Glucose, a simple sugar, is the fundamental energy source for the majority of cells and a vital precursor for numerous biochemical processes. Given that every cell in the body requires glucose, glucose transporters are equally essential. These proteins are ubiquitously expressed on the surface of all cells, facilitating glucose uptake. Recent advances in genetics have significantly enhanced our understanding of the diverse types and physiological roles of glucose transporters. Primarily, they are categorized into two main families: sodium-glucose linked transporters (SGLTs) and facilitated diffusion glucose transporters (GLUTs), each with further subcategories. These transporters exhibit variations in substrate specificity, tissue distribution, and regulatory mechanisms. Due to their critical role in glucose metabolism, glucose transporters have become significant therapeutic targets for a wide range of diseases. This review aims to provide a clear and concise overview of this complex subject, intended for researchers and anyone interested in biochemistry and pharmacology.
Introduction
Glucose is indispensable as the primary fuel source for most living organisms and their cells. However, due to its polar nature and relatively large molecular size, glucose cannot passively diffuse across the cell’s lipid bilayer membrane. Instead, cells rely on a large family of structurally related transport proteins, known as glucose transporters, to mediate glucose entry. These glucose transporters are broadly classified into two main types: sodium-glucose linked transporters (SGLTs) and facilitated diffusion glucose transporters (GLUTs). Glut Transporters are the focus of this article.
Structural Overview of SGLTs and GLUTs
Sodium–glucose linked transporter-1 (SGLT1) was the first member of the SGLT family to be identified and extensively characterized. SGLT1 protein is composed of 14 transmembrane helices, with both its amino (NH2) and carboxyl (COOH) terminals oriented towards the extracellular space. The SGLT family members are glycoproteins ranging from 60 to 80 kDa in molecular weight and contain between 580 to 718 amino acids.
In contrast, GLUTs, the facilitative glucose transporters, are characterized by 12 transmembrane domains with both the amino and carboxyl termini located intracellularly. Amino acid sequence comparisons have revealed that GLUT proteins share 28–65% sequence identity with GLUT1. Based on sequence similarity and phylogenetic analysis, facilitative glucose transporters are further divided into three classes: Class I, II, and III.
Functional Roles of SGLTs and GLUTs in Glucose Transport
Sodium–glucose linked transporters (SGLTs) operate via a symport mechanism, meaning they transport glucose across the cell membrane in conjunction with sodium ions, moving in the same direction. Notably, SGLTs do not directly consume ATP for energy. Instead, they harness the electrochemical gradient of sodium ions, which is maintained by the sodium-potassium ATPase pump, to drive glucose transport against its concentration gradient. SGLTs are strategically located on the apical membranes of epithelial cells lining the small intestine, where they are crucial for absorbing dietary glucose. They are also found in the renal tubules of the kidneys, where they play a critical role in reabsorbing glucose from the glomerular filtrate, preventing glucose loss in urine. Table 1 summarizes the key characteristics of the major SGLT subtypes.
Table 1. Key Characteristics of Sodium–Glucose Linked Transporters (SGLTs)
| SGLT Type | Location | Function | Nature |
|---|---|---|---|
| SGLT1 | Apical membranes of small intestinal cells | Absorption of glucose from the intestinal lumen | High affinity |
| Straight cells (S3 segment) of the proximal tubule in the nephron | Reabsorption of remaining glucose from the urine filtrate | High affinity, low capacity | |
| SGLT2 | Proximal convoluted tubule of the nephron (S1 and S2 segments) | Reabsorption of the majority of glucose from the glomerular filtrate | Low affinity, high capacity |
| SGLT3 | Intestine, testes, uterus, lung, brain, thyroid | Functions as a glucose sensor to regulate glucose levels in the gut and brain | -a |
| SGLT4 | Intestine, kidney, liver, brain, lung, uterus, pancreas | Absorption and/or reabsorption of mannose, 1,5-anhydro-D-glucitol, fructose, and glucose | Low affinity |
| SGLT5 | Kidney cortex | Transport of glucose and galactose | -a |
| SGLT6 | Brain, kidney, intestine | Preferred substrate is D-chiro-inositol | High affinity for myo-inositol, low affinity for glucose |
SGLT, Sodium–glucose linked transporter (sodium-dependent glucose transporter)
aNature not known
Facilitative Glucose Transporters (GLUTs) and Their Roles
GLUT transporters facilitate glucose transport across the plasma membrane through facilitated diffusion, a process that does not require metabolic energy. This section will delve into the different classes of GLUT transporters and their specific functions.
Class I GLUT Transporters
Class I GLUT transporters include GLUT1, GLUT2, GLUT3, and GLUT4. GLUT2 is predominantly expressed in pancreatic beta cells, liver, and kidney. While GLUT2 acts as a key glucose sensor in beta cells in some marine organisms, human beta cells primarily express GLUT1. Glucose sensing in pancreatic beta cells is a two-step process: (1) glucose entry into the cell, mediated by GLUTs, and (2) glucose phosphorylation by glucokinase. Research indicates that glucokinase, rather than GLUT1 or GLUT2, is the primary glucose sensor in human pancreatic beta cells. In liver cells (hepatocytes), GLUT1 is involved in bidirectional glucose transport, which is regulated by hormones like thyroid hormone. GLUT2 in hepatocytes regulates both the uptake and release of glucose, thereby controlling overall hepatic glucose metabolism. In contrast, GLUT2 in intestinal and kidney cells is responsible for glucose absorption and reabsorption, respectively.
GLUT3 is mainly found in neurons of the brain and exhibits a high affinity for glucose. This high affinity ensures efficient glucose uptake into brain cells, which have a high and continuous energy demand. GLUT4 is particularly important as the insulin-responsive glucose transporter. It is primarily located in insulin-sensitive tissues such as heart, skeletal muscle, adipose tissue, and also in the brain. In the absence of insulin, GLUT4 is sequestered in vesicles within the cytoplasm. Upon insulin stimulation, these vesicles rapidly translocate to the plasma membrane, increasing the number of GLUT4 transporters on the cell surface. This insulin-mediated GLUT4 translocation leads to a substantial (10 to 20-fold) increase in glucose uptake in these tissues, playing a crucial role in postprandial glucose disposal.
Class II GLUT Transporters
Class II GLUT transporters consist of GLUT5, GLUT7, GLUT9, and GLUT11. GLUT5 is primarily a fructose transporter and is found in the small intestine, testes, and kidney. In the small intestine, GLUT5 facilitates the absorption of dietary fructose. GLUT7 exhibits high affinity for both glucose and fructose and is expressed in the small intestine, colon, testis, and prostate. GLUT9 exists in multiple isoforms in humans and is predominantly expressed in the proximal tubules of the kidney, liver, and placenta. GLUT11 shares significant sequence homology with GLUT5 (42% identity) and, unlike GLUT5, transports both glucose and fructose. Three isoforms of GLUT11 (GLUT11A, -B, and -C) have been identified in humans, with varying tissue distributions including heart, skeletal muscle, kidney, placenta, and adipose tissue. Interestingly, the GLUT11 gene is absent in rodents.
Class III GLUT Transporters
Class III facilitative glucose transporters include GLUT6, GLUT8, GLUT10, GLUT12, and GLUT13 (also known as HMIT). A distinguishing feature of this class is that their glycosylation site is located on loop 9, unlike Class I and II transporters, where it is on loop 1.
GLUT6 is mainly expressed in the brain, spleen, and peripheral leukocytes. GLUT8 is predominantly found in testicular germ cells and is a low-affinity glucose transporter localized intracellularly, with membrane translocation that is not insulin-dependent. GLUT8 is a high-affinity transporter for glucose, but its transport is inhibited by fructose and galactose. While GLUT8 translocation is hormonally regulated, it is not controlled by insulin. It is mainly distributed in the brain and testis and is thought to facilitate sugar transport across intracellular membranes, such as mitochondrial, endoplasmic reticulum, and lysosomal membranes. Studies in Slc2a8 knockout mice (lacking GLUT8) have shown that these mice are viable with near-normal growth, although subtle alterations in brain, heart, and sperm cells are observed. Sperm cells in these mice have reduced ATP levels and motility.
GLUT10 is widely expressed in various tissues, including skeletal muscle, heart, lung, brain, placenta, kidney, liver, and pancreas. GLUT12 shows sequence similarity to GLUT10 but shares functional characteristics with GLUT4. Similar to GLUT4, insulin can induce GLUT12 translocation to the cell membrane in skeletal muscle. However, recent research in isolated cardiomyocytes suggests that GLUT12 expression on the cardiomyocyte surface might not be solely insulin-dependent, indicating a role for GLUT12 as a basal glucose transporter.
HMIT (H+-driven myoinositol transporter), or GLUT13, is found in adipose tissue and kidney cells, but is most prominently expressed in the brain, particularly in the hippocampus, hypothalamus, cerebellum, and brainstem. It is primarily intracellular and translocates to the membrane upon depolarization or protein kinase C activation in neuronal cells. Unlike other GLUTs, GLUT13 is mainly involved in the transport of myo-inositol, specifically inositol-3-phosphate. In the brain, myo-inositol is a precursor for phosphatidylinositol, a crucial regulator of various signaling pathways, and disruptions in this pathway have been implicated in psychiatric disorders like bipolar disorder.
Diseases Associated with SGLTs and GLUTs
Genetic defects and dysregulation of SGLTs and GLUTs are implicated in various diseases. Mutations in the SGLT1 gene can cause glucose–galactose malabsorption, an autosomal recessive disorder characterized by severe diarrhea upon ingestion of glucose, galactose, or lactose. SGLT2, the primary glucose reabsorber in the kidney, when mutated, leads to impaired glucose reabsorption and glucosuria (excess glucose in urine). SGLT2 gene mutations are also linked to arterial tortuosity syndrome (ATS), a connective tissue disorder affecting major arteries and other tissues.
Increased SGLT activity has been observed in the intestines of diabetic individuals, potentially exacerbating glucose absorption. Cardiac SGLT1 expression is elevated in type 2 diabetes mellitus (T2DM) and ischemia but decreased in type 1 diabetes mellitus (T1DM), correlating with insulin levels. Insulin stimulates SGLT1 activity and membrane recruitment via protein kinase C activation, contributing to increased glucose uptake in cardiomyocytes in T2DM.
In the bile ducts, SGLT1 and GLUT1 reabsorb glucose, creating an osmotic gradient for water reabsorption, which reduces bile volume. Elevated bile glucose levels in diabetic patients, due to hyperglycemia, can lead to increased glucose transport and reduced bile flow, potentially contributing to the low bile secretion seen in diabetes.
Increased SGLT1 expression in salivary gland ductal cells in diabetic and hypertensive individuals may reduce salivary flow, increasing susceptibility to oral complications. Conversely, SGLT1 has been shown to play a protective role in gastrointestinal infections by mediating anti-inflammatory effects through interleukin-10.
GLUT2 gene mutations can result in Fanconi–Bickel Syndrome, a severe disorder characterized by hypoglycemia, hyperglycemia, hepatomegaly, renal dysfunction, and dwarfism.
Insulin resistance in T2DM is marked by impaired glucose utilization in skeletal muscle. While GLUT4 levels may be normal, their translocation to the membrane is often defective, possibly due to insulin signaling pathway disruptions or abnormal GLUT4 trafficking.
Increased fructose consumption in modern diets has highlighted the role of fructose transporters like GLUT5 in diseases such as diabetes, obesity, hypertension, and nonalcoholic fatty liver disease. In T2DM, GLUT5 mRNA and protein levels are increased in skeletal muscle but decreased in adipose tissue. Obesity and hypoxia can stimulate GLUT5 expression and activity in adipose cells, while hypertension increases GLUT5 expression in the kidney but decreases it in the small intestine. Gastrointestinal inflammation reduces GLUT5 expression and activity in the small intestine. Upregulation of GLUT9 isoforms has also been observed in diabetic mice. Although the GLUT10 gene is located at a T2DM susceptibility locus, a direct correlation between GLUT10 polymorphisms and T2DM has not been consistently established.
Therapeutic Exploitation of GLUTs and SGLTs
The high glucose demand of cancer cells, driven by their rapid growth, makes glucose transporters attractive therapeutic targets. Overexpression of glucose transporters, including GLUTs, is a hallmark of many types of tumor cells. One proposed mechanism for tumor cell survival involves the stabilization of SGLT1 on the cell membrane by epidermal growth factor receptor (EGFR), preventing apoptosis. This has led to strategies involving cytotoxic drugs conjugated to D-glucose to enhance drug delivery into tumor cells via glucose transporters. Another approach is to directly inhibit glucose transport into tumor cells. D-Allose, a rare sugar, can interfere with glucose transport and inhibit the growth of head and neck carcinoma cells. Antisense oligonucleotides targeting GLUT5 have been shown to reduce proliferation in breast cancer cell lines by blocking GLUT5 expression. GLUT11, GLUT4, and GLUT8 are also implicated in multiple myeloma cell growth and are being explored as therapeutic targets.
SGLT1’s role in secretory diarrhea is exploited in oral rehydration therapy (ORT). ORT utilizes the SGLT1-mediated co-transport of glucose and sodium to enhance water absorption in the gut, effectively combating dehydration in diarrheal diseases. This principle led to the WHO/UNICEF-recommended oral rehydration salts formulation.
SGLT2 is a significant drug target for diabetes treatment. Inhibiting SGLT2 in the kidneys promotes glucose excretion in urine, lowering blood glucose levels. Phlorizin, an SGLT2 inhibitor, demonstrated blood sugar reduction in animal models without causing hypoglycemia. Dapagliflozin, the first FDA-approved SGLT2 inhibitor drug, is now used for treating T2DM.
Conclusion
Glucose transporters, particularly GLUT transporters, are fundamentally important in biology, acting as critical gateways for glucose, the primary energy molecule of life. Beyond their normal physiological roles, they are central to diseases like diabetes mellitus and cancer. Ongoing research and development in diabetes therapeutics continue to emphasize glucose transporters as key targets for blood sugar control. The clinical relevance of GLUT transporters is set to expand as new antidiabetic and anticancer drugs targeting these proteins are developed and become available.
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Conflicts of interest
Archana M. Navale declares that she has no conflict of interest.
Archana N. Paranjape declares that she has no conflict of interest.
Ethical approval
This article does not contain any studies with human participants or animals performed by any of the authors.
Contributor Information
Archana M. Navale, Phone: +91-9879690685, Email: [email protected]
Archana N. Paranjape, Email: [email protected]
