Molecular architecture of GLUT4 trafficking and exocytosis in adipocytes and skeletal muscle: A systematic review and integrated conceptual framework.

Introduction: GLUT4 exocytosis links insulin signaling to cellular glucose disposal in adipocytes and skeletal muscle. Evidence for its molecular regulation is dispersed across experimental models, trafficking stages, and signaling pathways. We systematically mapped the molecular evidence underlying GLUT4 vesicle mobilization, tethering, docking, and membrane fusion and compared adipocyte and skeletal-muscle mechanisms. Methods: We searched PubMed (MEDLINE), Scopus, and Embase, supplemented by ProQuest Dissertations & Theses and preprint repositories. Primary experimental studies examining molecular regulators of GLUT4 exocytosis using in vitro and in vivo models were eligible. Two reviewers independently performed study selection, data extraction, and quality appraisal in accordance with PRISMA 2020. The protocol was prospectively registered in PROSPERO. Findings were synthesized narratively and mapped using the prespecified evidence-tier framework. Results: Of 15,835 identified records, 350 primary experimental studies met the eligibility criteria. The evidence map identified 206 distinct molecular entries in adipocyte studies and 109 in skeletal-muscle studies, representing the breadth of reported associations rather than uniformly validated regulators. Both tissues showed partially overlapping late trafficking machinery involving SNARE- and exocyst-related components. Adipocyte evidence most consistently supported AKT2 -TBC1D4 (AS160) -RAB10 signaling together with TC10- and RAC1-associated cortical modules. Skeletal-muscle pathways integrated insulin-responsive signaling with contraction-, AMPK-, and calcium-associated inputs involving TBC1D1/TBC1D4, RAC1, and RAB8A/RAB13. Direct imaging and perturbation experiments provided the strongest evidence for step-specific roles, but much of the evidence derived from differentiated cell lines and rodent models. Discussion: GLUT4 trafficking in both tissues follows a shared broad logic of signal-dependent vesicle release, cortical targeting, and membrane insertion, while individual regulatory nodes differ in their contribution and evidence base. These findings support signal-to-trafficking coupling as a relevant mechanistic layer of insulin resistance and identify pathways requiring validation in physiologically relevant human models before therapeutic translation. Systematic Review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD420251105528.