Insulin Receptor Substrate 2 (IRS2)-Deficient Mice Show Sensorineural Hearing Loss That Is Delayed by Concomitant Protein Tyrosine Phosphatase 1B (PTP1B) Loss of Function
The insulin receptor substrate (IRS) proteins are key mediators of insulin and insulinlike growth factor 1 (IGF-1) signaling. Protein tyrosine phosphatase (PTP)-1B dephosphorylates and inactivates both insulin and IGF-1 receptors. IRS2-deficient mice present altered hepatic insulin signaling and β-cell failure and develop type 2-like diabetes. In addition, IRS2 deficiency leads to developmental defects in the nervous system. IGF1 gene mutations cause syndromic sensorineural hearing loss in humans and mice. However, the involvement of IRS2 and PTP1B, two IGF-1 downstream signaling mediators, in hearing onset and loss has not been studied. Our objective was to study the hearing function and cochlear morphology of Irs2-null mice and the impact of PTP1B deficiency. We have studied the auditory brainstem responses and the cochlear morphology of systemic Irs2−/−Ptpn1+/+, Irs2+/+Ptpn1−/− and Irs2−/−Ptpn1−/− mice at different postnatal ages. The results indicated that Irs2−/−Ptpn1+/+ mice present a profound congenital sensorineural deafness before the onset of diabetes and altered cochlear morphology with hypoinnervation of the cochlear ganglion and aberrant stria vascularis, compared with wild-type mice. Simultaneous PTP1B deficiency in Irs2−/−Ptpn1−/− mice delays the onset of deafness. We show for the first time that IRS2 is essential for hearing and that PTP1B inhibition may be useful for treating deafness associated with hyperglycemia and type 2 diabetes.
We thank Julie Chowen (Hospital Niño Jesús, Madrid) for the critical reading of the manuscript and comments and J Pérez, R Martínez-Vega (Institute of Biomedical Research), D Morales, A De Las Heras (Medical School, Autonoma University of Madrid) and J Contreras (Veterinary Faculty, Complutense University of Madrid) for technical and scientific support. This work was supported by the Ministerio de Ciencia e Innovacion (SAF2008-00470 and SAF2011 to I Varela-Nieto and SAF2009-08114 to AM Valverde) and the Fundacion Mutua Madrileña to IV Varela-Nieto. S Murillo-Cuesta, A Gonzalez-Rodriguez and G Camarero hold postdoctoral contracts from the CIBERER, CIBERDEM and CSIC Junta para la Ampliación de Estudios (JAE) programs, respectively.
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