What is GLUT4?
GLUT4 is the insulin -regulated glucose transporter found primarily in adipose tissues and striated muscle (skeletal and cardiac). The first evidence for this distinct glucose transport protein was provided by David James in 1988.
What is the biology of glucose transporter protein GLUT4?
The principal glucose transporter protein that mediates this uptake is GLUT4, which plays a key role in regulating whole body glucose homeostasis. This review focuses on recent advances on the biology of GLUT4.
What is the function of GLUT4 storage vesicles?
In the presence of insulin or exercise, GLUT4 storage vesicles undergo exocytosis to the plasma membrane, as well as the sarcolemma and T-tubules of skeletal muscle cells, where it can carry out its function on glucose transport.
What stimulates GLUT4 translocation?
In skeletal muscle, muscle contractions increase GLUT4 translocation several fold, and this is likely regulated by RAC1 and AMP-activated protein kinase. Muscle stretching also stimulates GLUT4 translocation and glucose uptake in rodent muscle via RAC1.
How does GLUT4 affect glucose?
Glucose is an important fuel for contracting muscle, and normal glucose metabolism is vital for health. Glucose enters the muscle cell via facilitated diffusion through the GLUT4 glucose transporter which translocates from intracellular storage depots to the plasma membrane and T-tubules upon muscle contraction.
What does GLUT4 do without insulin?
In the absence of insulin, Glut4 slowly recycles between the plasma membrane and vesicular compartments within the cell, where most of the Glut4 resides.
What does the glut transporter do?
Glucose transporter (GLUT) is a facilitative transport protein involved in glucose translocation across the cell membrane.
Does GLUT4 increase glucose?
B. The increase in muscle glucose transport during exercise is primarily due to translocation of GLUT4 from intracellular sites to the sarcolemma and T-tubules, although it is possible that changes in intrinsic activity may also occur.
Why is regulation of GLUT4 needed?
GLUT4 plays an important role in the adaptation of skeletal muscle to increased metabolic demand during periods of prolonged muscle contraction. It is this latter function that may explain the mechanism by which exercise promotes insulin sensitivity in healthy, insulin-resistant people.
How is GLUT4 regulated by insulin?
Insulin stimulates glucose transport by promoting translocation of the insulin-sensitive glucose transporter isoform 4 (GLUT4) from an intracellular compartment to the cell surface. This movement is accomplished by stimulation of GLUT4 exocytosis as well as inhibition of endocytosis.
Is GLUT4 active or passive transport?
passiveNo, GLUT4 is a passive transporter of glucose down the concentration gradient. It is a glucose transporter present in the adipose tissues, skeletal and cardiac muscles.
What is GLUT2 and GLUT4?
GLUT1 is the major glucose transporter in brain, placenta and erythrocytes, GLUT2 is found in the pancreas, liver and kidneys, GLUT3 is neuronal and placental, while GLUT4 is the insulin-responsive transporter found in skeletal muscle, heart and adipose tissue.
What transport transports glucose into the cell?
facilitated diffusionBoth diffusion and facilitated diffusion are driven by the potential energy differences of a concentration gradient. Glucose enters most cells by facilitated diffusion.
How is GLUT4 activated?
The first response involves the recruitment of GLUT4 transporters from intracellular reserves and their subsequent insertion into the plasma membrane. The second pathway results in an increase in the intrinsic activity of the transporters.
What is the role of insulin and the GLUT4 transporter in glycolysis in skeletal muscle?
The major cellular mechanism for disposal of an exogenous glucose load is insulin-stimulated glucose transport into skeletal muscle. Skeletal muscle both stores glucose as glycogen and oxidizes it to produce energy following the transport step.
What is GLUT4 expression?
GLUT4 is expressed in adipocytes, where insulin stimulates its translocation from intracellular locations to the cell membrane, which leads to increase of glucose uptake[88]. High expression levels of GLUT4 in adipose tissue can enhance insulin sensitivity and glucose tolerance[89].
What happens to glucose without insulin?
Without enough insulin, glucose builds up in the bloodstream instead of going into the cells. This buildup of glucose in the blood is called hyperglycemia. The body is unable to use the glucose for energy. This leads to the symptoms of type 1 diabetes.
Can cells use glucose without insulin?
Glucose is the main energy source used by cells. Insulin allows cells in the muscles, liver and fat (adipose tissue) to take up this glucose and use it as a source of energy so they can function properly. Without insulin, cells are unable to use glucose as fuel and they will start malfunctioning.
Which cells can uptake glucose without insulin?
It should be noted here that there are some tissues that do not require insulin for efficient uptake of glucose: important examples are brain and the liver. This is because these cells don't use GLUT4 for importing glucose, but rather, another transporter that is not insulin-dependent. 2.
Do you not need insulin for glucose uptake?
Brain and liver cells do not require insulin for glucose uptake.
Introduction
Among the numerous homeostatic events maintained by the human body, the blood glucose level is a significant physiologic aspect under persistent tight regulation. Glucose is an essential energy source that requires careful regulation within the body as both too much or too little glucose can cause detrimental effects.
Cellular
GLUT4 is part of a family of glucose transporter proteins containing 12-transmembrane domains. It is expressed primarily in skeletal muscle and adipose tissue. Unique N-terminal and COOH-terminal sequences are responsible for GLUT4’s responsiveness to insulin signaling and membrane trafficking.
Function
GLUT4 exists in skeletal muscle cells, adipocytes, and cardiomyocytes. It is principally responsible for insulin-stimulated glucose uptake into muscle and adipose cells. Approximately 80% of glucose gets transported into muscle cells.
Mechanism
Insulin-regulated GLUT4 translocation can occur by two signaling pathways. One pathway involves lipid kinase phosphatidylinositol 3-kinase (PI3K). Insulin binds to the insulin receptor found on the target cell surface, causing the receptor to undergo a conformational change which activates its tyrosine-kinase domain intracellularly.
Clinical Significance
Type 2 diabetes mellitus (T2DM) has increased dramatically over the years and continues to do so at an alarming rate. It is a disease characterized by insulin resistance, meaning the insulin produced by the body is not enough to meet the glucose transport demands, leading to an elevated amount of glucose remaining in the body’s circulating plasma.
What is the mechanism of GLUT4?
The mechanism for GLUT4 is an example of a cascade effect, where binding of a ligand to a membrane receptor amplifies the signal and causes a cellular response. In this case, insulin binds to the insulin receptor in its dimeric form and activates the receptor's tyrosine-kinase domain.
What is the GLUT4 gene?
GLUT4. Glucose transporter type 4 ( GLUT-4 ), also known as solute carrier family 2, facilitated glucose transporter member 4, is a protein encoded, in humans, by the SLC2A4 gene. GLUT4 is the insulin -regulated glucose transporter found primarily in adipose tissues and striated muscle (skeletal and cardiac).
What is the primary transporter of glucose?
GLUT4, however, is still believed to be the primary transporter for glucose. Much like in other tissues, GLUT4 also responds to insulin signaling, and is transported into the plasma membrane to facilitate the diffusion of glucose into the cell.
What is a GLUT4 carrier?
The GLUT4 carrier vesicles are either transferrin positive or negative, and are recruited by different stimuli. Transferrin-positive GLUT4 vesicles are utilized during muscle contraction while the transferrin-negative vesicles are activated by insulin stimulation as well as by exercise.
What is the UBX domain of GLUT4?
Structure. GLUT4 also contains a UBX-domain. These are ubiquitin -regulatory regions that can assist with cell signaling. Like all proteins, the unique amino acid arrangement in the primary sequence of GLUT4 is what allows it to transport glucose across the plasma membrane.
Why does GLUT4 increase in skeletal muscle cells?
In striated skeletal muscle cells, GLUT4 concentration in the plasma membrane can increase as a result of either exercise or muscle contraction. During exercise, the body needs to convert glucose to ATP to be used as energy.
Where is GLUT4 stored?
Increased insulin levels cause the uptake of glucose into the cells. GLUT4 is stored in the cell in transport vesicles, and is quickly incorporated into the plasma membrane of the cell when insulin binds to membrane receptors. Under conditions of low insulin, most GLUT4 is sequestered in intracellular vesicles in muscle and fat cells.
GLUT4: What is it and how does it help me to lose weight?
Once again, weight loss is at the top of the public health agenda, with a recent Victorian State Government campaign featuring graphic images of “toxic fat”. The rise and rise of obesity in Australia has contributed to exponential increases in health costs which are unsustainable in the long term.
EXCESS SUGAR AND CALORIES
Sugar has been heavily added to our foods over the past decade and is a major contributing factor to the rapid increase of diabetes and obesity in our population. Sugar can be easily over-consumed due to its low satiety value (how full a food makes you feel), which ultimately means an excess consumption of calories.
GLUCOSE TRANSPORTER 4 (GLUT4)
Glucose Transporter 4, or GLUT4, is a naturally-occurring protein in your body that can do amazing things with the excess sugar and calories in your body. To expend calories, and in this specific example, sugar, you need three biological processes to happen:
EXERCISE IMPROVES GLUCOSE TRANSPORT
What sort of exercise will give you the most GLUT4 activity? Resistance training! That is, using and moving loads or weights. Research has found that resistance training improves insulin-mediated glucose transport, and increases GLUT4 activity through muscular contraction ( Holten et al., 2004; Dela & Kjaer, 2006; Ivy, 1997 ).
What is the function of Glut4?
GLUT4 is one of 13 sugar transporter proteins (GLUT1- GLUT12, and HMIT) encoded in the human genome that catalyzes hexose transport across cell membranes through an ATP-independent, facilitative diffusion mechanism. GLUT4 is highly espresse in adipose tissue and skeletal muscle.
What are the structural features of GLUT4?
Figure 1. Structural Features of the Insulin-Regulated GLUT4 Glucose Transporter Protein The unique sensitivity of GLUT4 to insulin-mediated translocation appears to derive from sequences shown in the N-terminal (required phenylalanine) and COOH-terminal (required dileucine and acidic residues) regions. These sequences are likely involved in rapid internalization and sorting of GLUT4 in intracellular membranes termed GLUT4 storage vesicles (GSV), as outlined in Figure 3. See text for further details. GLUT4 Is a Key Determinant of Glucose Homeostasis A central role for GLUT4 in whole-body metabolism is strongly supported by a variety of genetically engineered mouse models where expression of the transporter is either enhanced or ablated in muscle or adipose tissue or both. The whole-body GLUT4−/− mouse itself may be less informative due to upregulation of compensatory mechanisms that may promote survival of these animals (Katz et al., 1995; Stenbit et al., 1996). However, heterozygous GLUT4+/− mice that display decreased GLUT4 protein in muscle and adipose tissue show the expected insulin resistance and propensity toward diabetes that is consistent with a major role of GLUT4 in glucose disposal (Rossetti et al., 1997; Stenbit et al., 1997; Li et al., 2000). Interestingly, overexpression of GLUT4 expression in skeletal muscle of such GLUT4+/− animals through crosses with transgenic mice normalizes insulin sensitivity and glucose tolerance (Tsao et al., 1999). Transgenic mice expressing high levels of GLUT4 in adipose tissue (Shepherd et al., 1993; Tozzo et al., 1995) or in skeletal muscle (Tsao et al., 1996, 2001) in turn are both highly insulin sensitive and glucose tolerant. Conversely, conditional depletion of GLUT4 in either adipose tissue or skeletal muscle c Continue reading >>
What is the role of glucose transporter 4?
The glucose transporter 4 (GLUT4) is responsible for glucose uptake in the skeletal muscle. Insulin-induced translocation of GLUT4 to the plasma membrane requires phosphatidylinositol 3-kinase activation-mediated generation of phosphatidylinositol 3,4,5-trisphosphate PIP3 and subsequent activation of Akt.
Where is Glut4 found?
GLUT4 is the insulin-regulated glucose transporter found primarily in adipose tissues and striated muscle (skeletal and cardiac).
What is the function of glycoproteins in the blood?
These 50- to 60-kDa glycoproteins are ubiquitously expressed in mammalian tissues and are responsible for the uptake of sugar from the blood into cells, supplying cellular glucose for ATP production and for a wide variety of anabolic reactions.
What is the human tau40 cDNA construct?
Human Tau40 cDNA construct was kindly provided by Dr. Mandelkow ( 22 , 23 ). Rabbit polyclonal anti-GLUT4 antibody was raised against the C-terminal 12 amino acids. Rabbit polyclonal anti-Tau antibody and anti-tubulin were from Sigma. Goat polyclonal anti-GLUT4 was from Santa Cruz Biotechnology (Santa Cruz, CA). The rhodamine-conjugated or fluorescein isothiocyanate (FITC)1-conjugated goat anti-mouse rabbit antibodies were from BioSource International (Camarillo, CA). Cy3- and Cy5-conjugated donkey anti-mouse and rabbit IgG were from Jackson Immuno Research (West Grove, PA). Rhodamine-conjugated phalloidin was purchased from Molecular Probes, Inc. (Eugene, OR). Nocodazole and colchicine were purchased from Sigma, and latrunculin B was obtained from Calbiochem and dissolved in Me2SO. Recombinant adenovirus encoding the hTau40 was constructed after the method described in He et al. ( 24 ). hTau40 cDNA was cloned into the BglII-XbaI site of pAdTrack-CMV shuttle vector. This vector was linearized with PmeI and was electroporated into electrocompetent BJ5183 cells having the pAdEasy-1 plasmid to generate recombinant adenovirus. After the recombinant plasmid was amplified, DNA was digested with PacI. This adenovirus was transfected into 293 cells and monitored with green fluorescent protein expression. After the virus amplification, cell lysate was stored at 80 C. For the adenovirus infection, 3T3-L1 adipocytes were grown and differentiated on coverslips in 6-well plates and then infected at a multiplicity of infection of 50 with either a control virus expressing green fluorescent protein only or the recombinant adenovirus encoding hTau40 adenovirus. On the next day, cells were serum-starved overnight in Dulbecco's modified Eagle's medium (DMEM) with 0.5% bovine serum albumi Continue reading >>
When insulin levels rise during the postprandial period, fat and muscle tissue become the major sites of glucose metabolism and
Conversely, when the insulin level rises during the postprandial period in response to ingested carbohydrates, fat and muscle tissue become the major sites of glucose metabolism and storage . The appropriate output or uptake of glucose from these tissues via the Glut proteins is critical to health and survival.
What is the role of glucose in muscle?
Exercise, GLUT4, and skeletal muscle glucose uptake. Glucose is an important fuel for contracting muscle, and normal glucose metabolism is vital for health. Glucose enters the muscle cell via facilitated diffusion through the GLUT4 glucose transporter which translocates from intracellular storage depots to the plasma membrane ...
How does glucose enter the muscle cell?
Glucose enters the muscle cell via facilitated diffusion through the GLUT4 glucose transporter which translocates from intracellular storage depots to the plasma membrane and T-tubules upon muscle contraction.
Overview
Glucose transporter type 4 (GLUT4), also known as solute carrier family 2, facilitated glucose transporter member 4, is a protein encoded, in humans, by the SLC2A4 gene. GLUT4 is the insulin-regulated glucose transporter found primarily in adipose tissues and striated muscle (skeletal and cardiac). The first evidence for this distinct glucose transport protein was provided by David James in 1988. The gene that encodes GLUT4 was cloned and mapped in 1989.
Structure
Like all proteins, the unique amino acid arrangement in the primary sequence of GLUT4 is what allows it to transport glucose across the plasma membrane. In addition to the phenylalanine on the N-terminus, two Leucine residues and acidic motifs on the COOH-terminus are believed to play a key role in the kinetics of endocytosis and exocytosis.
Tissue distribution
In striated skeletal muscle cells, GLUT4 concentration in the plasma membrane can increase as a result of either exercise or muscle contraction.
During exercise, the body needs to convert glucose to ATP to be used as energy. As G-6-P concentrations decrease, hexokinase becomes less inhibited, and the glycolytic and oxidative pathways that make ATP are able to proceed. This als…
Regulation
Insulin is released from the pancreas and into the bloodstream in response to increased glucose concentration in the blood. Insulin is stored in beta cells in the pancreas. When glucose in the blood binds to glucose receptors on the beta cell membrane, a signal cascade is initiated inside the cell that results in insulin stored in vesicles in these cells being released into the blood stream. Increase…
Interactions
GLUT4 has been shown to interact with death-associated protein 6, also known as Daxx. Daxx, which is used to regulate apoptosis, has been shown to associate with GLUT4 in the cytoplasm. UBX-domains, such as the one found in GLUT4, have been shown to associate with apoptotic signaling. So this interaction aids in the translocation of Daxx within the cell.
In addition, recent reports demonstrated the presence of GLUT4 gene in central nervous system …
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.
External links
• GLUT4+Protein at the US National Library of Medicine Medical Subject Headings (MeSH)
• USCD—Nature molecule pages: The signaling pathway", "GLUT4"; contains a high-resolution network map. Accessed 25 December 2009.