Skeletal Muscle Insulin Resistance in Three Dimensions: Mechanisms, Myokines, and Microphysiological Platform

Skeletal muscle insulin resistance is a major determinant of impaired glucose disposal in type 2 diabetes. The mechanisms underlying insulin resistance in muscles are shaped by tissue architecture, contraction, extracellular-matrix signalling, mitochondrial function, and endocrine communication; processes that are not fully reproduced by conventional cell-based two-dimensional (monolayer) models of disease. This narrative review integrates our current understanding of canonical IRS-1-PI3K-AKT-GLUT4 signalling with contraction-dependent pathways, lipotoxicity, mitochondrial and endoplasmic-reticulum stress, inflammation, extracellular-matrix remodelling, and myokine dysregulation. We then evaluate experimental models, with particular emphasis on three-dimensional (3D) engineered muscle tissues (EMTs). Current evidence indicates that 3D EMTs can provide aligned myofibres, matrix-dependent mechanosignalling, measurable force and calcium handling, insulin-stimulated glucose uptake, and contraction-regulated myokine secretion. Emerging co-culture and myosteatosis models also recapitulate aspects of adipose-muscle crosstalk. However, current platforms remain limited by incomplete fibre maturation, absent or immature neuromuscular junctions, limited vascularisation and perfusion, variability across cell and scaffold systems, and sparse validation against patient-specific multi-omic signatures. Integrating patient-derived cells, innervation, perfusion, controlled mechanics, and multi-tissue modules could make 3D EMTs a more predictive microphysiological platform for mechanistic studies, therapeutic screening, and precision metabolic medicine.