GLUT2

Abstract: Facilitative glucose transport is mediated by members of the Glut protein family that belong to a much larger superfamily of 12 transmembrane segment transporters. Six members of the Glut family have been described thus far. These proteins are expressed in a tissue- and cell-specific manner and exhibit distinct kinetic and regulatory properties that reflect their specific functional roles. Glut1 is a widely expressed isoform that provides many cells with their basal glucose requirement. It also plays a special role in transporting glucose across epithelial and endothelial barrier tissues. Glut2 is a high-K m isoform expressed in hepatocytes, pancreatic β cells, and the basolateral membranes of intestinal and renal epithelial cells. It acts as a high-capacity transport system to allow the uninhibited (non-rate-limiting) flux of glucose into or out of these cell types. Glut3 is a low-K m isoform responsible for glucose uptake into neurons. Glut4 is expressed exclusively in the insulin-sensitive tissues, fat and muscle. It is responsible for increased glucose disposal in these tissues in the postprandial state and is important in whole-body glucose homeostasis. Glut5 is a fructose transporter that is abundant in spermatozoa and the apical membrane of intestinal cells. Glut7 is the transporter present in the endoplasmic reticulum membrane that allows the flux of free glucose out of the lumen of this organelle after the action of glucose-6-phosphatase on glucose 6-phosphate. This review summarizes recent advances concerning the structure, function, and regulation of the Glut proteins.

Abstract: We review evidence that increased tissue levels of fatty acyl CoA cause the beta-cell abnormalities of nondiabetic obesity and ultimately result in obesity-dependent diabetes. Nondiabetic obesity in Zucker rats is characterized by hypersecretion of insulin at normal fasting and subfasting glucose concentrations. This is a result of beta-cell hyperplasia and increased low Km glucose usage and oxidation. These abnormalities, the hyperinsulinemia, the hyperplasia of beta-cells, i.e., its in vitro equivalent, enhanced bromodeoxyuridine incorporation, and the increased low Km glucose usage can be induced by culturing normal islets with 2 mmol/l free fatty acids (FFAs). Once obese Zucker diabetic fatty rats become diabetic, glucose-stimulated insulin secretion (GSIS) is absent and beta-cell GLUT2 reduced. Islet triglyceride (TG) content is increased 10-fold, probably reflecting increased FFA delivery (plasma FFA levels > 1.5 mmol/l) beginning about 2 weeks before the onset of diabetes. These beta-cell abnormalities, GSIS loss, GLUT2 loss, and TG accumulation, are prevented by reducing plasma FFAs by caloric restriction and by nicotinamide injection. The loss of GSIS and the accumulation of TGs, but not the GLUT2 loss, can be induced in vitro in normal islets cultured in a 2 mmol/l FFA-containing medium, but prediabetic islets seem far more vulnerable to FFA-induced functional impairment and TG accumulation. It is proposed that in uncomplicated obesity, increased lipid availability (FFA levels < 1.5 mmol/l) induces both hyperinsulinemia and insulin resistance in parallel fashion, thereby maintaining normoglycemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract: The oxidation of glucose represents a major source of metabolic energy for mammaliancells However, because the plasma membrane is impermeable to polar molecules such as glucose, the cellular uptake of this important nutrient is accomplished by membrane-associated carrier proteins that bind and transfer it across the lipid bilayer Two classes of glucose carriers have been described in mammalian cells: the Na+-glucose cotransporter and the facilitative glucose transporter The Na+-glucose cotransporter transports glucose against its concentration gradient by coupling its uptake with the uptake of Na+ that is being transported down its concentration gradient Facilitative glucose c rriers accelerate the transport of glucose down its concentration gradient by facilitative diffusion, a form of passive transport cDNAs have been isolated from human tissues encoding a Na+-glucose-cotransporter protein and five functional facilitative glucosetransporter isoforms The Na+-glucose cotransporter is expressed by absorptive epithelial cells of the small intestine and is involved in the dietary uptake of glucose The same or a related protein may be responsible for the reabsorption of glucose by the kidney Facilitative glucose carriers are expressed by most if not all cells The facilitative glucose-transporter isoforms have distinct tissue distributions and biochemical properties and contribute to the precise disposal of glucose under varying physiological conditions The GLUT1 (erythrocyte) and GLUT3 (brain) facilitative glucose-transporter isoforms may be responsible for basal or constitutive glucose uptake The GLUT2 (liver) isoform mediates the bidirectional transport of glucose by the hepatocyte and is responsible, at least in part, for the movement of glucose out of absorptive epithelial cells into the circulation in the small intestine and kidney This isoform may also comprise part of the glucosesensing mechanism of the insulin-producing β-cell The subcellular localization of the GLUT4 (muscle/fat) isoform changes in response to insulin, and this isoform is responsible for most of the insulin-stimulated uptake of glucose that occurs in muscle and adipose tissue The GLLJT5 (small intestine) facilitative glucose-transporter isoform is expressed at highest levels in the small intestine and may be involved in the transcellular transport of glucose by absorptive epithelial cells The exon-intron organizations of the human GLUT1 , GLUT2 , and GLUT4 genes have been determined In addition, the chromosomal locations of the genes encoding the Na+-dependent and facilitative glucose carriers have been determined Restriction-fragment-length polymorphisms have also been identified at several of these loci The isolation and characterization of cDNAs and genes for these glucose transporters will facilitate studies of their role in the pathogenesis of disorders characterized by abnormal glucose transport, including diabetes mellitus, the glucose-galactose malabsorption syndrome, and benign renal glycosuria

Abstract: To study the late beta-cell-specific function of the homeodomain protein IPF1/PDX1 we have generated mice in which the Ipf1/Pdx1 gene has been disrupted specifically in beta cells. These mice develop diabetes with age, and we show that IPF1/PDX1 is required for maintaining the beta cell identity by positively regulating insulin and islet amyloid polypeptide expression and by repressing glucagon expression. We also provide evidence that IPF1/PDX1 regulates the expression of Glut2 in a dosage-dependent manner suggesting that lowered IPF1/PDX1 activity may contribute to the development of type II diabetes by causing impaired expression of both Glut2 and insulin.