Hyperinsulinemia drives glomerular podocyte injury and albuminuria via a self-perpetuating GSK3β–IRS1 insulin desensitization circuit

knock-in mice exhibited impaired insulin signaling and podocyte injury with albuminuria. Conversely, tideglusib treatment in prediabetic db/db mice attenuated podocyte injury and insulin resistance, thereby improving albuminuria. Collectively, hyperinsulinemia directly elicits albuminuria and renal impairment via a cascade of molecular events involving insulin receptor exhaustion, reduced insulin signaling, and GSK3β hyperactivity, which promotes IRS1 inhibition and thereby forms a self-amplifying GSK3β-IRS1 circuit of insulin desensitization and podocyte injury. Targeting GSK3β could disrupt this pathogenic loop and mitigate hyperinsulinemia-induced renal injury.