Facilitative glucose transporter (GLUT) (GLUT)

Facilitative glucose transporters (GLUTs), belonging to the solute carrier family 2 (SLC2A), are a group of 14 transmembrane proteins that facilitate the passive movement of glucose and other hexoses across cell membranes [3, 6]. These transporters are critical for cellular metabolism and are expressed in a tissue-specific manner; for example, GLUT1 provides basal glucose uptake and is essential for the blood-brain barrier, while GLUT4 is the primary insulin-responsive transporter in muscle and adipose tissue [5, 9]. In many pathological states, particularly cancer, GLUTs are overexpressed to meet the high energy demands of rapid cell proliferation, a phenomenon known as the Warburg effect [11, 12]. Consequently, GLUTs have emerged as significant therapeutic targets, with various small-molecule inhibitors being developed to starve tumor cells of glucose [1, 13]. Beyond oncology, GLUTs are implicated in metabolic disorders such as diabetes mellitus and rare genetic conditions like GLUT1 deficiency syndrome [15, 17]. Pharmacological modulation of GLUTs includes both inhibition for cancer therapy and activation or translocation enhancement for treating insulin resistance [4, 10]. However, therapeutic application is challenged by the need for isoform selectivity to prevent adverse effects such as systemic hypoglycemia or neurotoxicity resulting from the inhibition of essential glucose transport in healthy tissues [14, 15]. Current research focuses on developing highly selective inhibitors, such as BAY-876 for GLUT1, to minimize off-target effects while effectively disrupting disease-associated metabolic pathways [10, 14].

Other names

SLC2A familyGlucose transporter familyMonosaccharide transport proteinsSolute carrier family 2

GLUT inhibitors typically function by binding to the transporter and preventing the conformational shift between outward-facing and inward-facing states, thereby blocking the passage of glucose into the cell [11, 14]. Some drugs, like HIV protease inhibitors, act as competitive or non-competitive inhibitors of specific isoforms like GLUT4 [4]. Conversely, certain agents can act as activators by promoting the translocation of transporters to the plasma membrane or increasing their intrinsic activity [4, 10].