Abstract
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.
Highlights
The insulin receptor substrate (IRS)proteins are key molecules in the signaling pathways induced by insulin and insulinlike growth factor 1 (IGF-1) and mediate their pleiotropic effects, including cell growth, survival, development and glucose metabolism [1].Among the six known IRS proteins, IRS1 and IRS2 serve as adaptor proteins to both the insulin receptor (IR) and the IGF-1 receptor (IGF1R), activating the phosphatidylinositol 3-kinase and mitogen-activated protein kinase (MAPK) pathways [2]
IRS2 coordinates IGF-1/IGF1R signaling in the central nervous system, where this factor is essential for the regulation of cell proliferation, growth, differentiation and metabolic demands during fetal and postnatal development [12]
Differences in auditory brainstem response (ABR) thresholds for pure tones between Irs2–/–Ptpn1+/+ mice and wildtype counterparts were of 30–40 decibel sound pressure level (dB SPL) (Table 1)
Summary
The insulin receptor substrate (IRS)proteins are key molecules in the signaling pathways induced by insulin and insulinlike growth factor 1 (IGF-1) and mediate their pleiotropic effects, including cell growth, survival, development and glucose metabolism [1].Among the six known IRS proteins, IRS1 and IRS2 serve as adaptor proteins to both the insulin receptor (IR) and the IGF-1 receptor (IGF1R), activating the phosphatidylinositol 3-kinase and mitogen-activated protein kinase (MAPK) pathways [2]. Proteins are key molecules in the signaling pathways induced by insulin and insulinlike growth factor 1 (IGF-1) and mediate their pleiotropic effects, including cell growth, survival, development and glucose metabolism [1]. Deletion of mouse IRS proteins 1 and 2 produces growth retardation and type 2 diabetes in mice, respectively [7,8]. Mice lacking IRS2 exhibit impaired suppression of hepatic glucose production [8,9,10] and β-cell failure [11], developing fasting hyperglycemia at 6–8 wks of age and severe type 2 diabetes at 10–12 wks of age [8]. IRS2 coordinates IGF-1/IGF1R signaling in the central nervous system, where this factor is essential for the regulation of cell proliferation, growth, differentiation and metabolic demands during fetal and postnatal development [12]
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