Glucose flux through the glucosamine pathway regulates the activity of transcription factors by promoting their O-GlcNAcylation ( 16). The transcription factor carbohydrate response element-binding protein (ChREBP) mediates the effect of glucose on glycolytic and lipogenic gene expression ( 32). Glucose can regulate gene transcription, enzyme activity, hormone secretion, and the activity of glucoregulatory neurons. In this context, glucose has acquired a role as a signaling molecule to control glucose and energy homeostasis. In higher organisms, the preservation of energetic integrity requires adaptation to external resources and extensive interorgan communication. Mechanisms have consequently evolved to utilize glucose as a major catabolic and anabolic substrate for the great majority of extant organisms in all three kingdoms. Glucose as a Substrate and a Regulator of Metabolic PathwaysĪs a major product of the carbon fixation carried out by photosynthetic organisms, glucose is undoubtedly one of the most abundant biological molecules on the earth, existing mostly in various polymerized forms such as cellulose. Here, we provide a very brief summary of the known properties of the 14 Glut proteins and suggest some avenues of future investigation in this area. Separate review articles on many of the Glut proteins have recently appeared in this journal. The well-established glucose transporter isoforms, Gluts 1–4, are known to have distinct regulatory and/or kinetic properties that reflect their specific roles in cellular and whole body glucose homeostasis. The primary physiological substrates for at least half of the 14 Glut proteins are either uncertain or unknown. Fourteen Glut proteins are expressed in the human and they include transporters for substrates other than glucose, including fructose, myoinositol, and urate. Most mammalian cells import glucose by a process of facilitative diffusion mediated by members of the Glut (SLC2A) family of membrane transport proteins. The ability to take up and metabolize glucose at the cellular level is a property shared by the vast majority of existing organisms.