{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nInsulin receptor substrate‐2 (IRS2) is a central adaptor protein that transduces signals from the insulin and insulin‐like growth factor receptors to promote cell growth, survival, and metabolism. In the endocrine pancreas, IRS2 is indispensable for maintaining beta‐cell mass and function, as it mediates actions of incretin hormones and glucose to prevent apoptosis and stimulate proliferation. Its expression is tightly regulated by transcription factors and kinases—including CREB, CaMK4, and ATF3—to support compensatory beta‐cell expansion under insulin resistance, thus delaying diabetes onset."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "10"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the central nervous system, IRS2 plays a neuroprotective role and modulates energy homeostasis that influences both cognitive function and longevity. Reduced IRS2 signaling in the brain is linked to extended lifespan and enhanced metabolic parameters in animal models, whereas its dysregulation is associated with impaired neuronal proliferation, tau hyperphosphorylation, and accumulation of neurotoxic aggregates. 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Structural studies have elucidated unique regions in IRS2 essential for its interaction with receptor kinases, and its phosphorylation by kinases such as JNK and GSK‐3 further fine‐tunes its signaling output."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "17", "end_ref": "34"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Ulupi S Jhala, Gianluca Canettieri, Robert A Screaton, et al. 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