TBC1D4 is a Rab GTPase-activating protein (GAP) that serves dual roles in glucose homeostasis and autophagy regulation. Its primary function involves insulin-stimulated glucose transporter GLUT4 translocation to the plasma membrane, increasing glucose uptake in skeletal muscle and adipose tissue 1. TBC1D4 acts as a GAP for Rab GTPases including RAB2A, RAB8A, RAB10, and RAB14 2, with Akt2-dependent phosphorylation at T642 being a key mechanism for insulin-stimulated glucose uptake 1. Beyond glucose transport, TBC1D4 functions as a molecular brake on autophagic and endocytic pathways by antagonizing RAB2A-mediated processes, suppressing both early autophagy initiation via ULK1 complex and late-stage autophagosome-lysosome fusion 2. Notably, TBC1D4-S711 phosphorylation by AMPK mediates post-exercise insulin sensitization in skeletal muscle 3. Mutations in TBC1D4 cause severe genetic insulin resistance syndrome and confer approximately tenfold increased type 2 diabetes risk in some populations 45. Loss of muscle-specific TBC1D4 isoforms results in severe skeletal muscle insulin resistance with markedly reduced GLUT4 expression, though exercise capacity remains intact 5. Epigenetic alterations affecting TBC1D4 expression in pancreatic islets associate with impaired insulin secretion and type 2 diabetes risk 6.