Insulin Receptor Substrate 2 ( IRS 2 )-Deficient Mice Show Sensorineural Hearing Loss That Is Delayed by Concomitant Protein Tyrosine Phosphatase 1 B ( PTP 1 B ) Loss of Function

INTRODUCTION 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). Although IRS1 and IRS2 share similar expression patterns in most tissues, several lines of evidence suggest that IRS-mediated signaling in growth and metabolism is tissue specific (3,4). Mutations in IR and IGF1R lead to severe defects in development and premature death in mice and humans (5,6). However, deletion of mouse IRS proteins 1 and 2 produces growth retardation and type 2 diabetes in mice, respectively (7,8). IRS2 integrates the effects of insulin in peripheral target tissues, mainly the liver, with those of IGF-1 in pancreatic β cells to maintain glucose homeostasis. Mice lacking IRS2 exhibit impaired suppression of hepatic glucose production (8–10) 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 also 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). Insulin Receptor Substrate 2 (IRS2)-Deficient Mice Show Sensorineural Hearing Loss That Is Delayed by Concomitant Protein Tyrosine Phosphatase 1B (PTP1B) Loss of Function

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