Class III facilitative glucose transporters: Beyond glucose transport in health and disease

Glucose is an essential metabolic substrate for ATP production in virtually all life forms; however, due to its size and polarity, its cellular uptake requires specialized membrane transporters. The facilitative glucose transporters (GLUTs) are a conserved family of membrane proteins which facilitate the transport of glucose across the cellular plasma membrane. This family is evolutionarily conserved across phyla and ubiquitously expressed in mammalian tissues, positioning GLUTs as one of the central regulators of whole-body glucose homeostasis under both physiological and pathophysiological conditions and as important therapeutic targets. The GLUT isoforms, of which there are currently 14 knowns, are organized into three classes based on sequence homology. While the class III encompasses most of the novel GLUT isoforms (e.g., GLUT6, GLUT8, GLUT10, GLUT12) it has received less attention than the class I. Emerging evidence highlights their diverse and critical roles in cellular metabolic regulation. Beyond glucose transport, Class III GLUTs participate in redox balance, immunometabolism, intracellular trafficking, and proton-coupled substrate transport. They have also been increasingly implicated in the pathophysiology of a wide range of common and serious diseases, including metabolic, cardiovascular, neurodegenerative, and neoplastic diseases. In this review, we synthesize current knowledge on the physiological functions, regulatory mechanisms, and pathophysiological roles of the Class III GLUTs across multiple organs and species, and highlight their potential as novel therapeutic targets, as well as key directions for future research.