Müller Cells

“…The common GPCR, beta-adrenergic receptors have been previously shown to lose signaling capabilities with the onset of diabetes in various tissues throughout the body including the eye. 28,29,92,96,122 -adrenergic receptor as the dominant receptor subtype in regulation of insulin receptor signaling in retinal Müller cells.…”

“…39,59,103,122,[125][126][127] At a 2007 summer meeting of the Association for Research in Vision and Ophthalmology, it was suggested that diabetic retinopathy be defined as "structural and functional changes in the retina due to diabetes." The hyperglycemic environment caused by diabetes produces a number of vascular and neuronal changes in the retina, making the disease very difficult to describe and develop treatments.…”

“…In addition to these effects, Müller cells have also been shown to possess insulin receptors, which are suggested to be impaired in diabetic retinopathy. 39,52,58,95,122,125 Although elevated glucose levels characterize diabetes, the underlying cause for these complications can be attributed to deficiencies in the production or usage of insulin. Insulin is only able to mediate its actions by binding the insulin receptor, with the receptor propagating the signal to carry out various protein and energy requirements.…”

Compound 49b: A Novel Beta-Adrenergic Receptor Agonist in the Treatment of Diabetic Retinopathy

“…Our data support this finding that insulin receptor phosphorylation is significant reduced in retinal lysates from untreated diabetic rats. Insulin has been reported to be a survival factor for R28 cells (a retinal ganglion cell line) (Xiaochua et al 2004), as well as retinal endothelial cells (Panjala & Steinle 2011). The anti apoptotic actions of insulin occur through activation of Akt (Reiter et al 2006).…”