Facilitative glucose transporters: regulatory mechanisms and dysregulation in diabetes.

Introduction Maintenance of normal glucose homeostasis results from the precise orchestration ofthree processes: glucose absorption via the gut, production by the liver, and utilization by nearly all tissues in the body. In the fasting state, most ofglucose utilization is by brain and is independent of insulin. Glucose levels are maintained during a fast by the tightly regulated release of glucose from the liver. Postprandially, increased insulin levels promote enhanced glucose uptake, metabolism, and storage in muscle and adipose cells, with skeletal muscle quantitatively most important. The increment in insulin and decrement in glucagon concentrations in the portal circulation inhibit he-patic glucose production. States such as diabetes and obesity are characterized by resistance to the effect of insulin on both the stimulation of peripheral glucose utilization as well as the inhibition of hepatic glucose production. Diabetes is further marked by inadequate insulin secretion to meet the increased demands resulting from peripheral insulin resistance. In mammalian cells, glucose is not freely permeable across the lipid bilayer but enters by facilitated diffusion, a process in which specific integral membrane proteins passively transport glucose down a concentration gradient. Glucose can also be concentrated in epithelial cells of the intestine and the proxi-mal tubule ofthe kidney by an active process in which Na+/glu-cose cotransporters (reviewed in 1) utilize the electrochemical potential ofNa' as an energy source. Molecular cloning studies over the last seven years have revealed a family of facilitated diffusion glucose transporter proteins which are structurally related but are encoded by distinct genes that are expressed in a tissue specific manner (reviewed in 2-4) (Table I). These are structurally and genetically distinct from the Na+-linked glucose cotransporters but bear considerable sequence homology with sugar transporters in bacteria, yeast, and protozoa (3). Recent studies have begun to unravel the mechanisms by which facilitated diffusion transporters participate in the regulation of glucose utilization in various tissues. This Perspectives will discuss evidence that altered expression, localization, and/ or function of facilitative glucose transporters may contribute to the pathogenesis of diseases such as diabetes.