Our findings suggest a model by which SMPDL3b may affect podocyte function and survival, where excessive SMPDL3b expression may cause the displacement of IR from caveolin-1-rich domain in a C1P-dependent manner, resulting in impaired ability to phosphorylate AKT thus promoting podocyte injury in vitro and development of DKD in vivo. Here, AKT1 is linked to diabetic kidney disease.