Glucose transport -
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Chapter Membrane Transport and Active Transporters Back To Chapter. TABLE OF CONTENTS. Chapter 1: Cells, Genomes, and Evolution. Chapter 2: Biochemistry of the Cell. Chapter 3: Energy and Catalysis. Chapter 4: Introduction to Metabolism.
Chapter 5: Protein Structure. Chapter 6: Protein Function. Chapter 7: Structure and Organization of DNA. Chapter 8: DNA Replication and Repair.
Chapter 9: Transcription: DNA to RNA. Chapter Translation: RNA to Protein. Chapter Control of Gene Expression. Chapter Membrane Structure and Components. Chapter Membrane Transport and Active Transporters. Chapter Channels and the Electrical Properties of Membranes.
Chapter Transmembrane Transport in Endoplasmic Reticulum and Peroxisomes. Chapter Intracellular Compartments and Protein Sorting. Chapter Intracellular Membrane Traffic.
Chapter Endocytosis and Exocytosis. Chapter Mitochondria and Energy Production. Chapter Chloroplasts and Photosynthesis. Chapter Principles of Cell Signaling. Chapter Signaling Networks of G Protein-coupled Receptors.
Chapter Signaling Networks of Kinase Receptors. Chapter Alternative Signaling Routes in Gene Expression. Chapter The Cytoskeleton I: Actin and Microfilaments. Chapter The Cytoskeleton II: Microtubules and Intermediate Filaments.
Chapter Extracellular Matrix in Animals. Chapter Cell-Matrix Interactions. Chapter Cell-Cell Interactions. Chapter Cell Polarization and Migration.
Chapter Plant Cell Structure and Organization. Chapter Analyzing Cells and Proteins. Chapter Visualizing Cells, Tissues, and Molecules.
Chapter Cell Proliferation. Chapter Cell Division. Chapter Meiosis. Chapter Cell Death. Chapter Cancer. Chapter Stem Cell Biology And Renewal in Epithelial Tissue.
Chapter A Hierarchical Stem-Cell System: Blood Cell Formation. Chapter Fibroblast Transformation and Muscle Stem Cells. Chapter Regeneration and Repair. Chapter Embryonic and Induced Pluripotent Stem Cells. Full Table of Contents.
To watch the full video start a free trial today. JoVE Core Cell Biology. Previous Video Next Video. The JoVE video player is compatible with HTML5 and Adobe Flash. Next Video Embed Languages Share. A human body has 14 different types of GLUTs, named GLUT 1 to GLUT Navale, Archana M.
Wright, Ernest M. Deng, Dong, and Nieng Yan. Jia, Baolei, Xiao Feng Zhu, Zhong Ji Pu, Yu Xi Duan, Lu Jiang Hao, Jie Zhang, Li-Qing Chen, Che Ok Jeon, and Yuan Hu Xuan. You might already have access to this content!
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Reset Password. Alterations in GLUTs have also been observed in rodent models of AD. In a longitudinal study of 3xTgAD mice between 3 and 15 months of age, glucose transporters GLUT1 55 and 45 kDa , and GLUT3 were found to change in both AD and wild-type animals but with differing temporal trajectories Ding et al.
In AD mice, GLUT1 55 kDa and GLUT3 were found to decrease with age, whereas GLUT1 45 kDa was found to increase with age. In wild-types, non-monotonic changes with age were observed for GLUT1 55 kDa , whereas GLUT1 45 kDa was unchanged. GLUT3 decreased, and GLUT4 increased with age.
Unfortunately, a formal comparison between glucose transporter expression between 3xTgAD mice and wild-types was not performed. In another longitudinal study, Do et al. Griffith et al. They found similar timing of effects on GLUT3 as observed for GLUT1 by Do et al. Young rats exhibited reduced glucose tolerance as early as 1 month , but GLUT3 did not change relative to wild-types until at least 18—20 months.
GLUT4 was unaltered at all ages. Similar results were found in other AD models. Hooijmans et al. Changes were found in the hippocampus, but not the cortex. In the Tg model, Kuznetsova and Schliebs showed that cortical GLUT1 was unaltered at 10 months compared to wild-types, but at 18 months after development of amyloid pathology, AD mice had significantly lower cortical GLUT1.
A study by Kouznetsova et al. In cortical regions with high amyloid load, GLUT1 staining was reduced compared to regions with low amyloid load. The authors also showed that GLUT1 staining was reduced nearer large senile plaques, relative to changes observed near smaller diffuse plaques.
Gil-Iturbe et al. The authors found reduced GLUT1 and GLUT3, and increased GLUT12 in both strains. No age dependent effects on GLUTs were observed, conflicting with results from Ding et al. Merlini et al. They observed reductions in BBB and astrocytic GLUT1 in the cortex and hippocampus from 9 to 12 months onward, which coincided with changes in glucose uptake as measured using microdialysis.
However, GLUT3 was unaltered. By 16—22 months, IgG extravasation was observed, indicating loss of BBB integrity. In 5xFAD aged 4. GLUT3 was not studied.
A study by Chua et al. Brain glucose levels were measured to be lower than wildtypes at 12 and 15 months of age, but GLUT3 and GLUT4 were found to be upregulated, not decreased Chua et al.
Unfortunately, changes to GLUT1 were not studied. Shang et al. In normal APP23 mice, GLUT1 reductions were observed at 12 months, which were further reduced in APP23 mice with chronic cerebral hypoperfusion Shang et al.
A number of studies have investigated GLUT expression in a rat model of AD produced by administering streptozotocin via intracerebroventricular injection. These studies found reduced expression of GLUT1 Deng et al. Friedland et al. No difference in the transport rate constants, K 1 and k 2 , or the utilization rate k 3 , were observed between groups.
Two later FDG-PET studies in AD patients showed different results; Jagust et al. Kimura and Naganawa performed dynamic PET studies in three subjects, a year-old normal subject, a year-old subject with mild AD, and a year-old subject with severe AD.
Glucose transport was globally reduced in both AD cases compared to the normal subject. Glucose phosphorylation was diminished in gray matter of the severe case of AD, excluding the sensory, motor, and visual cortices. In the mild case, phosphorylation was reduced in the right parieto-temporal area.
In another dynamic FDG-PET study of seven patients with mild AD and six normal age-matched controls, Mosconi et al. A small number of tracer studies have been performed in rodents, which all support reduced transport of glucose in AD.
Do et al. No difference in [3H]-D-glucose uptake was found in 3xTgAD mice compared to wild-types aged 6 or 8 months, but a significant decrease was found in 3xTgAD mice at 18 months. The reduced uptake at 18 month was associated with reduced expression of GLUT1 at the same timepoint.
Ding et al. FDG-PET signals were measured at 40 min post injection of FDG, and are likely to reflect both transport and utilization. Reductions in the FDG-PET signal were found in both AD and wild-type animals with age, but while no formal comparison was made, FDG-PET signals did not appear to differ across genotype.
Last, Merlini et al. The effects of GLUT disruptions on the brain have been studied in rodent models. Abdul Muneer et al. This led to a reduction in BBB tight junction proteins, indicating that GLUTs may play a role in regulating BBB integrity.
Winkler et al. These included reduced brain capillary levels of low-density lipoprotein receptor-related protein 1 LRP1 , a transporter at the BBB which clears Aβ from the brain Zlokovic, , , diminished cerebral blood flow, early BBB breakdown, accelerated Aβ deposition in the hippocampus and cortex, neuronal dysfunction and cognitive impairment.
They also observed that vascular changes preceded neuronal dysfunction in these mice. Decreased levels of GLUT1 and GLUT3 were found in a rat model of sporadic AD, achieved through the intracerebroventricular injection of streptozotocin, alongside impaired insulin signaling and abnormalities in phosphorylation and microtubule binding activity of tau Deng et al.
Effects of severe glucose transporter depletion on early brain development can be observed in human GLUT1 deficiency syndrome, a rare genetic disorder characterized by impaired glucose metabolism due to a deficiency in GLUT1. Clinical features include intellectual disability, movement disorders and epileptic seizures refractory to treatment.
Late-onset GLUT1 deficiency syndrome affects children at an older age, with evidence showing mild to moderate intellectual disability Leen et al. A later study by the same group followed up patients with GLUT1 deficiency syndrome between 18 and 41 years old.
Their results showed that while the prominent feature during childhood is epilepsy, this diminishes later in life and new movement disorders become apparent during adolescence. Cognitive function, however, did not appear to worsen with age Leen et al.
There is no evidence of GLUT1 deficiency syndrome manifesting in late adulthood. Deficits in transport and metabolism in AD may result from impaired insulin signaling, particularly due to alterations in the function of insulin-sensitive transporters.
Mullins et al. Their findings showed that GLUT1 was positively correlated, whereas GLUT4 was negatively correlated, with insulin signaling proteins including IRS In a mouse model of AD, Chua et al.
In the STZ rat model of AD, increases in GLUT2 were accompanied by decreases in insulin receptors Knezovic et al. In the same model, Deng et al. Insulin resistance has been targeted as a means to restore glucose transport by number of groups. In a small randomized control trial, Gejl et al.
In their study, 18 participants received liraglutide and 20 received placebo in a week period. Salkovic-Petrisic et al. This systematic review examines the evidence for alterations in glucose transport in AD and the effect of these alterations on the brain.
The majority of studies investigating GLUT1 and GLUT3 suggest that both transporters are reduced in the hippocampus and cortex of AD brains.
Longitudinal rodent studies did not find changes at early timepoints, but consistently observed reductions in transporter expression after Aβ pathology had developed, indicating that Aβ itself may be responsible. There were fewer studies investigating other GLUTs including GLUT2, GLUT4, GLUT12, and GLUT A rise in GLUT2 in AD brain tissue was observed by Liu et al.
In the study by Liu et al. It is possible that GLUT2 increases to serve as a compensatory mechanism of GLUT1 and GLUT3 loss. The role of GLUT2, therefore, requires further investigation.
A study by Purcell et al. The findings by Wang et al. Further work is required to determine the role of these lesser-studied GLUTs in AD and gauge their therapeutic potential. The cause of glucose transporter expression in AD remains unclear.
One suggestion for the reduction of GLUT1 in the AD brain is an abnormality in the translation process of the transporter. Brains of AD patients have been found to express low levels of transcription factor hypoxia-inducible factor 1α, a protein complex which regulates GLUT1 and GLUT3 expression Liu et al.
However, Mooradian et al. Another study proposed that the activation of calpain I, a calcium sensitive protease, is a potential cause of GLUT3 under-expression Jin et al. Calpain I has also been associated with downregulation of protective mechanisms against tau phosphorylation Gu et al.
AD pathologies such as Aβ or tau may directly reduce GLUT expression. The low capillary density found within Aβ plaques in the study by Kawai et al. Findings by An et al. Studies using amyloidogenic mouse models support a link between spatial proximity of Aβ to glucose transporter alterations Kouznetsova et al.
Mark et al. Their results demonstrate that Aβ deposition impairs glucose transport through a mechanism involving membrane lipid peroxidation. The authors suggest that this mechanism may further lead to neurodegeneration in AD. In a drosophila study, Niccoli et al.
Similar results were demonstrated when using metformin, an anti-diabetic drug designed to stimulate glucose uptake into cells. Human studies are yet to confirm these findings. Without measuring glucose uptake into brain tissue, it is difficult to know how changes in GLUTs affect glucose availability in parenchymal cells.
Tracer studies that measure uptake of glucose and glucose-analogs into brain are therefore crucial for determining the impact of GLUT changes on glucose transport.
Uptake of glucose can be measured using a range of methods from invasive perfusion-based approaches, to non-invasive imaging techniques such as FDG-PET.
Generally, tracer-based studies performed to date show that transport of glucose into the brains of AD patients and rodent models of AD is reduced. Unfortunately, these studies cannot distinguish between glucose transport through the BBB or through cell membranes. Furthermore, Lund-Andersen and Pardridge argue that because the total surface area and mass of GLUTs on parenchymal cells far exceeds that of endothelial cells, glucose uptake into the intracellular space is limited by GLUT1 at the BBB, not by astrocyte GLUT1 or neuronal GLUT3.
Therefore, it is likely that reductions in uptake of glucose or glucose-analogs into brain tissue reflect mainly reductions to GLUT1 at the BBB.
GLUT1 and GLUT3 are considered insulin-independent glucose transporters, and therefore are assumed not to be affected by insulin or insulin-like growth factors. It is therefore expected that insulin-resistance does not alter uptake of glucose through these transporters.
However, there is some evidence that GLUT1 and GLUT3 may be moderately affected by insulin. Hernandez-Garzón et al.
Muhič et al. The effects of insulin on endothelial GLUT1 has not been studied. Hypoglycemia is known to cause upregulation of BBB GLUT1 and neuronal GLUT3, an adaptive mechanism to ensure sufficient glucose is delivered to the brain Kumagai et al.
It is possible these changes occur due to hyperinsulinemia—a study in man showed that insulin increases uptake of glucose across the BBB, however the dose of insulin required to detect an effect was non-physiological.
It is likely the dominant driver of GLUT1 changes at the BBB is glucose itself; in-vitro studies show hyperglycemia increases GLUT1 and glucose uptake in the absence of insulin Takakura et al.
Despite this, the studies of Deng et al. It is possible the link between insulin resistance and alterations to insulin-insensitive GLUTs occurs via a joint relationship with AD pathologies Aβ and tau.
Insulin is known to promote Aβ clearance Watson et al. It is suggested that a positive feedback loop subsequently occurs as Aβ oligomers lead to increased phosphorylation of insulin signaling proteins Yoon et al. The results from the randomized controlled trial on the use of liraglutide in AD provides further insight into the possible link between insulin resistance, glucose transporters and AD Gejl et al.
Their results show an improvement in glucose transport capacity with liraglutide. It is not clear whether this improvement reflects an increase in glucose transporters or an increase in postprandial insulin levels, however, as liraglutide does not cross the BBB, it is possible that it causes a direct effect on the BBB itself.
Altered glucose metabolism occurs several years before evidence of cognitive impairment in AD Chen and Zhong, Altered glucose transport has also been observed in mild cognitive impairment MCI Mosconi et al.
This suggests that drugs targeting the restoration of normal GLUT expression may be highly effective at reducing cognitive decline and transition from MCI to AD. Only a small proportion of drugs are able to cross the BBB, mainly due to the characteristic properties of desolvation, lipophilicity, molecular volume and dipole moment required for molecules to cross the BBB Fong, Additionally, the BBB has tight control over what molecules leave the brain, making drug development in neurodegenerative disease more challenging Pardridge, GLUT1 therefore becomes a highly attractive therapeutic target since it is present on the BBB itself.
GLUTs play a significant role in AD pathology with substantial evidence suggesting that GLUT1 and GLUT3 reductions occur following amyloid accumulation, but may precede the onset of clinical symptoms, while GLUT2 and GLUT12 appear to increase and may have a compensatory role.
FDG-PET imaging could provide a means to detect reduced glucose transport in a clinical setting. Repurposing anti-diabetic drugs shows promising results in human studies of AD Gejl et al. With evidence suggesting that metabolic changes can accurately predict subsequent cognitive decline De Leon et al.
NK, BD, HE, LP, and OS contributed to the conception and design of the study. NK wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version.
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We would like to thank all contributors to this systematic literature review, our funders, and the University of Manchester for the facilities provided to NK.
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evidence for simultaneous occupation of the carrier by maltose and cytochalasin B. Biochemistry 30, — Castello, M. On the origin of Alzheimer's disease. trials and tribulations of the amyloid hypothesis.
Ageing Res. Chen, Z. Decoding Alzheimer's disease from perturbed cerebral glucose metabolism: Implications for diagnostic and therapeutic strategies. Chételat, G. Relationship between atrophy and β-amyloid deposition in Alzheimer disease.
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Ding, F. Early decline in glucose transport and metabolism precedes shift to ketogenic system in female aging and Alzheimer's mouse brain: Implication for bioenergetic intervention.
PLoS ONE 8:e Do, T. Altered cerebral vascular volumes and solute transport at the blood-brain barriers of two transgenic mouse models of Alzheimer's disease. Neuropharmacology 81, — Fong, C. Permeability of the blood—brain barrier: molecular mechanism of transport of drugs and physiologically important compounds.
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Blood-brain barrier abnormalities in Alzheimer's diseasea. Harr, S. Functional alterations in Alzheimer's disease: decreased glucose transporter 3 immunoreactivity in the perforant pathway terminal zone. Hase, Y. White matter capillaries in vascular and neurodegenerative dementias.
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Gluose you sure you want to trigger topic in Glucose transport Anconeus AI Glucose transport Would you Menstrual health wellness to start learning session with this topic items scheduled for future? Please confirm topic selection. No Yes. Please confirm action. You are done for today with this topic. Questions Questions. Glucode you for visiting nature. You are using a Natural herb remedies version with limited support for Glucose transport. To obtain Transpoort best experience, we recommend you use a more up to date browser or turn off compatibility mode in Internet Explorer. In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript. Following a meal, insulin secretion from the pancreas facilitates the removal of glucose from the bloodstream. Glucose transoort are a wide group transpotr membrane proteins that facilitate the transport of glucose Glucoxe the plasma membranea process known as facilitated diffusion.
Glucos glucose is a vital source of energy G,ucose all life, these transporters are present in Gpucose phyla.
The GLUT or SLC2A family Oral medications for diabetes control a protein family that is found in most transpirt cells. GLUT is a type of transoort transporter protein.
Most non- autotrophic transporg are unable to produce free glucose because they lack expression Glufose glucosephosphatase and, thus, are involved only in glucose uptake and catabolism.
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In Saccharomyces cerevisiae trans;ort transport takes transpirt through facilitated diffusion. Psychological factors in dietary choices are integral membrane proteins that contain 12 membrane-spanning helices with both the amino and carboxyl transporh exposed on the cytoplasmic side of the Sports specialization considerations membrane.
GLUT proteins translort glucose Glucose transport related Glucoose according to trnasport model of Quinoa stir fry recipes conformation, [5] [6] [7] which predicts that trannsport transporter exposes a single substrate binding site toward either the Gluclse or Glucose transport inside transpott the cell.
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In Augustin PragueRobert K. Crane presented for the first time his discovery of the sodium-glucose cotransport as the mechanism for intestinal glucose absorption. This hypothesis was rapidly tested, refined, and extended [to] encompass the active transport of a diverse range of molecules and ions into virtually every cell type.
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Download as PDF Printable version. In other projects. Wikimedia Commons. Family of monosaccharide transport proteins. FEMS Yeast Research. doi : PMID cerevisiae ". FEMS Microbiology Reviews. S2CID Bibcode : Natur. Reversible redox-dependent interconversions of tetrameric and dimeric GLUT1".
The Journal of Biological Chemistry. Evidence for cytosolic sugar binding sites in erythrocytes". Molecular Membrane Biology. The American Journal of Physiology.
American Journal of Physiology. Endocrinology and Metabolism. PMC Diabetes Care. Medical Physiology: A Cellular And Molecular Approaoch. ISBN In Kleinzeller A, Kotyk A eds. Membrane Transport and Metabolism. Proceedings of a Symposium held in Prague, August 22—27, Prague: Czech Academy of Sciences.
Pflügers Archiv. Experimental Physiology. The insight from this time that remains in all current text books is the notion of Robert Crane published originally as an appendix to a symposium paper published in Crane et al. The key point here was 'flux coupling', the cotransport of sodium and glucose in the apical membrane of the small intestinal epithelial cell.
Half a century later this idea has turned into one of the most studied of all transporter proteins SGLT1the sodium—glucose cotransporter. Membrane proteinscarrier proteins : membrane transport proteins solute carrier TC 2A. high affinity glutamate and neutral amino-acid transporter SLC1A1 2 3 4 5 6 7.
facilitative GLUT transporter SLC2A1 2 3 4 5 6 7 8 9 10 11 12 13 heavy subunits of heterodimeric amino-acid transporters SLC3A1 2. bicarbonate transporter SLC4A1 2 3 4 5 6 7 8 9 10 sodium glucose cotransporter SLC5A1 2 3 4 5 6 7 8 9 10 11 sodium - and chloride - dependent sodium:neurotransmitter symporters SLC6A1 SLC6A2 SLC6A3 SLC6A4 SLC6A5 SLC6A6 SLC6A7 SLC6A8 SLC6A9 SLC6A10 SLC6A11 SLC6A12 SLC6A13 SLC6A14 SLC6A15 SLC6A16 SLC6A17 SLC6A18 SLC6A19 SLC6A sodium bile salt cotransport SLC10A1 SLC10A2 SLC10A3 SLC10A4 SLC10A5 SLC10A6 SLC10A7 10A1 10A2 10A3 10A7.
proton coupled metal ion transporter SLC11A1 SLC11A2 11A3. electroneutral cation-Cl cotransporter SLC12A1 SLC12A2 SLC12A3 SLC12A4 SLC12A5 SLC12A6 SLC12A7 SLC12A8 SLC12A9. urea transporter SLC14A1 SLC14A2.
proton oligopeptide cotransporter SLC15A1 SLC15A2 SLC15A3 SLC15A4. monocarboxylate transporter SLC16A1 SLC16A2 SLC16A3 SLC16A4 SLC16A5 SLC16A6 SLC16A7 SLC16A8 SLC16A9 SLC16A10 SLC16A11 SLC16A12 SLC16A13 SLC16A Vesicular glutamate transporter 1 SLC17A1 SLC17A2 SLC17A3 SLC17A4 SLC17A5 SLC17A6 SLC17A7 SLC17A8 SLC17A9.
vesicular monoamine transporter SLC18A1 SLC18A2 SLC18A3. Organic anion-transporting polypeptide SLCO1A2 SLCO1B1 SLCO1B3 SLCO1B4 SLCO1C1 SLCO2A1 SLCO2B1 SLCO3A1 SLCO4A1 SLCO4C1 SLCO5A1 SLCO6A1.
mitochondrial carrier SLC25A1 SLC25A2 SLC25A3 SLC25A4 SLC25A5 SLC25A6 SLC25A7 SLC25A8 SLC25A9 SLC25A10 SLC25A11 SLC25A12 SLC25A13 SLC25A14 SLC25A15 SLC25A16 SLC25A17 SLC25A18 SLC25A19 SLC25A20 SLC25A21 SLC25A22 SLC25A23 SLC25A24 SLC25A25 SLC25A26 SLC25A27 SLC25A28 SLC25A29 SLC25A30 SLC25A31 SLC25A32 SLC25A33 SLC25A34 SLC25A35 SLC25A36 SLC25A37 SLC25A38 SLC25A39 SLC25A40 SLC25A41 SLC25A42 SLC25A43 SLC25A44 SLC25A45 SLC25A multifunctional anion exchanger SLC26A1 SLC26A2 SLC26A3 SLC26A4 SLC26A5 SLC26A6 SLC26A7 SLC26A8 SLC26A9 SLC26A10 SLC26A fatty acid transport proteins SLC27A1 SLC27A2 SLC27A3 SLC27A4 SLC27A5 SLC27A6.
facilitative nucleoside transporter SLC29A1 SLC29A2 SLC29A3 SLC29A4. zinc efflux SLC30A1 SLC30A2 SLC30A3 SLC30A4 SLC30A5 SLC30A6 SLC30A7 SLC30A8 SLC30A9 SLC30A copper transporter SLC31A1. Vesicular glutamate transporter 1 SLC32A1.
Acetyl-CoA transporter SLC33A1. nucleoside-sugar transporter SLC35A1 SLC35A2 SLC35A3 SLC35A4 SLC35A5 SLC35B1 SLC35B2 SLC35B3 SLC35B4 SLC35C1 SLC35C2 SLC35D1 SLC35D2 SLC35D3 SLC35E1 SLC35E2 SLC35E3 SLC35E4.
proton-coupled amino-acid transporter SLC36A1 SLC36A2 SLC36A3 SLC36A4 36A2. metal ion transporter SLC39A1 SLC39A2 SLC39A3 SLC39A4 SLC39A5 SLC39A6 SLC39A7 SLC39A8 SLC39A9 SLC39A10 SLC39A11 SLC39A12 SLC39A13 SLC39A basolateral iron transporter SLC40A1.
Magnesium transporter E SLC41A1 SLC41A2 SLC41A3. Ammonia transporter RhAG RhBG RhCG. Choline-like transporter SLC44A1 SLC44A2 SLC44A3 SLC44A4 SLC44A5. Putative sugar transporter SLC45A1 SLC45A2 SLC54A3 SLC45A4. Folate transporter SLC46A1 SLC46A2.
multidrug and toxin extrusion SLC47A1 SLC47A2. Heme transporter. O1A2 O1B1 O1B3 O2B1 O O4A1. Ion pumps. see also solute carrier disorders. Sodium-glucose transporter modulators. Inhibitors: Phloretin Phlorizin T TA. Inhibitors: Atigliflozin Bexagliflozin Canagliflozin Dapagliflozin Empagliflozin Enavogliflozin Ertugliflozin Henagliflozin Ipragliflozin Janagliflozin Licogliflozin Luseogliflozin Mizagliflozin Phloretin Phlorizin Remogliflozin Sergliflozin T TA Tofogliflozin Velagliflozin Antisense oligonucleotides: ISIS Inhibitors: Sotagliflozin.
Categories : Transport proteins Integral membrane proteins Solute carrier family.
: Glucose transport| SYSTEMATIC REVIEW article | Martens, S. Translocation of the glucose transporter GLUT4 to Glucose transport cell surface in Glucosd Glucose transport trznsport effects of ATP, insulin and GTPγS and gransport of GLUT4 to clathrin lattices. CAS PubMed PubMed Central Google Scholar Fletcher, L. The glucose transporter GLUT4 facilitates insulin-stimulated glucose uptake into muscle and adipose tissue. Most members of classes II and III have been identified recently in homology searches of EST databases and the sequence information provided by the various genome projects. |
| Regulated transport of the glucose transporter GLUT4 | Nature Reviews Molecular Cell Biology | They found similar timing of effects on GLUT3 as observed for GLUT1 by Do et al. Young rats exhibited reduced glucose tolerance as early as 1 month , but GLUT3 did not change relative to wild-types until at least 18—20 months. GLUT4 was unaltered at all ages. Similar results were found in other AD models. Hooijmans et al. Changes were found in the hippocampus, but not the cortex. In the Tg model, Kuznetsova and Schliebs showed that cortical GLUT1 was unaltered at 10 months compared to wild-types, but at 18 months after development of amyloid pathology, AD mice had significantly lower cortical GLUT1. A study by Kouznetsova et al. In cortical regions with high amyloid load, GLUT1 staining was reduced compared to regions with low amyloid load. The authors also showed that GLUT1 staining was reduced nearer large senile plaques, relative to changes observed near smaller diffuse plaques. Gil-Iturbe et al. The authors found reduced GLUT1 and GLUT3, and increased GLUT12 in both strains. No age dependent effects on GLUTs were observed, conflicting with results from Ding et al. Merlini et al. They observed reductions in BBB and astrocytic GLUT1 in the cortex and hippocampus from 9 to 12 months onward, which coincided with changes in glucose uptake as measured using microdialysis. However, GLUT3 was unaltered. By 16—22 months, IgG extravasation was observed, indicating loss of BBB integrity. In 5xFAD aged 4. GLUT3 was not studied. A study by Chua et al. Brain glucose levels were measured to be lower than wildtypes at 12 and 15 months of age, but GLUT3 and GLUT4 were found to be upregulated, not decreased Chua et al. Unfortunately, changes to GLUT1 were not studied. Shang et al. In normal APP23 mice, GLUT1 reductions were observed at 12 months, which were further reduced in APP23 mice with chronic cerebral hypoperfusion Shang et al. A number of studies have investigated GLUT expression in a rat model of AD produced by administering streptozotocin via intracerebroventricular injection. These studies found reduced expression of GLUT1 Deng et al. Friedland et al. No difference in the transport rate constants, K 1 and k 2 , or the utilization rate k 3 , were observed between groups. Two later FDG-PET studies in AD patients showed different results; Jagust et al. Kimura and Naganawa performed dynamic PET studies in three subjects, a year-old normal subject, a year-old subject with mild AD, and a year-old subject with severe AD. Glucose transport was globally reduced in both AD cases compared to the normal subject. Glucose phosphorylation was diminished in gray matter of the severe case of AD, excluding the sensory, motor, and visual cortices. In the mild case, phosphorylation was reduced in the right parieto-temporal area. In another dynamic FDG-PET study of seven patients with mild AD and six normal age-matched controls, Mosconi et al. A small number of tracer studies have been performed in rodents, which all support reduced transport of glucose in AD. Do et al. No difference in [3H]-D-glucose uptake was found in 3xTgAD mice compared to wild-types aged 6 or 8 months, but a significant decrease was found in 3xTgAD mice at 18 months. The reduced uptake at 18 month was associated with reduced expression of GLUT1 at the same timepoint. Ding et al. FDG-PET signals were measured at 40 min post injection of FDG, and are likely to reflect both transport and utilization. Reductions in the FDG-PET signal were found in both AD and wild-type animals with age, but while no formal comparison was made, FDG-PET signals did not appear to differ across genotype. Last, Merlini et al. The effects of GLUT disruptions on the brain have been studied in rodent models. Abdul Muneer et al. This led to a reduction in BBB tight junction proteins, indicating that GLUTs may play a role in regulating BBB integrity. Winkler et al. These included reduced brain capillary levels of low-density lipoprotein receptor-related protein 1 LRP1 , a transporter at the BBB which clears Aβ from the brain Zlokovic, , , diminished cerebral blood flow, early BBB breakdown, accelerated Aβ deposition in the hippocampus and cortex, neuronal dysfunction and cognitive impairment. They also observed that vascular changes preceded neuronal dysfunction in these mice. Decreased levels of GLUT1 and GLUT3 were found in a rat model of sporadic AD, achieved through the intracerebroventricular injection of streptozotocin, alongside impaired insulin signaling and abnormalities in phosphorylation and microtubule binding activity of tau Deng et al. Effects of severe glucose transporter depletion on early brain development can be observed in human GLUT1 deficiency syndrome, a rare genetic disorder characterized by impaired glucose metabolism due to a deficiency in GLUT1. Clinical features include intellectual disability, movement disorders and epileptic seizures refractory to treatment. Late-onset GLUT1 deficiency syndrome affects children at an older age, with evidence showing mild to moderate intellectual disability Leen et al. A later study by the same group followed up patients with GLUT1 deficiency syndrome between 18 and 41 years old. Their results showed that while the prominent feature during childhood is epilepsy, this diminishes later in life and new movement disorders become apparent during adolescence. Cognitive function, however, did not appear to worsen with age Leen et al. There is no evidence of GLUT1 deficiency syndrome manifesting in late adulthood. Deficits in transport and metabolism in AD may result from impaired insulin signaling, particularly due to alterations in the function of insulin-sensitive transporters. Mullins et al. Their findings showed that GLUT1 was positively correlated, whereas GLUT4 was negatively correlated, with insulin signaling proteins including IRS In a mouse model of AD, Chua et al. In the STZ rat model of AD, increases in GLUT2 were accompanied by decreases in insulin receptors Knezovic et al. In the same model, Deng et al. Insulin resistance has been targeted as a means to restore glucose transport by number of groups. In a small randomized control trial, Gejl et al. In their study, 18 participants received liraglutide and 20 received placebo in a week period. Salkovic-Petrisic et al. This systematic review examines the evidence for alterations in glucose transport in AD and the effect of these alterations on the brain. The majority of studies investigating GLUT1 and GLUT3 suggest that both transporters are reduced in the hippocampus and cortex of AD brains. Longitudinal rodent studies did not find changes at early timepoints, but consistently observed reductions in transporter expression after Aβ pathology had developed, indicating that Aβ itself may be responsible. There were fewer studies investigating other GLUTs including GLUT2, GLUT4, GLUT12, and GLUT A rise in GLUT2 in AD brain tissue was observed by Liu et al. In the study by Liu et al. It is possible that GLUT2 increases to serve as a compensatory mechanism of GLUT1 and GLUT3 loss. The role of GLUT2, therefore, requires further investigation. A study by Purcell et al. The findings by Wang et al. Further work is required to determine the role of these lesser-studied GLUTs in AD and gauge their therapeutic potential. The cause of glucose transporter expression in AD remains unclear. One suggestion for the reduction of GLUT1 in the AD brain is an abnormality in the translation process of the transporter. Brains of AD patients have been found to express low levels of transcription factor hypoxia-inducible factor 1α, a protein complex which regulates GLUT1 and GLUT3 expression Liu et al. However, Mooradian et al. Another study proposed that the activation of calpain I, a calcium sensitive protease, is a potential cause of GLUT3 under-expression Jin et al. Calpain I has also been associated with downregulation of protective mechanisms against tau phosphorylation Gu et al. AD pathologies such as Aβ or tau may directly reduce GLUT expression. The low capillary density found within Aβ plaques in the study by Kawai et al. Findings by An et al. Studies using amyloidogenic mouse models support a link between spatial proximity of Aβ to glucose transporter alterations Kouznetsova et al. Mark et al. Their results demonstrate that Aβ deposition impairs glucose transport through a mechanism involving membrane lipid peroxidation. The authors suggest that this mechanism may further lead to neurodegeneration in AD. In a drosophila study, Niccoli et al. Similar results were demonstrated when using metformin, an anti-diabetic drug designed to stimulate glucose uptake into cells. Human studies are yet to confirm these findings. Without measuring glucose uptake into brain tissue, it is difficult to know how changes in GLUTs affect glucose availability in parenchymal cells. Tracer studies that measure uptake of glucose and glucose-analogs into brain are therefore crucial for determining the impact of GLUT changes on glucose transport. Uptake of glucose can be measured using a range of methods from invasive perfusion-based approaches, to non-invasive imaging techniques such as FDG-PET. Generally, tracer-based studies performed to date show that transport of glucose into the brains of AD patients and rodent models of AD is reduced. Unfortunately, these studies cannot distinguish between glucose transport through the BBB or through cell membranes. Furthermore, Lund-Andersen and Pardridge argue that because the total surface area and mass of GLUTs on parenchymal cells far exceeds that of endothelial cells, glucose uptake into the intracellular space is limited by GLUT1 at the BBB, not by astrocyte GLUT1 or neuronal GLUT3. Therefore, it is likely that reductions in uptake of glucose or glucose-analogs into brain tissue reflect mainly reductions to GLUT1 at the BBB. GLUT1 and GLUT3 are considered insulin-independent glucose transporters, and therefore are assumed not to be affected by insulin or insulin-like growth factors. It is therefore expected that insulin-resistance does not alter uptake of glucose through these transporters. However, there is some evidence that GLUT1 and GLUT3 may be moderately affected by insulin. Hernandez-Garzón et al. Muhič et al. The effects of insulin on endothelial GLUT1 has not been studied. Hypoglycemia is known to cause upregulation of BBB GLUT1 and neuronal GLUT3, an adaptive mechanism to ensure sufficient glucose is delivered to the brain Kumagai et al. It is possible these changes occur due to hyperinsulinemia—a study in man showed that insulin increases uptake of glucose across the BBB, however the dose of insulin required to detect an effect was non-physiological. It is likely the dominant driver of GLUT1 changes at the BBB is glucose itself; in-vitro studies show hyperglycemia increases GLUT1 and glucose uptake in the absence of insulin Takakura et al. Despite this, the studies of Deng et al. It is possible the link between insulin resistance and alterations to insulin-insensitive GLUTs occurs via a joint relationship with AD pathologies Aβ and tau. Insulin is known to promote Aβ clearance Watson et al. It is suggested that a positive feedback loop subsequently occurs as Aβ oligomers lead to increased phosphorylation of insulin signaling proteins Yoon et al. The results from the randomized controlled trial on the use of liraglutide in AD provides further insight into the possible link between insulin resistance, glucose transporters and AD Gejl et al. Their results show an improvement in glucose transport capacity with liraglutide. It is not clear whether this improvement reflects an increase in glucose transporters or an increase in postprandial insulin levels, however, as liraglutide does not cross the BBB, it is possible that it causes a direct effect on the BBB itself. Altered glucose metabolism occurs several years before evidence of cognitive impairment in AD Chen and Zhong, Altered glucose transport has also been observed in mild cognitive impairment MCI Mosconi et al. This suggests that drugs targeting the restoration of normal GLUT expression may be highly effective at reducing cognitive decline and transition from MCI to AD. Only a small proportion of drugs are able to cross the BBB, mainly due to the characteristic properties of desolvation, lipophilicity, molecular volume and dipole moment required for molecules to cross the BBB Fong, Additionally, the BBB has tight control over what molecules leave the brain, making drug development in neurodegenerative disease more challenging Pardridge, GLUT1 therefore becomes a highly attractive therapeutic target since it is present on the BBB itself. GLUTs play a significant role in AD pathology with substantial evidence suggesting that GLUT1 and GLUT3 reductions occur following amyloid accumulation, but may precede the onset of clinical symptoms, while GLUT2 and GLUT12 appear to increase and may have a compensatory role. FDG-PET imaging could provide a means to detect reduced glucose transport in a clinical setting. Repurposing anti-diabetic drugs shows promising results in human studies of AD Gejl et al. With evidence suggesting that metabolic changes can accurately predict subsequent cognitive decline De Leon et al. NK, BD, HE, LP, and OS contributed to the conception and design of the study. NK wrote the first draft of the manuscript. All authors contributed to manuscript revision, read, and approved the submitted version. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We would like to thank all contributors to this systematic literature review, our funders, and the University of Manchester for the facilities provided to NK. Abdul Muneer, P. 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Membrane curvature in synaptic vesicle fusion and beyond. Okada, S. Synip phosphorylation is required for insulin-stimulated Glut4 translocation. Synip phosphorylation does not regulate insulin-stimulated GLUT4 translocation. Fujita, Y. Tomosyn: a syntaxinbinding protein that forms a novel complex in the neurotransmitter release process. Neuron 20 , — Martens, S. How synaptotagmin promotes membrane fusion. Science , — Lipschutz, J. Exocytosis: the many masters of the exocyst. Rosen, E. Adipocytes as regulators of energy balance and glucose homeostasis. Herman, M. Glucose transport and sensing in the maintenance of glucose homeostasis and metabolic harmony. Download references. This work was supported by a US National Institutes of Health NIH grant R01DK The authors thank M. Uhm and D. Bridges for their critical reading and discussions of the manuscript. Life Sciences Institute, University of Michigan, Washtenaw Avenue, Ann Arbor, , Michigan, USA. Departments of Molecular and Integrative Physiology and Internal Medicine, Life Sciences Institute, Ann Arbor, , Michigan, USA. You can also search for this author in PubMed Google Scholar. Correspondence to Dara Leto or Alan R. Alan R. Saltiel's homepage. The terminal Golgi stack where proteins are sorted and packaged into vesicles for delivery to their cellular destination. Physiological condition that is defined by a failure of tissues and organs to respond to normal concentrations of insulin. A chronic metabolic disorder that is characterized by increased plasma glucose levels that result from an inability of tissues to respond to insulin. Secreted peptide that signals to cells to upregulate metabolic processes that convert simple energy sources into macromolecules. Hormones and cytokines that are released by adipocytes and signal to other tissues to alter feeding behaviour and metabolism. A family of enzymes that activate GTPases by catalysing GDP release, thus allowing cytoplasmic GTP to bind to the GTPase. Soluble N -ethylmaleimide-sensitive factor attachment protein receptor regulatory proteins. A family of small helical proteins that bridge two membranes and drive membrane fusion events. An evolutionarily conserved protein complex that consists of eight subunits and targets exocytic vesicles to sites of docking and fusion at the plasma membrane. A mechanism for internalizing extracellular molecules and portions of the plasma membrane. This pathway is dependent on the membrane curvature-inducing coat protein clathrin. A clathrin-independent mechanism for internalizing molecules. This mechanism is blocked by drugs that deplete cellular cholesterol and often requires the lipid raft protein caveolin. A membrane compartment that is localized close to the cell surface where recently endocytosed proteins are delivered and sorted for degradation or recycling. Membrane compartments that many recycling proteins pass through before returning to the cell surface. Reprints and permissions. Leto, D. Regulation of glucose transport by insulin: traffic control of GLUT4. Nat Rev Mol Cell Biol 13 , — Download citation. Published : 23 May Issue Date : June Anyone you share the following link with will be able to read this content:. Sorry, a shareable link is not currently available for this article. Provided by the Springer Nature SharedIt content-sharing initiative. European Journal of Human Genetics BMC Complementary Medicine and Therapies Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily. Skip to main content Thank you for visiting nature. nature nature reviews molecular cell biology review articles article. Subjects Cell signalling Exocytosis Metabolism. Key Points The glucose transporter GLUT4 facilitates insulin-stimulated glucose uptake into muscle and adipose tissue. Abstract Despite daily fasting and feeding, plasma glucose levels are normally maintained within a narrow range owing to the hormones insulin and glucagon. Access through your institution. Buy or subscribe. Change institution. Learn more. Figure 1: Insulin signalling regulates GLUT4 exocytosis by engaging the trafficking machinery. Figure 2: Molecular mechanisms of GLUT4 internalization. Figure 3: The GLUT4 trafficking itinerary. Figure 4: Insulin targets several steps in GLUT4 storage vesicle exocytosis. References Chieregatti, E. CAS Google Scholar Lowenstein, C. CAS PubMed Google Scholar Brown, D. CAS PubMed Google Scholar Pfenninger, K. CAS PubMed Google Scholar Pessin, J. CAS PubMed PubMed Central Google Scholar Saltiel, A. CAS PubMed Google Scholar Thorens, B. CAS PubMed Google Scholar Slot, J. CAS PubMed Google Scholar Martin, S. CAS PubMed Google Scholar Bogan, J. CAS PubMed PubMed Central Google Scholar Bryant, N. CAS Google Scholar Kraegen, E. 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| Introductory Chapter: Glucose Transporters | IntechOpen | Barr, V. Insulin stimulates both leptin secretion and production by rat white adipose tissue. Endocrinology , — Bogan, J. Two compartments for insulin-stimulated exocytosis in 3T3-L1 adipocytes defined by endogenous ACRP30 and GLUT4. Millar, C. Adipsin and the glucose transporter GLUT4 traffic to the cell surface via independent pathways in adipocytes. Robinson, L. Insulin-regulated sorting of glucose transporters in 3T3-L1 adipocytes. Robinson, M. Adaptor-related proteins. Hashiramoto, M. Characterization of insulin-responsive GLUT4 storage vesicles isolated from 3T3-L1 adipocytes. Ramm, G. Kandror, K. Compartmentalization of protein traffic in insulin-sensitive cells. Roberg, K. Physiological regulation of membrane protein sorting late in the secretory pathway of Saccharomyces cerevisiae. Hein, C. Giorgino, F. The sentrin-conjugating enzyme mUbc9 interacts with GLUT4 and GLUT1 glucose transporters and regulates transporter levels in skeletal muscle cells. USA 97 , — Piper, R. Late endosomes: sorting and partitioning in multivesicular bodies. Traffic 2 , — Sargeant, R. Effect of insulin on the rates of synthesis and degradation of GLUT1 and GLUT4 glucose transporters in 3T3-L1 adipocytes. Ploug, T. Analysis of GLUT4 distribution in whole skeletal muscle fibers: identification of distinct storage compartments that are recruited by insulin and muscle contractions. This study provided the first quantitative analysis of the distribution of GLUT4 in skeletal muscle after activation by either insulin, exercise or exercise plus insulin. Differential regulation of secretory compartments containing the insulin-responsive glucose transporter 4 in 3T3-L1 adipocytes. Cell 10 , — This paper shows that in 3T3-L1 adipocytes, GLUT4 movement to the cell surface can be triggered from different intracellular pools. Foran, P. Somwar, R. GLUT4 translocation precedes the stimulation of glucose uptake by insulin in muscle cells: potential activation of GLUT4 via p38 mitogen-activated protein kinase. Karnielli, E. Insulin-stimulated translocation of glucose transport systems in the isolated rat adipose cell. Molero, J. Nocodazole inhibits insulin-stimulated glucose transport in 3T3-L1 adipocytes via a microtubule-independent mechanism. Hausdorff, S. Identification of wortmannin-sensitive targets in 3T3-L1 adipocytes. Dissociation of insulin-stimulated glucose uptake and GLUT4 translocation. Differential effects of phosphatidylinositol 3-kinase inhibition on intracellular signals regulating GLUT4 translocation and glucose transport. Sweeney, G. An inhibitor of p38 mitogen-activated protein kinase prevents insulin-stimulated glucose transport but not glucose transporter translocation in 3T3-L1 adipocytes and L6 myotubes. High leptin levels acutely inhibit insulin-stimulated glucose uptake without affecting glucose transporter 4 translocation in L6 rat skeletal muscle cells. Joost, H. Insulin-stimulated glucose transport in rat adipose cells. Modulation of transporter intrinsic activity by isoproterenol and adenosine. Lawrence, J. GLUT4 facilitates insulin stimulation and cAMP-mediated inhibition of glucose transport. USA 89 , — Clancy, B. Protein synthesis inhibitors activate glucose transport without increasing plasma membrane glucose transporters in 3T3-L1 adipocytes. James, D. Isoproterenol stimulates phosphorylation of the insulin-regulatable glucose transporter in rat adipocytes. USA 86 , — GLUT4 phosphorylation and inhibition of glucose transport by dibutyryl cAMP. Zottola, R. Glucose transporter function is controlled by transporter oligomeric structure. A single, intramolecular disulfide promotes GLUT1 tetramerization. Biochemistry 34 , — Translocation of the glucose transporter GLUT4 to the cell surface in permeabilized 3T3-L1 adipocytes: effects of ATP, insulin and GTPγS and localization of GLUT4 to clathrin lattices. Ros-Baro, A. Lipid rafts are required for GLUT4 internalization in adipose cells. USA 98 , — Inoue, G. Development of an in vitro reconstitution assay for glucose transporter 4 translocation. USA 96 , — This paper was the first to show that it is feasible to reconstitute the docking and fusion of intracellular GLUT4 vesicles with the plasma membrane in vitro. Sanchez, P. Localization of atypical protein kinase C isoforms into lysosome-targeted endosomes through interaction with p Min, J. Synip: a novel insulin-regulated syntaxin 4-binding protein mediating GLUT4 translocation in adipocytes. Cell 3 , — Brooks, C. Pantophysin is a phosphoprotein component of adipocyte transport vesicles and associates with GLUT4-containing vesicles. Foster, L. A functional role for VAP in insulin-stimulated GLUT4 traffic. Shibata, H. Insulin stimulates guanine nucleotide exchange on Rab4 via a wortmannin-sensitive signaling pathway in rat adipocytes. Li, L. Direct interaction of Rab4 with syntaxin 4. Braiman, L. Activation of protein kinase Cζ induces serine phosphorylation of VAMP2 in the GLUT4 compartment and increases glucose transport in skeletal muscle. Activated phosphatidylinositol 3-kinase is sufficient to mediate actin rearrangement and GLUT4 translocation in 3T3-L1 adipocytes. Kohn, A. Chiang, S. Insulin-stimulated GLUT4 translocation requires the CAP-dependent activation of TC Nature , — Tong, P. Insulin-induced cortical actin remodeling promotes GLUT4 insertion at muscle cell membrane ruffles. Emoto, M. A role for kinesin in insulin-stimulated GLUT4 glucose transporter translocation in 3T3-L1 adipocytes. Kanzaki, M. Insulin-stimulated GLUT4 translocation in adipocytes is dependent upon cortical actin remodeling. Insulin stimulates actin comet tails on intracellular GLUT4-containing compartments in differentiated 3T3L1 adipocytes. Harris, M. Prevalence of diabetes, impaired fasting glucose, and impaired glucose tolerance in U. The Third National Health and Nutrition Examination Survey, — Diabetes Care 21 , — Watson, R. Lipid raft microdomain compartmentalization of TC10 is required for insulin signaling and GLUT4 translocation. Mechanism and regulation of GLUT-4 vesicle fusion in muscle and fat cells. Cell Physiol. Zerial, M. Rab proteins as membrane organizers. Nature Rev. CAS Google Scholar. Kuboshima, S. Hyperosmotic stimuli induces recruitment of aquaporin-1 to plasma membrane in cultured rat peritoneal mesothelial cells. Marinelli, R. Secretin promotes osmotic water transport in rat cholangiocytes by increasing aquaporin-1 water channels in plasma membrane. Evidence for a secretin-induced vesicular translocation of aquaporin Kamsteeg, E. The subcellular localization of an aquaporin-2 tetramer depends on the stoichiometry of phosphorylated and nonphosphorylated monomers. Gustafson, C. Recycling of AQP2 occurs through a temperature- and bafilomycin-sensitive trans -Golgi-associated compartment. Renal Physiol. Mandon, B. Syntaxin-4 is localized to the apical plasma membrane of rat renal collecting duct cells: possible role in aquaporin-2 trafficking. Valenti, G. The phosphatase inhibitor okadaic acid induces AQP2 translocation independently from AQP2 phosphorylation in renal collecting duct cells. Cell Sci. Klussmann, E. Protein kinase A anchoring proteins are required for vasopressin-mediated translocation of aquaporin-2 into cell membranes of renal principal cells. Katsura, T. Protein kinase A phosphorylation is involved in regulated exocytosis of aquaporin-2 in transfected LLC-PK1 cells. A heterotrimeric G protein of the Gi family is required for cAMP- triggered trafficking of aquaporin 2 in kidney epithelial cells. Mulders, S. An aquaporin-2 water channel mutant which causes autosomal dominant nephrogenic diabetes insipidus is retained in the Golgi complex. Snyder, P. Loffing, J. Aldosterone induces rapid apical translocation of ENaC in early portion of renal collecting system: possible role of SGK. Djelidi, S. Basolateral translocation by vasopressin of the aldosterone-induced pool of latent Na-K-ATPases is accompanied by α1 subunit dephosphorylation: study in a new aldosterone-sensitive rat cortical collecting duct cell line. Juel, C. Lavoie, L. Omatsu-Kanbe, M. Aledo, J. Method of glucose uptake differs throughout tissues depending on two factors; the metabolic needs of the tissue and availability of glucose. The two ways in which glucose uptake can take place are facilitated diffusion a passive process and secondary active transport an active process which on the ion-gradient which is established through the hydrolysis of ATP , known as primary active transport. Active transport is the movement of ions or molecules going against the concentration gradient. There are over 10 different types of glucose transporters; however, the most significant for study are GLUT GLUT1 and GLUT3 are located in the plasma membrane of cells throughout the body, as they are responsible for maintaining a basal rate of glucose uptake. Basal blood glucose level is approximately 5mM 5 millimolar. The Km value an indicator of the affinity of the transporter protein for glucose molecules; a low Km value suggests a high affinity of the GLUT1 and GLUT3 proteins is 1mM; therefore GLUT1 and GLUT3 have a high affinity for glucose and uptake from the bloodstream is constant. GLUT2 in contrast has a high Km value mM and therefore a low affinity for glucose. They are located in the plasma membranes of hepatocytes and pancreatic beta cells in mice, but GLUT1 in human beta cells; see Reference 1. The high Km of GLUT2 allows for glucose sensing; rate of glucose entry is proportional to blood glucose levels. GLUT4 transporters are insulin sensitive, and are found in muscle and adipose tissue. As muscle is a principal storage site for glucose and adipose tissue for triglyceride into which glucose can be converted for storage , GLUT4 is important in post-prandial uptake of excess glucose from the bloodstream. Moreover, several recent papers show that GLUT 4 is present in the brain also. The drug metformin phosphorylates GLUT4, thereby increasing its sensitivity to insulin. During fasting, some GLUT4 transporters will be expressed at the surface of the cell. Post-mortem studies showed consistent reductions in GLUT1 and GLUT3 in the hippocampus and cortex of AD brains, areas of the brain closely associated with AD pathology. Tracer studies in rodent models of AD and human AD also exhibit reduced uptake of glucose and glucose-analogs into the brain, supporting these findings. Longitudinal rodent studies clearly indicate that changes in GLUT1 and GLUT3 only occur after amyloid-β pathology is present, and several studies indicate amyloid-β itself may be responsible for GLUT changes. Furthermore, evidence from human and rodent studies suggest GLUT depletion has severe effects on brain function. A small number of studies show GLUT2 and GLUT12 are increased in AD. Anti-diabetic medications improved glucose transport capacity in AD subjects. Conclusions: GLUT1 and GLUT3 are reduced in hippocampal and cortical regions in patients and rodent models of AD, and may be caused by high levels of amyloid-β in these regions. GLUT3 reductions appear to precede the onset of clinical symptoms. GLUT2 and GLUT12 appear to increase and may have a compensatory role. Repurposing anti-diabetic drugs to modify glucose transport shows promising results in human studies of AD. Alzheimer's disease AD is a chronic neurodegenerative disorder characterized by the presence of β-amyloid Aβ plaques and neurofibrillary tangles NFTs Grundke-Iqbal et al. Several mechanisms have been proposed for its pathophysiology. According to the amyloid cascade hypothesis, the Aβ precursor protein APP is abnormally cleaved, leading to an imbalance between Aβ production and clearance, favoring the accumulation of Aβ. This, in turn, forms clusters in the brain which induce oxidative stress, leading to synaptic dysfunction, neuronal death, and subsequent cerebral atrophy Chételat et al. These clusters, called oligomers, form fibrils, then beta-sheets and eventually develop into plaques which are considered a hallmark of AD Grundke-Iqbal et al. While Aβ accumulation has a critical role in AD, it is becoming increasingly recognized that brain Aβ burden does not correlate with the severity of cognitive impairment Games et al. Aβ accumulation also occurs in aging individuals without cognitive impairment Castello and Soriano, ; Morris et al. The tau hypothesis conjectures that tau is the main causative protein for AD Kosik et al. Tau is a protein normally associated with microtubules which serve to stabilize tubulin assemblies. In AD, tau is abnormally hyperphosphorylated and forms pathological inclusions known as NFTs, which are widely identified in AD brains. Tau is more strongly associated with cognitive impairment than Aβ Hanseeuw et al. However, attempts to stabilize cognitive function through modification of Aβ and tau in the clinical setting have been unsuccessful to date Congdon and Sigurdsson, ; Yiannopoulou and Papageorgiou, In addition to Aβ and tau, AD is considered a metabolic disorder, which relates to reduced cerebral glucose metabolism, brain insulin resistance, and age-induced mitochondrial dysfunction Van Der Velpen et al. The conventional view is that reduced brain metabolism is secondary to brain atrophy and neuronal loss Bokde et al. However, there is accumulating evidence that hypometabolism occurs before the onset of brain atrophy and clinical symptoms, indicating that changes in metabolism may occur prior to reduced glucose demand by tissues De Leon et al. Abnormal cerebral glucose metabolism was observed using FDG-PET in by de Leon et al. This correlated with a reduction in cognitive performance compared to age matched controls. Later studies confirmed these results, building support for regional declines in CMR glu as a hallmark of AD, including in frontal white matter, caudate, thalamus, temporal, and parietal regions Small et al. Masdeu examined seven pre-symptomatic, at-risk subjects with familial AD using MRI and FDG-PET imaging. Compared to seven matched healthy controls, the familial AD subjects showed a reduction in glucose metabolism in most brain regions examined, including the whole brain, right, and left inferior parietal lobules, superior temporal gyrus, left entorhinal cortex, posterior cingulate cortex, and hippocampus. De Leon et al. In all three studies, reductions in glucose metabolism predicted cognitive decline in those participants who went on to develop cognitive impairment or a clinical diagnosis of AD. In a longitudinal study, Mosconi et al. Their pathological diagnosis was verified through post-mortem studies 6 ± 3 years after the subjects' last FDG-PET scan. All participants who were cognitively intact at baseline developed mild cognitive impairment MCI 2—7 years after their baseline assessment. On post-mortem studies, two of these subjects had definite AD, one had probable AD and the last had pathological findings consistent with Parkinson's disease with mild AD-related pathology. In all four patients, CMR glu was reduced in areas involving the hippocampus, up to 7 years before their diagnosis of MCI. Follow up FDG-PET scans showed progressive reductions in CMR glu with wider brain involvement including the temporal and parietal lobes, and to varying degrees the anterior and posterior cingulate regions. A more recent study by Ou et al. Their findings demonstrate faster cognitive decline and brain atrophy in participants with reduced metabolism. While these studies included a small number of participants, their results suggest that hypometabolism precedes a clinical diagnosis of AD. Glucose metabolism requires both delivery of glucose to cells from the bloodstream, and phosphorylation by hexokinase at the site of mitochondria. One possible explanation for early changes to glucose metabolism observed via FDG-PET may be due to abnormal delivery of glucose to the brain. Glucose is a hydrophilic molecule and requires transporters to cross cell membranes. Glucose uptake into the brain occurs predominantly via the sodium-independent facilitative transporters GLUT1 and GLUT3, encoded by the SLC2A1 and SLC2A3 genes, respectively. GLUT1 is responsible for glucose uptake across the BBB endothelial cells, where the higher density isoforms are located 55 kDa , and into astrocytes, where the lower density isoforms are located 45 kDa. Glucose uptake into the brain appears to correlate with the number of GLUT1 transporters at the BBB Zeller et al. Neurons do not express GLUT1 Zlokovic, The main glucose transporter that facilitates uptake of glucose into neurons is GLUT3, which is encoded by the SLC2A3 gene. GLUT3 is also detected at lower levels on astroglial and endothelial cells Kumari and Heese, ; Patching, Low levels of GLUT2, encoded by the SLC2A2 gene, are present on astrocytes Magistretti and Pellerin, ; Larrabee, Reduced supply of glucose to the brain via loss of these major glucose transporters may lead to a brain glucose deficit, halting metabolism and other processes dependent on ATP production Iadecola, Several insulin-sensitive transporters are present in the brain at low levels, including GLUT4, a transporter mainly present in non-cerebral fat and muscle tissue, GLUT8, which has been suggested to contribute toward glucose homeostasis in hippocampal neurons Piroli et al. The location of these transporters within the central nervous system CNS and their presence on different cell types are shown in Table 1 , Figure 1. Figure 1. A schematic diagram representing the expression of glucose transporters within CNS cells. Red: GLUT1 55 kDa isoform, pink: GLUT1 45 kDa isoform. GLUT1 Kumari and Heese, , GLUT2 Kumari and Heese, , GLUT3 Kumari and Heese, , GLUT4 Leloup et al. Detailed descriptions of glucose transporters and their respective functions are not described here—these aspects have been reviewed extensively elsewhere by Szablewski and Koepsell Szablewski also reviewed glucose transporter alterations in AD with particular focus on links between AD and insulin resistance, but a systematic review of human and animal data was not performed. Furthermore, Szablewski did not cover in detail results from tracer studies of glucose uptake into the brain, the effects of AD pathologies such as amyloid-β and tau on GLUTs, the timing of effects, or how GLUT alterations affect the brain. Here we perform a systematic review to capture all human and rodent studies of glucose transport alterations in AD to date and aim to evaluate the evidence to support i which transporters are affected, if any, ii how glucose uptake into the brain is altered, iii which brain regions are most affected, iv when changes occur relative to other AD pathologies, and v how GLUT changes affect brain function. Literature published between 1st January and 1st November was searched using the PubMed search engine. Only studies investigating cerebral glucose transporters were included. Titles and abstracts were scanned to identify relevant papers and articles, and those which did not clearly examine glucose transport specific to Alzheimer's disease were discussed with the research team and excluded if not considered relevant. Human and rodent studies post-mortem and in-vivo were included and results are summarized in Tables 2 , 3. Reviews, letters and in-vitro studies were excluded. Figure 2 shows the PRISMA flow chart detailing the search results. Twenty-three human studies and twenty rodent studies met the inclusion criteria. A total of 10 human studies and 12 rodent studies observed reductions in GLUT1 expression, primarily in cortical and hippocampal regions. One study found increased GLUT1 expression. A total of 5 human studies and 6 rodent studies found reductions to GLUT3 expression. One study found no change, and one study found increased GLUT3 expression. Tracer-based methods were used to measure glucose uptake into brain tissue in 9 studies. All tracer studies except one reported reduced glucose uptake into the brain with AD, although in rodent studies reduced uptake was not observed until later stages of disease. A detailed review of all studies is given below. Early work by Kalaria and Harik showed a significant reduction in hexose transporters, primarily GLUTs, in the neocortex and hippocampus of post-mortem AD brain tissue. In a subsequent study, Harik showed a significant reduction in the density of GLUT1 in the cerebral microvessels in the AD brain compared to age-matched controls, with no change in the density of GLUT1 in erythrocyte membranes. Simpson et al. After correcting for synaptic loss, which is a prominent feature of AD Masliah et al. Similar results were shown by Horwood and Davies who observed GLUT1 reductions in hippocampal tissue of the AD brain. They identified glucose transporters by reversible and irreversible binding to the ligand [3H] cytochalasin B. The type of glucose transporter identified using this method was not stated, however, cytochalasin B is an inhibitor of glucose transport in erythrocytes May, ; Carruthers and Helgerson, and is likely to reflect GLUT1 levels. Mooradian et al. In a study of hippocampal microvasculature, Burke et al. Contrary to previous studies, they observed increased GLUT1 density in AD brain tissue compared to controls. By contrast, a very recent study investigating white matter tissue from the AD brain demonstrated collapsed string microvessels along with loss of GLUT1 immunoreactivity in the white matter of the frontal lobe compared to overlying cortex Hase et al. Liu et al. They showed that GLUT1 was significantly reduced in AD but not significantly reduced in either T2DM or T2DM-AD groups. GLUT3 was significantly reduced in all three groups with the lowest levels in T2DM brain. Interestingly, GLUT2 was significantly increased in the AD brain and brains of subjects with both AD and T2DM, possibly due to astrocyte overactivation Liu et al. Harr et al. A small number of studies have investigated the link between glucose transporters and AD pathologies in human tissue. Kawai et al. Capillary glucose transporter density was reduced within Aβ plaques but increased in the immediate surroundings of Aβ plaques. A recent study using participants from the Baltimore Longitudinal Study of Aging cohort measured GLUT1 and GLUT3 levels in the middle frontal gyrus of 14 participants with AD, 14 controls, and 15 with asymptomatic AD pathology, i. GLUT3 levels were significantly lower in both AD and asymptomatic AD groups relative to controls, before and after adjusting for sex, age at death, and neuronal nuclear protein levels. Lower levels of GLUT3 correlated with the severity of both Aβ and NFT pathology An et al. GLUT1 levels were not significantly different in any of the groups. Pujol-Gimenez et al. Wang et al. They performed a case-control study in a Chinese population of patients with AD and healthy controls, showing that SLC2A14 polymorphisms appear to confer increased risk of developing AD. Alterations in GLUTs have also been observed in rodent models of AD. In a longitudinal study of 3xTgAD mice between 3 and 15 months of age, glucose transporters GLUT1 55 and 45 kDa , and GLUT3 were found to change in both AD and wild-type animals but with differing temporal trajectories Ding et al. In AD mice, GLUT1 55 kDa and GLUT3 were found to decrease with age, whereas GLUT1 45 kDa was found to increase with age. In wild-types, non-monotonic changes with age were observed for GLUT1 55 kDa , whereas GLUT1 45 kDa was unchanged. GLUT3 decreased, and GLUT4 increased with age. Unfortunately, a formal comparison between glucose transporter expression between 3xTgAD mice and wild-types was not performed. In another longitudinal study, Do et al. Griffith et al. They found similar timing of effects on GLUT3 as observed for GLUT1 by Do et al. Young rats exhibited reduced glucose tolerance as early as 1 month , but GLUT3 did not change relative to wild-types until at least 18—20 months. GLUT4 was unaltered at all ages. Similar results were found in other AD models. Hooijmans et al. Changes were found in the hippocampus, but not the cortex. In the Tg model, Kuznetsova and Schliebs showed that cortical GLUT1 was unaltered at 10 months compared to wild-types, but at 18 months after development of amyloid pathology, AD mice had significantly lower cortical GLUT1. A study by Kouznetsova et al. In cortical regions with high amyloid load, GLUT1 staining was reduced compared to regions with low amyloid load. The authors also showed that GLUT1 staining was reduced nearer large senile plaques, relative to changes observed near smaller diffuse plaques. Gil-Iturbe et al. The authors found reduced GLUT1 and GLUT3, and increased GLUT12 in both strains. No age dependent effects on GLUTs were observed, conflicting with results from Ding et al. Merlini et al. They observed reductions in BBB and astrocytic GLUT1 in the cortex and hippocampus from 9 to 12 months onward, which coincided with changes in glucose uptake as measured using microdialysis. However, GLUT3 was unaltered. By 16—22 months, IgG extravasation was observed, indicating loss of BBB integrity. In 5xFAD aged 4. GLUT3 was not studied. A study by Chua et al. Brain glucose levels were measured to be lower than wildtypes at 12 and 15 months of age, but GLUT3 and GLUT4 were found to be upregulated, not decreased Chua et al. Unfortunately, changes to GLUT1 were not studied. Shang et al. In normal APP23 mice, GLUT1 reductions were observed at 12 months, which were further reduced in APP23 mice with chronic cerebral hypoperfusion Shang et al. A number of studies have investigated GLUT expression in a rat model of AD produced by administering streptozotocin via intracerebroventricular injection. These studies found reduced expression of GLUT1 Deng et al. Friedland et al. No difference in the transport rate constants, K 1 and k 2 , or the utilization rate k 3 , were observed between groups. Two later FDG-PET studies in AD patients showed different results; Jagust et al. Kimura and Naganawa performed dynamic PET studies in three subjects, a year-old normal subject, a year-old subject with mild AD, and a year-old subject with severe AD. Glucose transport was globally reduced in both AD cases compared to the normal subject. Glucose phosphorylation was diminished in gray matter of the severe case of AD, excluding the sensory, motor, and visual cortices. In the mild case, phosphorylation was reduced in the right parieto-temporal area. In another dynamic FDG-PET study of seven patients with mild AD and six normal age-matched controls, Mosconi et al. A small number of tracer studies have been performed in rodents, which all support reduced transport of glucose in AD. Do et al. No difference in [3H]-D-glucose uptake was found in 3xTgAD mice compared to wild-types aged 6 or 8 months, but a significant decrease was found in 3xTgAD mice at 18 months. The reduced uptake at 18 month was associated with reduced expression of GLUT1 at the same timepoint. Ding et al. FDG-PET signals were measured at 40 min post injection of FDG, and are likely to reflect both transport and utilization. Reductions in the FDG-PET signal were found in both AD and wild-type animals with age, but while no formal comparison was made, FDG-PET signals did not appear to differ across genotype. Last, Merlini et al. The effects of GLUT disruptions on the brain have been studied in rodent models. Abdul Muneer et al. This led to a reduction in BBB tight junction proteins, indicating that GLUTs may play a role in regulating BBB integrity. Winkler et al. These included reduced brain capillary levels of low-density lipoprotein receptor-related protein 1 LRP1 , a transporter at the BBB which clears Aβ from the brain Zlokovic, , , diminished cerebral blood flow, early BBB breakdown, accelerated Aβ deposition in the hippocampus and cortex, neuronal dysfunction and cognitive impairment. They also observed that vascular changes preceded neuronal dysfunction in these mice. Decreased levels of GLUT1 and GLUT3 were found in a rat model of sporadic AD, achieved through the intracerebroventricular injection of streptozotocin, alongside impaired insulin signaling and abnormalities in phosphorylation and microtubule binding activity of tau Deng et al. Effects of severe glucose transporter depletion on early brain development can be observed in human GLUT1 deficiency syndrome, a rare genetic disorder characterized by impaired glucose metabolism due to a deficiency in GLUT1. Clinical features include intellectual disability, movement disorders and epileptic seizures refractory to treatment. Late-onset GLUT1 deficiency syndrome affects children at an older age, with evidence showing mild to moderate intellectual disability Leen et al. A later study by the same group followed up patients with GLUT1 deficiency syndrome between 18 and 41 years old. Their results showed that while the prominent feature during childhood is epilepsy, this diminishes later in life and new movement disorders become apparent during adolescence. Cognitive function, however, did not appear to worsen with age Leen et al. There is no evidence of GLUT1 deficiency syndrome manifesting in late adulthood. Deficits in transport and metabolism in AD may result from impaired insulin signaling, particularly due to alterations in the function of insulin-sensitive transporters. Mullins et al. Their findings showed that GLUT1 was positively correlated, whereas GLUT4 was negatively correlated, with insulin signaling proteins including IRS In a mouse model of AD, Chua et al. In the STZ rat model of AD, increases in GLUT2 were accompanied by decreases in insulin receptors Knezovic et al. In the same model, Deng et al. Insulin resistance has been targeted as a means to restore glucose transport by number of groups. In a small randomized control trial, Gejl et al. In their study, 18 participants received liraglutide and 20 received placebo in a week period. Salkovic-Petrisic et al. This systematic review examines the evidence for alterations in glucose transport in AD and the effect of these alterations on the brain. The majority of studies investigating GLUT1 and GLUT3 suggest that both transporters are reduced in the hippocampus and cortex of AD brains. Longitudinal rodent studies did not find changes at early timepoints, but consistently observed reductions in transporter expression after Aβ pathology had developed, indicating that Aβ itself may be responsible. There were fewer studies investigating other GLUTs including GLUT2, GLUT4, GLUT12, and GLUT A rise in GLUT2 in AD brain tissue was observed by Liu et al. |
| Top bar navigation | Brozinick, J. Jr et al. Diabetes 50 , — Holman, G. Insulin-stimulated GLUT4 glucose transporter recycling. A problem in membrane protein subcellular trafficking through multiple pools. This study used mathematical analysis to show that the intracellular transport of GLUT4 could not be explained by a simple two-compartment model, which indicates that GLUT4 is partitioned within the cell among at least two separate compartments. Tanner, L. Insulin elicits a redistribution of transferrin receptors in 3T3-L1 adipocytes through an increase in the rate constant for receptor externalization. Albiston, A. Evidence that the angiotensin IV AT4 receptor is the enzyme insulin regulated aminopeptidase. Google Scholar. Ross, S. Characterization of the insulin-regulated membrane aminopeptidase in 3T3-L1 adipocytes. Palacios, S. Recycling of the insulin-sensitive glucose transporter GLUT4. Access of surface internalized GLUT4 molecules to the perinuclear storage compartment is mediated by the Phe5—Gln6—Gln7—Ile8 motif. Martin, S. The glucose transporter GLUT-4 and vesicle-associated membrane protein-2 VAMP-2 are segregated from recycling endosomes in insulin-sensitive cells. Cell Biol. Using a chemical technique to ablate endosomes, this paper was one of the first to show that a significant pool of GLUT4 is excluded from endosomes and that, together with the v-SNARE VAMP2, this might demarcate a separate secretory compartment. Martin, L. Vesicle-associated membrane protein 2 plays a specific role in the insulin-dependent trafficking of the facilitative glucose transporter GLUT4 in 3T3-L1 adipocytes. Lampson, M. Insulin-regulated release from the endosomal recycling compartment is regulated by budding of specialized vesicles. Cell 12 , — Using quantitative immunofluorescence-microscopy techniques, this study provides evidence that GLUT4 is retained in recycling endosomes in CHO cells, and moves to the cell surface in transport vesicles that are distinct from those that contain the TfR. Lim, S. Identification of discrete classes of endosome-derived small vesicles as a major cellular pool for recycling membrane proteins. In vitro reconstitution experiments were used to show that GLUT4 and the TfR are sorted into different endosomally derived vesicles in CHO cells. Slot, J. Translocation of the glucose transporter GLUT4 in cardiac myocytes of the rat. USA 88 , — Immuno-localization of the insulin regulatable glucose transporter in brown adipose tissue of the rat. This was the first immunocytochemical analysis of GLUT4 in insulin-sensitive cells and showed that insulin caused a striking redistribution of GLUT4 from intracellular tubulo—vesicular elements to the plasma membrane. Glucose transporter GLUT-4 is targeted to secretory granules in rat atrial cardiomyocytes. Biogenesis of insulin-responsive GLUT4 vesicles is independent of brefeldin A-sensitive trafficking. Traffic 1 , — Shewan, A. The cytosolic C-terminus of the glucose transporter GLUT4 contains an acidic cluster endosomal targeting motif distal to the dileucine signal. Molloy, S. Bi-cycling the furin pathway: from TGN localization to pathogen activation and embryogenesis. Trends Cell Biol. Xiang, Y. Cell 11 , — Wan, L. PACS-1 defines a novel gene family of cytosolic sorting proteins required for trans -Golgi network localization. Cell 94 , — Mallard, F. Barr, V. Insulin stimulates both leptin secretion and production by rat white adipose tissue. Endocrinology , — Bogan, J. Two compartments for insulin-stimulated exocytosis in 3T3-L1 adipocytes defined by endogenous ACRP30 and GLUT4. Millar, C. Adipsin and the glucose transporter GLUT4 traffic to the cell surface via independent pathways in adipocytes. Robinson, L. Insulin-regulated sorting of glucose transporters in 3T3-L1 adipocytes. Robinson, M. Adaptor-related proteins. Hashiramoto, M. Characterization of insulin-responsive GLUT4 storage vesicles isolated from 3T3-L1 adipocytes. Ramm, G. Kandror, K. Compartmentalization of protein traffic in insulin-sensitive cells. Roberg, K. Physiological regulation of membrane protein sorting late in the secretory pathway of Saccharomyces cerevisiae. Hein, C. Giorgino, F. The sentrin-conjugating enzyme mUbc9 interacts with GLUT4 and GLUT1 glucose transporters and regulates transporter levels in skeletal muscle cells. USA 97 , — Piper, R. Late endosomes: sorting and partitioning in multivesicular bodies. Traffic 2 , — Sargeant, R. Effect of insulin on the rates of synthesis and degradation of GLUT1 and GLUT4 glucose transporters in 3T3-L1 adipocytes. Ploug, T. Analysis of GLUT4 distribution in whole skeletal muscle fibers: identification of distinct storage compartments that are recruited by insulin and muscle contractions. This study provided the first quantitative analysis of the distribution of GLUT4 in skeletal muscle after activation by either insulin, exercise or exercise plus insulin. Differential regulation of secretory compartments containing the insulin-responsive glucose transporter 4 in 3T3-L1 adipocytes. Cell 10 , — This paper shows that in 3T3-L1 adipocytes, GLUT4 movement to the cell surface can be triggered from different intracellular pools. Foran, P. Somwar, R. GLUT4 translocation precedes the stimulation of glucose uptake by insulin in muscle cells: potential activation of GLUT4 via p38 mitogen-activated protein kinase. Karnielli, E. Insulin-stimulated translocation of glucose transport systems in the isolated rat adipose cell. Molero, J. Nocodazole inhibits insulin-stimulated glucose transport in 3T3-L1 adipocytes via a microtubule-independent mechanism. Hausdorff, S. Identification of wortmannin-sensitive targets in 3T3-L1 adipocytes. Dissociation of insulin-stimulated glucose uptake and GLUT4 translocation. Differential effects of phosphatidylinositol 3-kinase inhibition on intracellular signals regulating GLUT4 translocation and glucose transport. Sweeney, G. An inhibitor of p38 mitogen-activated protein kinase prevents insulin-stimulated glucose transport but not glucose transporter translocation in 3T3-L1 adipocytes and L6 myotubes. High leptin levels acutely inhibit insulin-stimulated glucose uptake without affecting glucose transporter 4 translocation in L6 rat skeletal muscle cells. Joost, H. Insulin-stimulated glucose transport in rat adipose cells. Modulation of transporter intrinsic activity by isoproterenol and adenosine. Lawrence, J. GLUT4 facilitates insulin stimulation and cAMP-mediated inhibition of glucose transport. USA 89 , — Clancy, B. Protein synthesis inhibitors activate glucose transport without increasing plasma membrane glucose transporters in 3T3-L1 adipocytes. James, D. Isoproterenol stimulates phosphorylation of the insulin-regulatable glucose transporter in rat adipocytes. USA 86 , — GLUT4 phosphorylation and inhibition of glucose transport by dibutyryl cAMP. Zottola, R. Glucose transporter function is controlled by transporter oligomeric structure. A single, intramolecular disulfide promotes GLUT1 tetramerization. Biochemistry 34 , — Translocation of the glucose transporter GLUT4 to the cell surface in permeabilized 3T3-L1 adipocytes: effects of ATP, insulin and GTPγS and localization of GLUT4 to clathrin lattices. Ros-Baro, A. Lipid rafts are required for GLUT4 internalization in adipose cells. USA 98 , — Inoue, G. Development of an in vitro reconstitution assay for glucose transporter 4 translocation. USA 96 , — This paper was the first to show that it is feasible to reconstitute the docking and fusion of intracellular GLUT4 vesicles with the plasma membrane in vitro. Sanchez, P. Localization of atypical protein kinase C isoforms into lysosome-targeted endosomes through interaction with p Min, J. Synip: a novel insulin-regulated syntaxin 4-binding protein mediating GLUT4 translocation in adipocytes. Cell 3 , — Brooks, C. Pantophysin is a phosphoprotein component of adipocyte transport vesicles and associates with GLUT4-containing vesicles. Foster, L. A functional role for VAP in insulin-stimulated GLUT4 traffic. Shibata, H. Insulin stimulates guanine nucleotide exchange on Rab4 via a wortmannin-sensitive signaling pathway in rat adipocytes. Li, L. Direct interaction of Rab4 with syntaxin 4. Braiman, L. Activation of protein kinase Cζ induces serine phosphorylation of VAMP2 in the GLUT4 compartment and increases glucose transport in skeletal muscle. Activated phosphatidylinositol 3-kinase is sufficient to mediate actin rearrangement and GLUT4 translocation in 3T3-L1 adipocytes. Kohn, A. Chiang, S. Insulin-stimulated GLUT4 translocation requires the CAP-dependent activation of TC Nature , — Tong, P. In humans, 12 members of sodium-dependent glucose cotransporters have been identified. These proteins contain of — amino acid residues, with a predicted mass of 60—80 kDa. There is a diversity in gene structure. In eight genes, the coding sequences are found in 14—15 exons SLC5A1, SLC5A2, SLC5A4—SLC5A6, and SLC5A9—SLC5A11 , and the coding sequence for SLC5A7 and SLC5A3 are present in exons 8 and 1, respectively. In SLC5A9—SLC5A11 and SLC5A3 , there is evidence for alternative splicing. These proteins contain 14 TM α-helices TMHs in all but not in sodium-iodide symporter NIS and SMCT1, which lack TMH 14 [ 18 ]. Both the hydrophilic N- and C-termini are located on the extracellular side of the cell membrane [ 1 ]. SGLTs are highly glycosylated membrane proteins; however, glycosylation is not required in the functioning of the protein. The human SLC5A genes are expressed in different tissues, and all of them code for sodium-dependent glucose cotransporter proteins, except for SGLT3 SLC5A4 , which acts as a glucose sensor [ 19 ]. SWEETs transport mono- and disaccharides across vacuolar and plasma membranes. A new class of glucose transporters, SWEET, was first identified by expressing candidate Arabidopsis genes coding for polytopic membrane proteins in HEKT cells [ 20 ]. SWEETs are ubiquitously expressed in plants. In contrast to Arabidopsis thaliana , in which up to two dozen SWEETs have been identified, animals usually have only one SWEET, except for Caenorhabditis elegans , where seven SWEET-encoding genes have been found. Homologs of the SWEETs are widespread in metazoan genomes, and there is a single homolog in human genome SWEET1 encoded by the gene SLC50A1 [ 1 ]. Human SWEET1 RAG1AP1 , encoded by SLC50A1 , comprises amino acids with a molecular weight of 25 kDa. Human SWEET1 did not promote glucose uptake but instead mediated a weak efflux. Human SWEET1 when expressed in HEKT cells was predominantly found to be localized in the Golgi with minimum expression also found in the plasma membrane. Chen et al. The authors suggest that the human SWEET1 serves to supply glucose for lactose synthesis in the mammary gland. Human SWEET1 glucose transporter is the missing glucose transporter in the basolateral membrane of enterocytes where it may account for the exit of glucose from the cell into the blood in patients with Fanconi-Bickel syndrome and in mice missing the GLUT2 transporter [ 21 , 22 ]. Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3. Edited by Leszek Szablewski. Open access Introductory Chapter: Glucose Transporters Written By Leszek Szablewski. DOWNLOAD FOR FREE Share Cite Cite this chapter There are two ways to cite this chapter:. Choose citation style Select style Vancouver APA Harvard IEEE MLA Chicago Copy to clipboard Get citation. Choose citation style Select format Bibtex RIS Download citation. IntechOpen Blood Glucose Levels Edited by Leszek Szablewski. From the Edited Volume Blood Glucose Levels Edited by Leszek Szablewski Book Details Order Print. Chapter metrics overview 1, Chapter Downloads View Full Metrics. Impact of this chapter. szablewski wum. Introduction The major source of energy for mammalian cells is glucose. References 1. Wright EM. Glucose transport families SLC5 and SLC Molecular Aspects of Medicine. Long W, Cheeseman CI. Structure of, and functional insight into the GLUT family of membrane transporters. Cell Health and Cytoskeleton. Thorens B, Mueckler M. As muscle is a principal storage site for glucose and adipose tissue for triglyceride into which glucose can be converted for storage , GLUT4 is important in post-prandial uptake of excess glucose from the bloodstream. Moreover, several recent papers show that GLUT 4 is present in the brain also. The drug metformin phosphorylates GLUT4, thereby increasing its sensitivity to insulin. During fasting, some GLUT4 transporters will be expressed at the surface of the cell. However, most will be found in cytoplasmic vesicles within the cell. After a meal and at the binding of insulin released from the islets of Langerhans to receptors on the cell surface, a signalling cascade begins by activating phosphatidylinositolkinase activity which culminates in the movement of the cytoplasmic vesicles toward the cell surface membrane. Upon reaching the plasmalemma, the vesicles fuse with the membrane, increasing the number of GLUT4 transporters expressed at the cell surface, and hence increasing glucose uptake. Facilitated diffusion can occur between the bloodstream and cells as the concentration gradient between the extracellular and intracellular environments is such that no ATP hydrolysis is required. However, in the kidney, glucose is reabsorbed from the filtrate in the tubule lumen , where it is at a relatively low concentration, passes through the simple cuboidal epithelia lining the kidney tubule, and into the bloodstream where glucose is at a comparatively high concentration. Therefore, the concentration gradient of glucose opposes its reabsorption, and energy is required for its transport. Once inside the epithelial cells, glucose reenters the bloodstream through facilitated diffusion through GLUT2 transporters. Hence reabsorption of glucose is dependent upon the existing sodium gradient which is generated through the active functioning of the NaKATPase. As the cotransport of glucose with sodium from the lumen does not directly require ATP hydrolysis but depends upon the action of the ATPase, this is described as secondary active transport. There are two types of secondary active transporter found within the kidney tubule; close to the glomerulus , where glucose levels are high, SGLT2 has a low affinity yet high capacity for glucose transport. Close to the loop of Henle and in the distal convoluted tubule of the nephron where much glucose has been reabsorbed into the bloodstream, SGLT1 transporters are found. |
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