Glucose uptake

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The method of glucose uptake varies across tissues based on two factors: the metabolic needs of the tissue and the availability of glucose. This uptake occurs through two mechanisms:

Contents

  1. Facilitated Diffusion - a passive process that relies on carrier proteins to transport glucose down a concentration gradient. [1]
  2. Secondary Active Transport - transport of a solute in the direction of increasing electrochemical potential via the facilitated diffusion of a second solute (usually an ion, in this case Na+) in the direction of decreasing electrochemical potential. [2] This gradient is established via primary active transport of Na+ ions (a process which requires ATP).

Facilitated diffusion

Glucose transporters (GLUTs) are classified into three groups based on sequence similarity, with a total of 14 members. All GLUT proteins share a common structure: 12 transmembrane segments, a single N-linked glycosylation site, a large central cytoplasmic linker, and both N- and C-termini located in the cytoplasm. [3] These transporters are expressed in nearly all body cells. While most GLUTs facilitate glucose transport, HMIT is an exception. [3] Among them, GLUT1-5 are the most extensively studied. However, for study GLUTs 1-4 or the Class I GLUTs are the most relevant. For more information on other GLUTs see sources 3 and 7, or the GLUT specific wikipedia pages.

GLUT1 is a hydrophobic protein and 50% of GLUT1 is in the lipid bilayer. GLUT1 is present in the placenta, brain, epithelial cells of the mammary gland, transformed cells, and fetal tissue. [4] Due to its ubiquitous presence, it is proposed that GLUT1 is at least somewhat responsible for basal glucose uptake. [4] Basal blood glucose levels are approximately 5 mM (milimolar). The Km value—which indicates the affinity of a transporter for glucose—is 1 mM for GLUT1 and GLUT3. Since a lower Km value corresponds to a higher affinity, these transporters have a strong ability to bind and transport glucose even at low concentrations. As a result, GLUT1 facilitates a consistent glucose uptake from the bloodstream, ensuring a steady supply to tissues that rely on glucose.

GLUT2 in contrast has a high Km value (15-20mM) 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). [5] The high Km of GLUT2 allows for glucose sensing; rate of glucose entry is proportional to blood glucose levels.

GLUT3 is primarily expressed in neurons, specifically in cell processes (axons and dendrites), however, it is also found in many other cells throughout the body. GLUT3 is primarily expressed in neurons, specifically in cell processes (axons and dendrites), however, it is also found in many other cells throughout the body. [6]

GLUT4 is an insulin-responsive glucose transporter located in the heart, skeletal muscle, brain, and adipose tissue. GLUT4 is generally in vesicles in the cytoplasm. In response to insulin, more GLUT4 transporters are relocated from these vesicles to the cell membrane. [7] 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.

GLUT4 has a Km value for glucose of about 5 mM, which as stated above is the normal blood glucose level in healthy individuals. GLUT4 is the most abundant glucose transporter in skeletal muscle and is thus considered to be rate limiting for glucose uptake and metabolism in resting muscles. [8] The drug metformin phosphorylates GLUT4, thereby increasing its sensitivity to insulin.

Secondary active transport

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 [9] . Therefore, the concentration gradient of glucose opposes its reabsorption, and energy is required for its transport.

The secondary active transport of glucose in the kidney is Na+ linked; therefore an Na+ gradient must be established. This is achieved through the action of the Na+/K+ pump, the energy for which is provided through the hydrolysis of ATP. Three Na+ ions are extruded from the cell in exchange for two K+ ions entering through the intramembrane enzyme Na+/K+-ATPase; this leaves a relative deficiency of Na+ in the intracellular compartment. Na+ ions diffuse down their concentration gradient into the columnar epithelia, co-transporting glucose. [10] 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 Na+/K+-ATPase. 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 [11] . SGLT1 transporters are found close to the loop of Henle and in the distal convoluted tubule of the nephron where much glucose has been reabsorbed into the bloodstream. These have a high affinity for glucose and a low capacity. [11] Functioning in conjunction, these two secondary active transporters ensure that only negligible amounts of glucose are wasted through excretion in the urine.

Related Research Articles

<span class="mw-page-title-main">Facilitated diffusion</span> Biological process

Facilitated diffusion is the process of spontaneous passive transport of molecules or ions across a biological membrane via specific transmembrane integral proteins. Being passive, facilitated transport does not directly require chemical energy from ATP hydrolysis in the transport step itself; rather, molecules and ions move down their concentration gradient according to the principles of diffusion.

<span class="mw-page-title-main">Beta cell</span> Type of cell found in pancreatic islets

Beta cells (β-cells) are specialized endocrine cells located within the pancreatic islets of Langerhans responsible for the production and release of insulin and amylin. Constituting ~50–70% of cells in human islets, beta cells play a vital role in maintaining blood glucose levels. Problems with beta cells can lead to disorders such as diabetes.

In cellular biology, active transport is the movement of molecules or ions across a cell membrane from a region of lower concentration to a region of higher concentration—against the concentration gradient. Active transport requires cellular energy to achieve this movement. There are two types of active transport: primary active transport that uses adenosine triphosphate (ATP), and secondary active transport that uses an electrochemical gradient. This process is in contrast to passive transport, which allows molecules or ions to move down their concentration gradient, from an area of high concentration to an area of low concentration, without energy.

<span class="mw-page-title-main">Passive transport</span> Transport that does not require energy

Passive transport is a type of membrane transport that does not require energy to move substances across cell membranes. Instead of using cellular energy, like active transport, passive transport relies on the second law of thermodynamics to drive the movement of substances across cell membranes. Fundamentally, substances follow Fick's first law, and move from an area of high concentration to an area of low concentration because this movement increases the entropy of the overall system. The rate of passive transport depends on the permeability of the cell membrane, which, in turn, depends on the organization and characteristics of the membrane lipids and proteins. The four main kinds of passive transport are simple diffusion, facilitated diffusion, filtration, and/or osmosis.

A membrane transport protein is a membrane protein involved in the movement of ions, small molecules, and macromolecules, such as another protein, across a biological membrane. Transport proteins are integral transmembrane proteins; that is they exist permanently within and span the membrane across which they transport substances. The proteins may assist in the movement of substances by facilitated diffusion, active transport, osmosis, or reverse diffusion. The two main types of proteins involved in such transport are broadly categorized as either channels or carriers. Examples of channel/carrier proteins include the GLUT 1 uniporter, sodium channels, and potassium channels. The solute carriers and atypical SLCs are secondary active or facilitative transporters in humans. Collectively membrane transporters and channels are known as the transportome. Transportomes govern cellular influx and efflux of not only ions and nutrients but drugs as well.

<span class="mw-page-title-main">Uniporter</span>

Uniporters, also known as solute carriers or facilitated transporters, are a type of membrane transport protein that passively transports solutes across a cell membrane. It uses facilitated diffusion for the movement of solutes down their concentration gradient from an area of high concentration to an area of low concentration. Unlike active transport, it does not require energy in the form of ATP to function. Uniporters are specialized to carry one specific ion or molecule and can be categorized as either channels or carriers. Facilitated diffusion may occur through three mechanisms: uniport, symport, or antiport. The difference between each mechanism depends on the direction of transport, in which uniport is the only transport not coupled to the transport of another solute.

<span class="mw-page-title-main">Antiporter</span> Class of transmembrane transporter protein

An antiporter is an integral membrane protein that uses secondary active transport to move two or more molecules in opposite directions across a phospholipid membrane. It is a type of cotransporter, which means that uses the energetically favorable movement of one molecule down its electrochemical gradient to power the energetically unfavorable movement of another molecule up its electrochemical gradient. This is in contrast to symporters, which are another type of cotransporter that moves two or more ions in the same direction, and primary active transport, which is directly powered by ATP.

<span class="mw-page-title-main">Cotransporter</span> Type of membrane transport proteins

Cotransporters are a subcategory of membrane transport proteins (transporters) that couple the favorable movement of one molecule with its concentration gradient and unfavorable movement of another molecule against its concentration gradient. They enable coupled or cotransport and include antiporters and symporters. In general, cotransporters consist of two out of the three classes of integral membrane proteins known as transporters that move molecules and ions across biomembranes. Uniporters are also transporters but move only one type of molecule down its concentration gradient and are not classified as cotransporters.

<span class="mw-page-title-main">GLUT2</span> Transmembrane carrier protein

Glucose transporter 2 (GLUT2) also known as solute carrier family 2, member 2 (SLC2A2) is a transmembrane carrier protein that enables protein facilitated glucose movement across cell membranes. It is the principal transporter for transfer of glucose between liver and blood Unlike GLUT4, it does not rely on insulin for facilitated diffusion.

<span class="mw-page-title-main">Glucose transporter</span> Family of monosaccharide transport proteins

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. Because glucose is a vital source of energy for all life, these transporters are present in all phyla. 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.

<span class="mw-page-title-main">GLUT4</span> Protein

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. 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.

<span class="mw-page-title-main">Ion transporter</span> Transmembrane protein that moves ions across a biological membrane

In biology, an ion transporter is a transmembrane protein that moves ions across a biological membrane to accomplish many different biological functions, including cellular communication, maintaining homeostasis, energy production, etc. There are different types of transporters including pumps, uniporters, antiporters, and symporters. Active transporters or ion pumps are transporters that convert energy from various sources—including adenosine triphosphate (ATP), sunlight, and other redox reactions—to potential energy by pumping an ion up its concentration gradient. This potential energy could then be used by secondary transporters, including ion carriers and ion channels, to drive vital cellular processes, such as ATP synthesis.

<span class="mw-page-title-main">GLUT1</span> Uniporter protein

Glucose transporter 1, also known as solute carrier family 2, facilitated glucose transporter member 1 (SLC2A1), is a uniporter protein that in humans is encoded by the SLC2A1 gene. GLUT1 facilitates the transport of glucose across the plasma membranes of mammalian cells. This gene encodes a facilitative glucose transporter that is highly expressed in erythrocytes and endothelial cells, including cells of the blood–brain barrier. The encoded protein is found primarily in the cell membrane and on the cell surface, where it can also function as a receptor for human T-cell leukemia virus (HTLV) I and II. GLUT1 accounts for 2 percent of the protein in the plasma membrane of erythrocytes.

The galactose permease or GalP found in Escherichia coli is an integral membrane protein involved in the transport of monosaccharides, primarily hexoses, for utilization by E. coli in glycolysis and other metabolic and catabolic pathways (3,4). It is a member of the Major Facilitator Super Family (MFS) and is homologue of the human GLUT1 transporter (4). Below you will find descriptions of the structure, specificity, effects on homeostasis, expression, and regulation of GalP along with examples of several of its homologues.

Sodium-dependent glucose cotransporters are a family of glucose transporter found in the intestinal mucosa (enterocytes) of the small intestine (SGLT1) and the proximal tubule of the nephron. They contribute to renal glucose reabsorption. In the kidneys, 100% of the filtered glucose in the glomerulus has to be reabsorbed along the nephron. If the plasma glucose concentration is too high (hyperglycemia), glucose passes into the urine (glucosuria) because SGLT are saturated with the filtered glucose.

<span class="mw-page-title-main">Blood sugar regulation</span> Hormones regulating blood sugar levels

Blood sugar regulation is the process by which the levels of blood sugar, the common name for glucose dissolved in blood plasma, are maintained by the body within a narrow range.

<span class="mw-page-title-main">Symporter</span> Class of membrane transport proteins

A symporter is an integral membrane protein that is involved in the transport of two different molecules across the cell membrane in the same direction. The symporter works in the plasma membrane and molecules are transported across the cell membrane at the same time, and is, therefore, a type of cotransporter. The transporter is called a symporter, because the molecules will travel in the same direction in relation to each other. This is in contrast to the antiport transporter. Typically, the ion(s) will move down the electrochemical gradient, allowing the other molecule(s) to move against the concentration gradient. The movement of the ion(s) across the membrane is facilitated diffusion, and is coupled with the active transport of the molecule(s). In symport, two molecule move in a 'similar direction' at the 'same time'. For example, the movement of glucose along with sodium ions. It exploits the uphill movement of other molecules from low to high concentration, which is against the electrochemical gradient for the transport of solute molecules downhill from higher to lower concentration.

Glucose transporter 3, also known as solute carrier family 2, facilitated glucose transporter member 3 (SLC2A3) is a protein that in humans is encoded by the SLC2A3 gene. GLUT3 facilitates the transport of glucose across the plasma membranes of mammalian cells. GLUT3 is most known for its specific expression in neurons and has originally been designated as the neuronal GLUT. GLUT3 has been studied in other cell types with specific glucose requirements, including sperm, preimplantation embryos, circulating white blood cells and carcinoma cell lines.

<span class="mw-page-title-main">Sodium/glucose cotransporter 1</span> Mammalian protein found in Homo sapiens

Sodium/glucose cotransporter 1 (SGLT1) also known as solute carrier family 5 member 1 is a protein in humans that is encoded by the SLC5A1 gene which encodes the production of the SGLT1 protein to line the absorptive cells in the small intestine and the epithelial cells of the kidney tubules of the nephron for the purpose of glucose uptake into cells. Recently, it has been seen to have functions that can be considered as promising therapeutic target to treat diabetes and obesity. Through the use of the sodium glucose cotransporter 1 protein, cells are able to obtain glucose which is further utilized to make and store energy for the cell.

The insulin transduction pathway is a biochemical pathway by which insulin increases the uptake of glucose into fat and muscle cells and reduces the synthesis of glucose in the liver and hence is involved in maintaining glucose homeostasis. This pathway is also influenced by fed versus fasting states, stress levels, and a variety of other hormones.

References

  1. ↑ McCall, Anthony L. (2019-01-01), Fink, George (ed.), "Chapter 22 - Glucose Transport", Stress: Physiology, Biochemistry, and Pathology, Academic Press, pp. 293–307, doi:10.1016/b978-0-12-813146-6.00022-9, ISBN   978-0-12-813146-6 , retrieved 2025-01-31
  2. ↑ Shechter, Emanuel (March 1986). "Transports actifs secondaires". Biochimie (in French). 68 (3): 357–365. doi:10.1016/S0300-9084(86)80002-5.
  3. 1 2 Mueckler, Mike; Thorens, Bernard (2013-04-01). "The SLC2 (GLUT) family of membrane transporters". Molecular Aspects of Medicine. The ABCs of membrane transporters in health and disease (SLC series). 34 (2): 121–138. doi:10.1016/j.mam.2012.07.001. ISSN   0098-2997. PMC   4104978 . PMID   23506862.
  4. 1 2 Mora, S.; Pessin, J. (2013-01-01), Lennarz, William J.; Lane, M. Daniel (eds.), "Glucose/Sugar Transport in Mammals", Encyclopedia of Biological Chemistry (Second Edition), Waltham: Academic Press, pp. 391–394, doi:10.1016/b978-0-12-378630-2.00041-4, ISBN   978-0-12-378631-9 , retrieved 2025-01-31
  5. ↑ Vos, A. De; Heimberg, H.; Quartier, E.; Huypens, P.; Bouwens, L.; Pipeleers, D.; Schuit, F. (1995-11-01). "Human and rat beta cells differ in glucose transporter but not in glucokinase gene expression". The Journal of Clinical Investigation. 96 (5): 2489–2495. doi:10.1172/JCI118308. ISSN   0021-9738. PMID   7593639.
  6. ↑ Simpson, Ian A.; Dwyer, Donard; Malide, Daniela; Moley, Kelle H.; Travis, Alexander; Vannucci, Susan J. (August 2008). "The facilitative glucose transporter GLUT3: 20 years of distinction". American Journal of Physiology-Endocrinology and Metabolism. 295 (2): E242 –E253. doi:10.1152/ajpendo.90388.2008. ISSN   0193-1849. PMC   2519757 . PMID   18577699.
  7. ↑ Navale, Archana M.; Paranjape, Archana N. (2016-03-01). "Glucose transporters: physiological and pathological roles". Biophysical Reviews. 8 (1): 5–9. doi:10.1007/s12551-015-0186-2. ISSN   1867-2469. PMC   5425736 . PMID   28510148.
  8. ↑ Chadt, Alexandra; Al-Hasani, Hadi (26 June 2020). "Glucose transporters in adipose tissue, liver, and skeletal muscle in metabolic health and disease". Pflügers Archiv - European Journal of Physiology. 472 (9): 1273–1298. doi:10.1007/s00424-020-02417-x. ISSN   0031-6768. PMC   7462924 . PMID   32591906.
  9. ↑ Mather, Amanda et al. (March 2011). "Glucose handling by the kidney", Kidney International, Volume 79, S1 - S6, https://www.kidney-international.org/action/showCitFormats?doi=10.1038%2Fki.2010.509&pii=S0085-2538%2815%2954763-7, retrieved 2025-01-31
  10. ↑ Baud, Gregory; Raverdy, Violeta; Bonner, Caroline; Daoudi, Mehdi; Caiazzo, Robert; Pattou, François (2016-07-01). "Sodium glucose transport modulation in type 2 diabetes and gastric bypass surgery". Surgery for Obesity and Related Diseases. 12 (6): 1206–1212. doi:10.1016/j.soard.2016.04.022. ISSN   1550-7289.
  11. 1 2 Kamitori, Kazuyo; Shirota, Matsuyuki; Fujiwara, Yuichiro (2022-03-15). "Structural Basis of the Selective Sugar Transport in Sodium-Glucose Cotransporters". Journal of Molecular Biology. 434 (5): 167464. doi:10.1016/j.jmb.2022.167464. ISSN   0022-2836.
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