Not all groups find a primary proximal defect in human obesity/T2DM, indicating heterogeneity across tissues and contexts (68, 69).The traditional focus on proximal IRS1–PI3K–Akt defects is increasingly balanced by evidence that insulin resistance often reflects downstream disturbances in GLUT4 trafficking and lipid handling, with no consistent defect at the proximal nodes (70). The gene discussed is INS; the disease is obesity due to melanocortin 4 receptor deficiency.