Glut 2 bidirectional relationship

GLUT2 - Wikipedia

glut 2 bidirectional relationship

Cloned 20 years ago, GLUT2 is a facilitative glucose transporter in the liver, pancreas, intestine, kidney, and brain. It ensures large bidirectional fluxes of glucose. Expression of two important glucose transporter proteins, GLUT 2. (which is the . 31, © American Association for Cancer .. in glucose transporter expression from GLUT 2 (bidirectional glucose transport) to. GLUT2 is a facilitative, bidirectional transporter. Human aldolase A natural mutants: relationship between flexibility of the C-terminal region.

During evolution, duplicated members acquired specialty such that they may either develop substrate specificity, or could be regulated in specialized ways that are advantageous to the species. In cells, multiple GLUTs are arranged in a tissue-specific manner, exhibiting different kinetic and regulatory properties [ 57 ].

glut 2 bidirectional relationship

All ectopically expressed GLUT members have demonstrated the ability to facilitate hexose transport [ 5 ], while some are specific to the transport of urate, myo-inositol or fructose. Fructose transport is especially important due to metabolic abnormalities acquired from high concentrations of fructose in the diet [ 8 ].

Defects in glucose and fructose transport are associated with insulin resistance, diabetes [ 9 ] and hyperfructosemia [ 10 ]. GLUT expression patterns are complex features. Much attention has been focused on characterizing mammalian GLUT members and elucidating their specific physiological roles.

Several studies have also examined the role of GLUTs among avian species, which have provided a basis for understanding GLUT expression patterns in various tissues during different stages of development. Glucose Transport After the breakdown of dietary polysaccharides, glucose, fructose and galactose are taken up by enterocytes lining the microvilli of the small intestine. GLUT5 on the lumenal surface of the small intestine mediates fructose uptake.

Sodium-dependent glucose cotransporters members of the sodium-glucose cotransporter SGLT protein family mediate the uptake of glucose and galactose.

GLUT2 on the basolateral surface of enterocytes facilitates the release of hexoses into the circulatory system for reuptake by other cells [ 11 ]. When monosaccharide levels are high, GLUT2 may facilitate hexose uptake from the gut lumen [ 12 ].

In hepatocytes and other somatic cells, GLUT5 mediates fructose uptake from the circulatory system. Phosphorylation by tissue-specific kinases converts cytosolic glucose to glucosephosphate G6P. The negative charge on G6P prevents it from crossing the cell membrane.

Glucokinase, which has a low affinity for glucose and is not inhibited by G6P, catalyzes this reaction in hepatocytes. When blood glucose concentrations are high, hepatocytes may accumulate G6P to buffer glucose concentrations. Glucosephosphatase allows G6P from gluconeogenesis and glycogen breakdown to exit liver and kidney cells.

Hexokinase isoforms, which have a high affinity for glucose and are feedback inhibited by G6P, catalyze the reaction of glucose to G6P in other body tissues.

glut 2 bidirectional relationship

Those tissues can take up glucose during times when blood glucose concentrations are low. However, they are not able to accumulate high levels of G6P. The absence of glucosephosphatase makes glucose uptake irreversible in those tissues [ 1314 ].

[Full text] Structure of, and functional insight into the GLUT family of membrane | CHC

The encoded protein is located primarily along the cell surface and in the cell membrane. GLUT1 may be responsible for constitutive or basal glucose uptake in cells and can transport a wide range of aldoses, including pentose and hexose [ 1617 ].

Gene mutations associated with GLUT1 deficiency in humans have been linked to microcephaly and childhood epilepsy [ 1819 ], hypoglycorrhachia [ 2021 ], cryohydrocytosis with reduced stomatin [ 22 ], paroxysmal dystonic choreathetosis [ 23 ], episodic ataxia [ 22 ], hemiplegic migraines [ 2425 ], spasticity and paroxysmal exertion-induced dyskinesia [ 26 ].

glut 2 bidirectional relationship

Overexpression of GLUT1 was shown to be an indicator for cancer [ 27 ] and to have an association with thymic carcinoma [ 28 ]. Chicken GLUT1 has ubiquitous expression, with abundant expression in the hypothalamus, and has demonstrated response to insulin and dexamethasone [ 31 ]. The encoded protein regulates bidirectional glucose transport across liver cells, pancreatic islet beta cells that store and release insulin, epithelial kidney cells and intestines. Similar to mammalian species, chickens have abundant GLUT2 expression in the liver [ 33 ], pancreatic beta cells, kidney and small intestine [ 34 ].

glut 2 bidirectional relationship

Due to its low affinity for glucose, GLUT2 may be a glucose sensor. Alternative gene splicing results in multiple transcript variants. Mammalian GLUT3 facilitates the uptake of glucose, 2-deoxyglucose, galactose, mannose, xylose, fucose and other monosaccharides across the cell membrane. GLUT3 does not mediate fructose transport [ 3638 ]. It is well known that GLUT4 is the major insulin sensitive glucose transporter in mammals.

The mechanism by which insulin regulates GLUT4 activity has been well studied. This constitutes the major portion of insulin-stimulated glucose uptake, especially in adipose tissue, skeletal muscle and cardiac muscle tissues.

Humans and most mammals rely on normal protein expression of GLUT4 for blood glucose homeostasis [ 41 ]. More important, this study proposed that the 12 TM topology of MFS may have arisen by two gene duplication events through an initial triple-helix bundle into the six-helix bundle, then into two linked pseudo symmetrical six-helix bundles. Consequently, it allowed the construction of a low resolution crystal structure of GLUT9. The structure revealed a transport cavity, which contains the plausible urate binding sites.

Avian and Mammalian Facilitative Glucose Transporters

These included amino acids: Finally, almost four decades after the first purified GLUT, a high resolution 3. The purified protein was generated using a baculovirus transfection system with High Five insect cells.

One additional feature was the presence of a helical bundle, an intracellualr coiled heical, ICH, domain, within the long intracellular loop. In addition, only a single sugar binding site was identified, located toward the C-domain of the transporter, which substrate could access from either side of the protein.

The N-domain of the structure is believed to play a role in regulation of the conformational change during transport. Note added in proof: TM7 forms an extracellular gate in the inward facing conformation of GLUT1, 84 and three of the potential binding residues were observed within the substrate-bound crystal structure.

However, only Q and Q were shown to be facing the aqueous environment, but not N Additional functional studies confirmed that replacement of I in GLUT9 with valine resulted in a loss of trans-stimulation between fructose and urate. It has been hypothesized that I in GLUT9 affects the rigid body movement of one of the two six-helix bundles, and subsequently the orientation of helix 7 TM7 in the translocation pore of the transporter.

B and C Views from the intracellular face and extracellular face. D Potential interactions of I indicate a hydrophobic network with residues within TM G Structural model of the mutant SLC2A5 IV, highlighting loss of the hydrophobic network, which subsequently leads to alteration in substrate specificity. Critical roles of two hydrophobic residues within human glucose transporter 9 hSLC2A9 in substrate selectivity and urate transport.

Initial explanations of how glucose is transported across the cell membrane were based on mathematical analysis of the transport activities of hexose utilizing erythrocyte preparations. The fluxes were best fit with the Michaelis—Menten enzyme kinetics model 89 — 90 which predicts that the rate of hexose absorption depends on both the initial hexose concentrations and the binding affinity of the protein for the substrate and that there is a maximum rate of transfer rate of transfer is saturable.

Moreover, Widdas postulated that both phosphorylation and metabolism of glucose were the two possible mechanisms providing the necessary energy for glucose transfer. However, due to the complexities of the erythrocyte system, differences between experimental methods and variations in kinetic data, many other models have been proposed over the same time period. Today there are two popular models still under consideration.

In another words, this model suggests that GLUT1 can work as an antiporter. However, human GLUTs all except GLUT13 were thought to be uniporters, in which they transport one hexose molecule at a time in a unidirectional approach, whereas an antiporter or exchanger will simultaneously transport two molecules in opposite directions.

glut 2 bidirectional relationship

It is argued that this two-site model can explain the complex asymmetry and multiphasic transport kinetics, while the simple carrier model cannot sufficiently account for these incidences without violating the energy conservation law.

In both dimers and tetramers of GLUT1, cis-allosteric hexose transport was observed, ie, hexose binding to one oligomer subunit induces the transport by other subunit s. Therefore, the GLUT1 dimers are able to transport cis- hexose in exchange with the trans side substrate, which is similar to the two-state model assumption; the tetramer GLUT1 cooperative transporter could also further explain the observed multiphasic transport.

Another proposed mechanism is the alternating access model, and this appears to be supported by the available MFS crystal structures. The newly crystallized GLUT1 also fits with the alternating access mechanism, 84 which predicts four conformational states during a complete hexose transport cycle: These four states appear as a slightly more detailed version of the original simple carrier theory that Widdas proposed in The recently reported GLUT3 crystal structure shows strong evidence to support the alternating access mechanism with a bound D-glucose in an outward-occluded conformation.

This was first observed in erythrocytes as uphill hexose counterflow other terms include countertransport acceleration and trans-stimulation transport. Rosenberg and Wilbrandt argued that the phenomenon was due to two different transport systems present in the red cell, which Naftalin and Holman referred to as a two binding site carrier.

It is the empty carrier return from the trans side to the cis side of the membrane that limits the rate of transport. Therefore, trans-acceleration occurs when hexose is presented on the trans side, which allows the carrier to return faster to the cis side with a bound substrate.

One study indicated that the ATP-binding site of GLUT1 contains residues that are necessary for glucose trans-acceleration to occur and proposed that mutations in the ATP-binding sites would alter the tertiary structure of GLUT1, and thus restrict the flexibility of the transporter for sensing substrates on both sides of the membrane. Hence, this study was not able to distinguish between the simple carrier model or the two-site model to explain trans-acceleration.

GLUT2 and GLUT4 do not show trans-acceleration of hexose transport; instead, they show symmetrical transport in both oocyte and mammalian cell systems. Insulin promotes their surface expression, but the regulatory mechanisms are thought to be different for the two proteins. Trafficking of GLUT1 from an intracellular pool to the plasma membrane is also increased by AMP kinase in murine brain microvasculature endothelium bEnd.

Cushman and Wardzala proposed the first schematic mechanism of how insulin stimulates GLUT translocation to and from the membrane in the rat adipose cell in Subsequently, numerous potential pathways involved in the insulin-dependent pathway have been identified.

Structure of, and functional insight into the GLUT family of membrane transporters

Muscle contraction activates several signaling messengers, including calcium, nitric oxide, and reactive oxygen species within the muscle cells themselves, that regulate glucose homeostasis endogenously. It has been proposed that this transporter provides a high capacity entry pathway for glucose and fructose at the start of a meal when the luminal concentrations are high, and is then withdrawn as the meal progresses, leaving SGLT1 to bring in the remaining hexose upward into the cells.

Another theory is that apical GLUT2 provides a shunt, moving glucose back out into the lumen and providing an osmotic control during the absorptive process. GLUT8 expression levels at the plasma membrane are controlled by glucose and insulin, and a t-SNARE protein, syntaxin 4, which has also been found in blastocyts to be necessary for the fusion of GLUT8 carrying vesicles with the plasma membrane.

Glucose transporter 2 (GLUT-2) mnemonic

In most situations, such mutations would be lethal for the embryo and development could not occur. However, it is now becoming appreciated that there are a number of disease states in which the expression patterns of hexose transporters are altered, providing an opportunity for diagnosis or even treatment. Therefore, this section covers the few documented GLUT-specific genetic diseases and then looks at recent advances in diagnosis and treatment.

The types of mutation are numerous and could affect functional activity of the protein directly, its ability to form dimers or tetramers, or its trafficking to the plasma membrane. Fanconi—Bickel syndrome This is an extremely rare glycogen storage disease, for which a little over affected patients have been reported worldwide, the first described in Patients also suffer from poor regulation of blood glucose and galactose levels, which after a meal, rise rapidly and are maintained for some time.

This condition could result from both the inability of the liver to take up hexoses and store them as glycogen and also probably from impaired insulin release by pancreatic beta cells as GLUT2 forms part of the normal blood glucose-sensing mechanism.

The lack of renal reabsorption of glucose would further exacerbate the situation, leading to hypoglycemia.