Figure 11. Proposed signal transduction cascades for IR-mediated signaling in RPE cells.

Under physiological (low, 10nM) insulin concentrations, insulin binding to its cognate receptor induces autophosphorylation of the beta subunit of the receptor, binding of scaffolding proteins such as IRS-1 or c-cbl, and downstream mitogenic and metabolic signaling via MAPK, PI3K and Glut4-mediated glucose transport. Simultaneously, low levels of insulin induce an acute spike in hydrogen peroxide which leads to inhibition of tyrosine phosphatase activity and feeds forward to further potentiate cellular survival and proliferation. However, the hydrogen peroxide can also contribute to the exacerbation of already elevated levels of oxidative stress in a hyperglycemic environment. In our RPEIRKO mice, we found that the loss of IR-mediated signaling both leads to reduced photoreceptor function, and a decrease in oxidative stress. We propose that these processes can occur due to the release of tyrosine phosphatase inhibition, causing a reduction in paracrine signaling to photoreceptors that ensures their proper function. Alternately, the reduction in generation of hydrogen peroxide reduces oxidative stress in the hyperglycemic environment.