In the liver, insulin controls both lipid and glucose metabolism through its cell surface receptor and intracellular mediators such as phosphatidylinositol 3-kinase and serine-threonine kinase AKT. The insulin signaling pathway is further modulated by protein tyrosine phosphatase or lipid phosphatase. Here, we investigated the function of phosphatase and tension homologue deleted on chromosome 10 (PTEN), a negative regulator of the phosphatidylinositol 3-kinase/AKT pathway, by targeted deletion of Pten in murine liver. Deletion of Pten in the liver resulted in increased fatty acid synthesis, accompanied by hepatomegaly and fatty liver phenotype. Interestingly, Pten liver-specific deletion causes enhanced liver insulin action with improved systemic glucose tolerance. Thus, deletion of Pten in the liver may provide a valuable model that permits the study of the metabolic actions of insulin signaling in the liver, and PTEN may be a promising target for therapeutic intervention for type 2 diabetes

Dr. David Barker first popularized the concept of fetal origins of adult disease (FOAD). Since its inception, FOAD has received considerable attention. The FOAD hypothesis holds that events during early development have a profound impact on one’s risk for development of future adult disease. Low birth weight, a surrogate marker of poor fetal growth and nutrition, is linked to coronary artery disease, hypertension, obesity, and insulin resistance. Clues originally arose from large 20th century, European birth registries. Today, large, diverse human cohorts and various animal models have extensively replicated these original observations. This review will focus on the pathogenesis related to FOAD and examines Dr. David Barker’s landmark studies, along with additional human and animal model data. Implications of the FOAD extend beyond the low birth weight population and include babies exposed to stress, both nutritional and non-nutritional, during different critical periods of development, which ultimately result in a disease state. By understanding FOAD, health care professionals and policy makers will make this issue a high healthcare priority and implement preventative measures and treatment for those at higher risk for chronic diseases.

Mammalian preimplantation blastocysts exhibit insulin-stimulated glucose uptake despite the absence of the only known insulinregulated transporter, GLUT4. We describe a previously unidentified member of the mammalian facilitative GLUT superfamily that exhibits Ϸ20 -25% identity with other murine facilitative GLUTs. Insulin induces a change in the intracellular localization of this protein, which translates into increased glucose uptake into the blastocyst, a process that is inhibited by antisense oligoprobes. Presence of this transporter may be necessary for successful blastocyst development, fuel metabolism, and subsequent implantation. Moreover, the existence of an alternative transporter may explain examples in other tissues of insulin-regulated glucose transport in the absence of GLUT4.

Monosaccharides enter cells by slow translipid bilayer diffusion by rapid, protein-mediated, cation-dependent cotransport and by rapid, protein-mediated equilibrative transport. This review addresses protein-mediated, equilibrative glucose transport catalyzed by GLUT1, the first equilibrative glucose transporter to be identified, purified, and cloned. GLUT1 is a polytopic, membranespanning protein that is one of 13 members of the human equilibrative glucose transport protein family. We review GLUT1 catalytic and ligand-binding properties and interpret these behaviors in the context of several putative mechanisms for protein-mediated transport. We conclude that no single model satisfactorily explains GLUT1 behavior. We then review GLUT1 topology, subunit architecture, and oligomeric structure and examine a new model for sugar transport that combines structural and kinetic analyses to satisfactorily reproduce GLUT1 behavior in human erythrocytes. We next review GLUT1 cell biology and the transcriptional and posttranscriptional regulation of GLUT1 expression in the context of development and in response to glucose perturbations and hypoxia in blood-tissue barriers. Emphasis is placed on transgenic GLUT1 overexpression and null mutant model systems, the latter serving as surrogates for the human GLUT1 deficiency syndrome. Finally, we review the role of GLUT1 in the absence or deficiency of a related isoform, GLUT3, toward establishing the physiological significance of coordination between these two isoforms. glucose transport; facilitated diffusion; major facilitator superfamily protein; bloodbrain barrier; placenta; diabetes; glucose transporter 1 deficiency syndrome; development MOST CELLS TRANSPORT SUGARS rapidly down the prevailing concentration gradient into or out of the cell. This equilibrative transport process is mediated by a family of sugar transporters called GLUTs. GLUT1 was the first glucose transporter isoform to be identified, purified (66, 132), and cloned (93) and is one of 13 proteins that comprise the human equilibrative glucose transporter family (63). GLUT1 is a membrane-spanning glycoprotein containing 12 transmembrane domains with a single N-glycosylation site, and its gene is located on chromosome 1 (1p35-31.3) (93). GLUT1 is expressed at the highest levels in the plasma membranes of proliferating cells forming the early developing embryo, in cells forming the blood-tissue barriers, in human erythrocytes and astrocytes, and in cardiac muscle (86). Having a catalytic turnover of ϳ1,200/s (115), glucose transporter 1 (GLUT1) provides an efficient pathway for cellular import and export of glucose. In addition, GLUT1 transports galactose and ascorbic acid (81,107). This review examines the catalytic properties, structure, molecular regulation, and physiology of GLUT1. GLUT1 CATALYTIC PROPERTIES Facilitated DiffusionThe cytoplasm of most cells equilibrates rapidly with nonmetabolizable extracellular sugars. This process is mediated by sugar transport proteins that catalyze unidirectional sugar up...

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Intrauterine growth restriction (IUGR) leads to obesity, glucose intolerance, and type 2 diabetes mellitus in the adult. To determine the mechanism(s) behind this “metabolic imprinting” phenomenon, we examined the effect of total calorie restriction during mid- to late gestation modified by postnatal ad libitum access to nutrients (CM/SP) or nutrient restriction (SM/SP) vs. postnatal nutrient restriction alone (SM/CP) on skeletal muscle and white adipose tissue (WAT) insulin-responsive glucose transporter isoform (GLUT4) expression and insulin-responsive translocation. A decline in skeletal muscle GLUT4 expression and protein concentrations was noted only in the SM/SP and SM/CP groups. In contrast, WAT demonstrated no change in GLUT4 expression and protein concentrations in all experimental groups. The altered in utero hormonal/metabolic milieu was associated with a compensatory adaptation that persisted in the adult and consisted of an increase in the skeletal muscle basal plasma membrane-associated GLUT4 concentrations. This perturbation led to no further exogenous insulin-induced GLUT4 translocation, thereby disabling the insulin responsiveness of the skeletal muscle but retaining it in WAT. These changes, which present at birth, collectively maximize basal glucose transport to the compromised skeletal muscle with a relative resistance to exogenous/postprandial insulin. Preservation of insulin responsiveness in WAT may serve as a sink that absorbs postprandial nutrients that can no longer efficiently access skeletal muscle. We speculate that, in utero, GLUT4 aberrations may predict type 2 diabetes mellitus, whereas postnatal nutrient intake may predict obesity, thereby explaining the heterogeneous phenotype of the IUGR adult offspring.

We examined transcriptional and epigenetic mechanism(s) behind diminished skeletal muscle GLUT4 mRNA in intrauterine growth-restricted (IUGR) female rat offspring. An increase in MEF2D (inhibitor) with a decline in MEF2A (

Glucose transporter isoform-3 (GLUT3) is the trophoblastic facilitative glucose transporter. To investigate the role of this isoform in embryonic development, we created a novel GLUT3-null mouse and observed arrested early embryonic development and loss at neurulation stage when both alleles were mutated. This loss occurred despite the presence of other related isoforms, particularly GLUT1. In contrast, when a single allele was mutated, despite increased embryonic cell apoptosis, adaptive changes in the subcellular localization of GLUT3 and GLUT1 in the preimplantation embryo led to postimplantation survival. This survival was compromised by decreased GLUT3-mediated transplacental glucose transport, causing late-gestation fetal growth restriction. This yielded young male and female adults demonstrating catch-up growth, with normal basal glucose, insulin, insulin-like growth factor-I and IGF-binding protein-3 concentrations, fat and lean mass, and glucose and insulin tolerance. We conclude that GLUT3 mutations cause a gene dose-dependent early pregnancy loss or late-gestation fetal growth restriction despite the presence of embryonic and placental GLUT1 and a compensatory increase in system A amino acid placental transport. This critical life-sustaining functional role for GLUT3 in embryonic development provides the basis for investigating the existence of human GLUT3 mutations with similar consequences during early pregnancy.