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Skeletal muscle is the principal tissue for insulin-stimulated glucose disposal, and it plays a key role in post-prandial glucose regulation. After ingestion, about 80% of glucose is taken up by skeletal muscle via insulin-dependent glucose uptake. Insulin-dependent and -independent skeletal muscle glucose disposal requires glucose delivery to the muscle from circulation, glucose traversing the extracellular matrix to the cell membrane, uptake via facilitative glucose transporters, and a glucose gradient to facilitate glucose transport modulated by intracellular glucose metabolism. The glucose transporter GLUT4 plays a crucial role in skeletal muscle glucose uptake, and its translocation to the plasma membrane is stimulated by insulin or exercise. Exercise intensity and duration also influence skeletal muscle glucose uptake, with dynamic exercise resulting in a substantial increase in glucose uptake.
| Characteristics | Values |
|---|---|
| Role | Principal tissue for insulin-stimulated glucose disposal, primary driver of whole-body glycemic control, and insulin-stimulated glucose uptake |
| Glucose Uptake | Insulin-dependent and insulin-independent |
| Insulin-Dependent Glucose Transporters | GLUT 1, 3, 4, 5, 8, 10, 11, and 12 |
| Insulin-Independent Glucose Transporters | GLUT 1, 3, 4, 5, 8, 10, 11, and 12 |
| Glucose Fate | Metabolized or stored as glycogen |
| GLUT4 | Increased by 20-70% with aerobic exercise training |
| Exercise | Increases skeletal muscle glucose uptake, improves glycemic control, and reduces blood glucose concentrations |
| STX4 | Associated with GLUT4 vesicle docking |
| DOC2B | Regulates glucose-stimulated insulin secretion in pancreatic β-cells and insulin-stimulated glucose uptake in skeletal muscle |
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What You'll Learn
Glucose uptake in skeletal muscle during exercise
Glucose is an important fuel for contracting muscles, and normal glucose metabolism is vital for health. Glucose enters the muscle cell via facilitated diffusion through the GLUT4 glucose transporter. GLUT4 is an intracellular protein that depends on stimulus (insulin or exercise) to translocate to the plasma membrane and facilitate glucose uptake.
During exercise, the turnover of ATP in skeletal muscle increases greatly and is fuelled by the catabolism of carbohydrates (intramuscular glycogen, blood glucose) and fatty acids (intramuscular triglycerides, blood lipids). The contribution of blood glucose to ATP resynthesis is initially relatively minor, but as exercise continues and muscle glycogen stores are depleted, the contribution of blood glucose becomes more substantial. The most influential factor for the magnitude of increase in muscle glucose uptake during exercise is likely exercise intensity, with skeletal muscle glucose uptake being greater at higher exercise intensities. This is probably due to a combination of greater fiber recruitment and higher metabolic stress on active muscle fibers at higher exercise intensities.
The increase in skeletal muscle glucose uptake during exercise results from a coordinated increase in rates of glucose delivery (higher capillary perfusion), surface membrane glucose transport, and intracellular substrate flux through glycolysis. There are three sites of regulation of skeletal muscle glucose uptake in vivo: glucose delivery to the skeletal muscle cells, surface membrane permeability to glucose (i.e., glucose transport), and flux through intracellular metabolism. The higher glucose transport with exercise mainly occurs due to higher amounts of glucose transport protein GLUT4 in surface membranes, more specifically the sarcolemma and transverse tubules (T-tubules).
The mechanism behind the movement of GLUT4 to surface membranes and the subsequent increase in transport by muscle contractions is largely unresolved, but it is likely to occur through intracellular signaling involving Ca2+-calmodulin-dependent protein kinase, 5′-AMP-activated protein kinase, and possibly protein kinase C. In addition to insulin stimulation, glucose uptake into skeletal muscle is increased by contraction during exercise. Both stimuli lead to the redistribution of the facilitative GLUT4 from intracellular storage vesicles to the cell surface, resulting in increased glucose clearance from the bloodstream. The process of contraction-mediated GLUT4 translocation is tightly regulated and, as of 2021, not fully understood. A major mechanism linking muscle contraction to GLUT4 translocation involves the activation of the serine/threonine protein kinase AMPK by AMP.
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Insulin-stimulated glucose disposal
Skeletal muscle is the largest tissue in the human body and is considered the primary target for insulin-stimulated glucose disposal. Insulin-stimulated glucose disposal is commonly used as an assessment of insulin-stimulated muscle glucose uptake. However, it does not provide a direct measure of insulin sensitivity in skeletal muscles. Insulin-stimulated whole-body glucose disposal is highly dependent on muscle fibre type composition and perfusion.
The increase in skeletal muscle glucose uptake during exercise is due to increased glucose delivery, surface membrane glucose transport, and intracellular substrate flux through glycolysis. The mechanism behind GLUT4's movement to surface membranes during exercise is largely unknown, but it likely involves intracellular signaling molecules such as Ca2+-calmodulin-dependent protein kinase, 5′-AMP-activated protein kinase, and protein kinase C. During exercise, skeletal muscle glucose uptake increases, depending on exercise intensity and duration. Regular exercise improves glycemic control and can reduce blood glucose concentrations in individuals with type II diabetes.
Exercise training has been shown to increase insulin-stimulated glucose disposal, particularly when combined with weight loss. This effect is maximized with aerobic exercise and is independent of hepatic glucose production. Exercise ameliorates insulin resistance via Ca2+ signals distinct from those of insulin for GLUT4 translocation in skeletal muscles. The protein DOC2B, expressed in skeletal muscle, regulates insulin-stimulated glucose uptake and promotes insulin secretion and peripheral insulin sensitivity.
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Insulin-dependent and -independent glucose transporters
Glucose is a primary energy source for most cells and is an important substrate for many biochemical reactions. Glucose transporters, therefore, play an important role in the body. Glucose transporters are a wide group of membrane proteins that facilitate the transport of glucose across the plasma membrane, a process known as facilitated diffusion.
The GLUT or SLC2A family are a protein family that is found in most mammalian cells. 14 GLUTS are encoded by the human genome. GLUT is a type of uniporter transporter protein. Most non-autotrophic cells are unable to produce free glucose because they lack expression of glucose-6-phosphatase and, thus, are involved only in glucose uptake and catabolism.
GLUT4 is an insulin-regulated glucose transporter found primarily in adipose tissues and striated muscle (skeletal and cardiac). It is encoded by the SLC2A4 gene. GLUT4 is distinctive because it is predominantly stored within intracellular vesicles, highlighting the importance of its trafficking and regulation as a central area of research. The first evidence for this glucose transport protein was provided by David James in 1988. The gene that encodes GLUT4 was cloned and mapped in 1989. 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. GLUT4 is transported into the plasma membrane to facilitate the diffusion of glucose into the cell.
GLUT6 and GLUT8 are insulin-independent glucose transporters. They are made of motifs that help retain them intracellularly and therefore prevent glucose transport. Insulin does not promote GLUT6 and GLUT8 cell-surface translocation.
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Intracellular glucose metabolism
Skeletal muscle is the largest organ in the body by mass and is the regulator of glucose homeostasis. It is responsible for 80% of postprandial glucose uptake from the circulation. Skeletal muscle is essential for metabolism, both for its role in glucose uptake and its importance in exercise and metabolic disease.
Glucose uptake by skeletal muscle involves three steps: glucose delivery to the skeletal muscle cells, surface membrane permeability to glucose (i.e. glucose transport), and flux through intracellular metabolism. Once glucose enters the muscle, it is trapped via phosphorylation to glucose-6-phosphate. The fate of this intracellular glucose is to either be metabolized or stored as glycogen.
There are three GLUTs responsible for mediating glucose uptake in skeletal muscle: GLUT4, GLUT1, and GLUT3 (expressed in fetal and neonatal muscle only). GLUT4 is the most highly expressed glucose transport protein in skeletal muscle. It is an intracellular protein that depends on a stimulus (insulin or exercise) to translocate to the plasma membrane and facilitate glucose uptake. Insulin-stimulated glucose uptake is rate-limited by the translocation of GLUT4-laden vesicles from the intracellular compartments to the plasma membrane.
During exercise, the turnover of ATP in skeletal muscle increases greatly and is fuelled by the catabolism of carbohydrates (intramuscular glycogen, blood glucose) and fatty acids (intramuscular triglycerides, blood lipids). As exercise continues and muscle glycogen stores are depleted, the contribution of blood glucose becomes more substantial, reaching ~35% of leg oxidative metabolism and close to 100% of muscle carbohydrate metabolism.
In summary, skeletal muscle plays a critical role in intracellular glucose metabolism, with GLUT4 being the primary mediator of glucose uptake. Exercise and insulin stimulation promote the translocation of GLUT4 to the plasma membrane, enhancing glucose uptake and utilization by skeletal muscle.
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Glucose gradient and facilitated transport
Glucose is a hydrophilic molecule that cannot directly penetrate the lipid bilayer of cells. Therefore, its uptake into cells is achieved by an energy-independent process of facilitated diffusion down its concentration gradient. This process is mediated by a family of glucose transporter proteins (GLUTs) composed of at least 12 membrane-spanning helices. These transporters allow the uptake of glucose into cells from the interstitial fluid, into which glucose diffuses from the bloodstream.
There are two main types of glucose transporters: sodium–glucose linked transporters (SGLTs) and facilitated diffusion glucose transporters (GLUTs). SGLTs symport (transport in the same direction) glucose in conjunction with sodium ions. They are present on the luminal surfaces of cells lining the small intestine, where they absorb glucose from dietary sources. SGLTs are also found in renal tubules, where they facilitate the reabsorption of glucose from the glomerular filtrate. SGLTs do not directly utilize ATP to transport glucose against its concentration gradient. Instead, they rely on the sodium concentration gradient generated by the sodium–potassium ATPase as a source of chemical potential.
GLUTs, on the other hand, are expressed in nearly all body cells and facilitate the transport of glucose down a concentration gradient in a saturable manner. There are different isoforms of GLUTs, with GLUT1 being the main isoform mediating glucose transport across the placenta during pregnancy. GLUT2 is located in the plasma membranes of hepatocytes and pancreatic beta cells and facilitates glucose sensing. GLUT3 is primarily expressed in neurons and various other cells throughout the body. GLUT4 is an insulin-responsive glucose transporter located in the heart, skeletal muscle, brain, and adipose tissue. It plays a crucial role in muscle glucose uptake during exercise, with higher levels facilitating increased glucose uptake and glycogen storage.
Facilitated diffusion is a passive process that relies on carrier proteins to transport glucose down a concentration gradient. This process does not require energy and moves substances along their concentration gradient. In contrast, active transport requires energy to move molecules against their concentration gradient.
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Frequently asked questions
Skeletal muscle is the primary driver of whole-body glycemic control.
GLUT4 is the main glucose transporter in skeletal muscle.
Exercise increases glucose uptake in skeletal muscle, with the magnitude of the effect depending on the duration and intensity of the exercise.
Once glucose enters skeletal muscle, it is phosphorylated to glucose-6-phosphate and can then be metabolized or stored as glycogen.
Insulin stimulates glucose uptake into skeletal muscle by increasing blood flow to the muscle and regulating the delivery of glucose and other nutrients.
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