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IRS2 deficiency limits the effects of inhibition of protein tyrosine phosphatase 1B in IGF-IR-mediated signalling in the retina

AuthorsArroba, Ana I. ; Revuelta-Cervantes, Jesús; González-Rodríguez, Águeda; Burks, Deborah J.; Valverde, Ángela M.
Issue Date2012
CitationEASD 2012
Abstract[Background and aims]: Mice with complete deletion of insulin receptor substrate (IRS) 2 develop type 2 diabetes. In the retina, IRS2 deficiency induced photoreceptor degeneration and apoptosis that is not rescued by normalization of glucose levels. On the other hand, protein tyrosine phosphatase 1B (PTP1B) inhibition by genetic deletion in IRS2-/- mice (double mutant IRS2-/-PTP1B-/-) restored peripheral insulin resistance and normalized glucose homeostasis. Since IGF-IR promotes survival of photoreceptors and also is a substrate of PTP1B, we aimed to investigate IGF-IR-mediated survival signalling and visual function in PTP1B-/-and IRS2-/-/PTP1B-/-in comparison to wild-type and IRS2-/-mice. [Materials and methods]: IGF-IR tyrosine phosphorylation and Akt serine 473 phosphorylation were analyzed by western blot in organotypic retinal explants stimulated with IGF-I. Immunohistochemistry was used to evaluate retinal structure preservation in mice at 10-12 weeks and programmed cell death was assessed by TUNEL. Visual function was evaluated by Electroretinographic (ERG) recording in mice at 5 and 10 weeks. [Results]: IGF-IR tyrosine phosphorylation and Akt serine 473 phosphorylation increased in retinal explants stimulated for 15 min with IGF-I in a dose-dependent manner. In PTP1B-/- retinal explants, these responses increased by twofold in IGF-IR phosphorylation and by threefold in Akt phosphorylation compared to the wild-type control (p=0.037 and p=0.04, respectively). Conversely, in IRS2-/- mice the response to IGF-I in Akt phosphorylation decreased compared to the wild-type control (p=0.04). Moreover, in IRS2-/- mice PTP1B deletion (double mutant IRS2-/- /PTP1B-/-) also enhanced IGF-IR tyrosine phosphorylation (p=0.01) but, unexpectedly, the response to IGF-I in the activation of Akt remained decreased as observed in the IRS2-/- mice. Histological evaluation revealed a significant thickness in whole retina in both IRS2-/- and double mutant IRS2-/-/PTP1B-/- mice, specifically in the outer nuclear layer (ONL) and retinal outer segments (ROS) (p<0.001). ERG analysis showed that PTP1B deficiency did not restored normal visual function in IRS2-/- mice. [Conclusion]: Although PTP1B deficiency significantly enhanced IGF-IR tyrosine phosphorylation in retinal explants of IRS2-/- mice, it was unable to restore Akt phosphorlyation and, therefore, the structural and functional visual of these mice defects were not improved.
DescriptionResumen del póster presentado al 48th European Association for the Study of Diabetes (EASD) Annual Meeting, celebrado en Berlin (Alemania) del 1 al 5 de octubre de 2012.
Appears in Collections:(IIBM) Comunicaciones congresos
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