Facilitative glucose transporters: regulatory mechanisms and dysregulation in diabetes.

Abstract

IntroductionMaintenance 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 hepatic 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 proximal tubule ofthe kidney by an active process in which Na+/glucose 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.

Weight-related differences in glucose metabolism and free fatty acid production in two South African population groups

“…These hypotheses obviously need to be tested but a differential degree of tissue sensitivity to insulin has previously been observed by Hansen et al (University of Maryland, personal communication) in a primate model of obesity and in studies showing that in obese and type 2 diabetic subjects the levels of glucose transporter 4 (GLUT-4) fall in adipocytes but remain the same in skeletal muscle. 38,39 In addition, insulin dose ± response curves for stimulation of glucose uptake, suppression of glucose production and suppression of lipolysis has been shown before. 38,39 Lipolysis is the most insulin sensitive process, followed by glucose production and only then by glucose uptake (with EC 50 's in the physiological range only for lipolysis and glucose production).…”

Immunogold labeling study of the distribution of GLUT-1 and GLUT-4 in cardiac tissue following stimulation by insulin or ischemia

“…To the best of our knowledge, there have not been any previous immunogold studies that have successfully localized GLUT-1 in cardiac tissue, although such experiments have been attempted (17). Although this may be due to the antibod- Fig.…”

Engagement of the insulin-sensitive pathway in the stimulation of glucose transport by α-lipoic acid in 3T3-L1 adipocytes

“…There is considerable evidence that a defect in glucose transport is responsible for the acquired insulin resistance of glucose uptake observed in diabetes [18]. This metabolic impairment could conceivably be explained by a variety of defects in GLUT4 regulation including alterations in GLUT4 expression and translocation, defects in the insulin signalling pathway and alterations in the temporal and spatial pattern of signalling molecules.…”