Title of project

Testing a novel GLUT4 localization-centric model of human muscle insulin resistance

Abstract

Insulin resistance (IR) in skeletal muscle remains a central and mechanistically poorly understood defect in the pathogenesis of type 2 diabetes and related metabolic disorders. While canonical models focus on impaired insulin signaling as the primary cause, some evidence suggests that intracellular mislocalization of the glucose transporter GLUT4—specifically defects in the trafficking and storage of GLUT4 in insulin-responsive vesicles (GSVs)—may represent a parallel and underexplored mechanism contributing to IR. Importantly, such defects may originate from altered basal, rather than insulin-stimulated signaling.

This international collaborative project aims to explore a novel model of IR in human skeletal muscle, proposing that defective GSV localization and basal signaling rather than impaired insulin signaling per se, is a primary cause. The project combines high-resolution adult muscle GLUT4 imaging, AI-designed minibinder probes, and CRISPR-based gene editing in human muscle, rodent models and in vitro systems to test whether GSV pool size and localization in the basal state predict insulin sensitivity. These tools enable detailed investigation of GLUT4 trafficking and regulation in physiologically relevant contexts and to directly test the role of candidate proteins in controlling these processes. By advancing our understanding of GLUT4 regulation beyond classical insulin signaling, this research could redefine our mechanistic view of insulin resistance and open new avenues for therapeutic strategies targeting GLUT4 trafficking in metabolic disease.