Glucose transporter type 4 (GLUT4), is a protein encoded by the SLC2A4 gene. 

GLUT4 is the major insulin regulated glucose transporter.

GLUT4 is the insulin-regulated glucose transporter found primarily in adipose tissues and striated muscle (skeletal and cardiac). 

GLUT4, short for Glucose Transporter 4, is a protein that plays a crucial role in glucose metabolism.

GLUT4 is responsible for transporting glucose from the bloodstream into these cells, where it can be used as a source of energy or stored as glycogen.

The regulation of GLUT4 is essential for maintaining proper blood glucose levels and insulin sensitivity.

When blood glucose levels are elevated, such as after a meal, the pancreas releases insulin into the bloodstream.

Insulin binds to receptors on the surface of adipose tissue and muscle cells, triggering a signaling cascade that leads to the translocation of GLUT4 from intracellular vesicles to the cell membrane.

Once on the cell membrane, GLUT4 acts as a transporter protein, facilitating the transport of glucose across the cell membrane into the cytoplasm.

This process is crucial because glucose cannot freely diffuse across the cell membrane due to its hydrophilic nature.

By increasing the number of GLUT4 transporters on the cell membrane, insulin promotes glucose uptake into adipose tissue and skeletal muscle, helping to lower blood glucose levels.

Impairments in GLUT4 translocation or function can contribute to insulin resistance, a condition in which cells become less responsive to insulin.

Insulin resistance is associated with various metabolic disorders, including type 2 diabetes and obesity.

In these conditions, the normal insulin-mediated translocation of GLUT4 to the cell membrane is disrupted, leading to reduced glucose uptake by cells and elevated blood glucose levels.

Medications such as metformin, thiazolidinediones, and insulin sensitizers aim to improve GLUT4 translocation and function, enhancing glucose uptake by cells and improving insulin sensitivity.

At the cell surface, GLUT4 permits the facilitated diffusion of circulating glucose down its concentration gradient into muscle and fat cells. 

Once within cells, glucose is rapidly phosphorylated by glucokinase in the liver and hexokinase in other tissues to form glucose-6-phosphate, which then enters glycolysis or is polymerized into glycogen. 

Glucose-6-phosphate cannot diffuse back out of cells, and serves to maintain the concentration gradient for glucose to passively enter cells.

GLUT4 also is a ubiquitin-regulatory regions that can assist with cell signaling.

Its unique amino acid arrangement in the primary sequence of GLUT4 allows it to transport glucose across the plasma membrane. 

There are 14 total GLUT proteins separated into 3 classes, based on sequence differences.

In obesity and type two diabetes, GLUT4 levels are down regulated in adipose tissue, but are normal in muscle.

Decreased GLUT4 levels correlate are highly correlated with insulin sensitivity and decreased glucose uptake in adipocytes could contribute to the development of diabetes.

Decreased adipose tissue GLUT4 levels are an early predictor of type two diabetes.

As muscles contract, they use ATP. 

The energy required  to make ATP comes from different pathways—such as glycolysis or oxidative phosphorylation, that ultimately use glucose as a starting material.

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 converts 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. 

Muscle cells are able to take in more glucose as its intracellular concentrations decrease. 

To allow increased glucose levels in the cell, GLUT4 is the primary transporter used in this facilitated diffusion.

Transferrin-positive GLUT4 vesicles are utilized during muscle contraction while the transferrin-negative vesicles are activated by insulin stimulation as well as by exercise.

Cardiac muscle at rest utilize fatty acids as their main energy source. 

As activity increases and it begins to pump faster, the cardiac muscles begin to oxidize glucose at a higher rate.

GLUT1 plays a larger role in cardiac muscles than it does in skeletal muscles.

GLUT4, however, is still believed to be the primary transporter for glucose.

GLUT4 responds to insulin signaling, and is transported into the plasma membrane to facilitate the diffusion of glucose into the cell. 

As the body takes in energy in the form of glucose, some is expended, and the rest is stored as glycogen, primarily in the liver, muscle cells, or as triglyceride in adipose tissue.

An imbalance in glucose intake and energy expenditure has been shown to lead to both adipose cell hypertrophy and hyperplasia, which lead to obesity.

Mutations in GLUT4 genes in adipocytes can also lead to increased GLUT4 expression in adipose cells, which allows for increased glucose uptake and therefore more fat stored. 

The overexpression of GLUT4 leading to increased adipose tissue mass.

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., and 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.

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.

With low insulin levels, most GLUT4 is sequestered in intracellular vesicles in muscle and fat cells. 

As the vesicles fuse with the plasma membrane, GLUT4 transporters are inserted and become available for transporting glucose, and glucose absorption increases. 

The insulin signal transduction pathway begins when insulin binds to the insulin receptor proteins, then the GLUT-4 storage vesicles becomes one with the cellular membrane, allowing glucose to be transported into the cell.

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. 

Muscle contraction stimulates muscle cells to translocate GLUT4 receptors to their surfaces, especially true in cardiac muscle, where continuous contraction increases the rate of GLUT4 translocation; but is observed to a lesser extent in increased skeletal muscle contraction.[

The GLUT4 gene is present in the central nervous system such as the hippocampus. 

Impairment in insulin-stimulated trafficking of GLUT4 in the hippocampus result in decreased metabolic activities and plasticity of hippocampal neurons, which leads to depressive like behavior and cognitive dysfunction.

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