Loss of protein tyrosine phosphatase 1B increases IGF-I receptor tyrosine phosphorylation but does not rescue retinal defects in IRS2-deficient mice

et al.[Purpose]: Mice with deletion of insulin receptor substrate (IRS) 2 develop type 2 diabetes and photoreceptor degeneration. Loss of protein tyrosine phosphatase 1B (PTP1B) in diabetic IRS2-/- mice restores insulin sensitivity and normalizes glucose homeostasis. Since insulinlike growth factor (IGF)-IR promotes survival of photoreceptors and is a substrate of PTP1B, we investigated IGF-IR-mediated survival signaling and visual function in PTP1B-/- and double mutant IRS2-/-/PTP1B-/- mice. [Methods]: IGF-IR-mediated Akt signaling was evaluated in IGF-I-stimulated retinal explants. Histologic and electroretinogram analysis was performed in wild-type (WT), IRS2-/-, PTP1B-/-, and the double mutant IRS2-/-/PTP1B/ mice. [Results]: IGF-I stimulated the tyrosine phosphorylation of its receptor and Akt activation in retinal explants of WT mice. In PTP1B-/- retinal explants, these responses were enhanced. Conversely, in retinas from IRS2-/- mice, expression of PTP1B was increased, coincident with decreased IGF-I-mediated Akt serine 473 phosphorylation. PTP1B deletion in IRS2 -/-mice also enhanced IGF-IR tyrosine phosphorylation but, unexpectedly, did not rescue Akt activation in response to IGF-I. One potential explanation is that PTEN was increased in retinas of IRS2-/- and IRS2-/-/PTP1B-/- mice. Histologic evaluation revealed alterations in various structures of the retina in IRS2-/- and IRS2-/-/PTP1B-/- mice, specifically in the outer nuclear layer (ONL) and retinal outer segments (ROS). Electroretinogram (ERG) analysis confirmed that PTP1B deficiency did not restore visual function in IRS2-/- mice. [Conclusions]: Although loss of PTP1B enhances tyrosine phosphorylation of the IGF-IR in retinal explants of IRS2-/- mice, Akt activation remains defective owing to elevated PTEN levels and, thus, structural and functional visual defects persist in this model. © 2013 The Association for Research in Vision and Ophthalmology, Inc.Supported by Grants SAF2012-33283, SAF2010-21879-C02-01 (MINECO, Spain), NEURORET-DIAB from CIBERDEM (Centro de Investigacion Biomedica en Red de Diabetes y Enfermedades Metabolicas Asociadas, Instituto Salud Carlos III, Spain), Comunidad de Madrid S2010/BMD-2423, and The European Consortium for the Early Treatment of Diabetic Retinopathy (278040 PCOLSMALL), a project funded by the FP7 Program of the European Community. AIA, JR-C, and AG-R hold postdoctoral contracts from CIBERDEM. ThPeer Reviewe