Glucose transporters (GLUTs) and sodium–glucose linked transporters (SGLTs) are the regulatory pathways essential for glucose homeostasis. Glucose is important as -
This post focuses on the GLUTs.
GLUTs -
Alterations in the function, location or expression of GLUT transporters results in -
The GLUT family comprises 14 members (GLUT1-GLUT14) that are grouped into 3 classes –
Dehydroascorbic acid (DHA) and glucose are sufficiently similar in structure that plasma glucose concentrations also likely affect DHA transport. Further, some GLUT transport proteins have a higher affinity for DHA than glucose.
Isoforms
GLUT1
Class 1
Role
responsible for basal glucose uptake in the body, particularly in adipose and muscle tissues.
important in the regulation of the reactive oxygen species in the skeletal muscle to minimise oxidative stress harm.
provides glucose for energy production in red blood cells and brain.
transports glucose across the blood-brain barrier.
essential in the transport of ascorbic acid into the mitochondria.
essential in maternal–placental glucose transport and regulation of the placenta–foetal glucose transport.
important in embryo implantation.
is critical to the maintenance of cellular homeostasis in response to hypoxia.
important for the proliferation and maintenance of the pool of airway progenitor cells (club cells).Location
ubiquitous in all tissues of the body.
Substrates
glucose, galactose, mannose, glucosamine and DHA.
has an affinity for DHA that is approximately 1,000-fold higher than for glucose.Inhibitors
cytochalasin B, curcumin, forskolin, genistein, glupin, glutor, quercetin.
rubusoside (Rub) - a natural sweetener from the Chinese sweet tea plant (Rubus suavissimus).
phloretin aka phlorizin (a naturally occurring dihydroxychalcone found in several fruits, e.g., apples and pears).GLUT2
CLASS I
Role
significant regulatory functions including glucose sensing and signalling.
essential in maintaining glucose homeostasis in many human tissues, such as the intestine, liver, kidney, and brain.
is a hepatoportal glucose sensor.
regulates the entry and exit of glucose to and from hepatocytes and consequently controls hepatic glucose metabolism.
regulates the rate of glucose transport into hepatocytes by controlling the secretion of glucose-stimulated insulin in pancreatic cells.
is essential for the absorption and reabsorption of glucose from intestinal brush border cells and kidney tubule cells respectively.
mediates vitamin C uptake from the gut lumen.
regulates homeostatic functions such as feeding and body temperature, as well as sympathetic and parasympathetic functions in the nervous system.
its upregulation enhances intestinal glucose absorption.Location
hepatocytes, kidney epithelial cells, liver, pancreatic beta cells, small intestine.
Substrates
glucose, glucosamine, fructose, galactose, mannose and DHA.
Inhibitors
cytochalasin B, epigallocatechin gallate (EGCG), forskolin, fructose, glucose and glutor.
flavonoids with limited potency such as apigenin, fisetin, isoquercitrin, myricetin and tiliroside.
more potent inhibitors flavonoids such as quercetin and phloretin (aka phlorizin and found in several fruits, e.g., apples and pears).GLUT3
CLASS I
Role
important in glucose metabolism.
has a higher affinity for glucose and is important for glucose uptake into cells when local glucose concentrations are low.
important in glucose and lactate uptake for energy generation in neurons.
levels correlate with regional brain glucose utilization.
expression regulated by the thyroid hormones.
expression enhanced by cigarette smoke indicating GLUT3 may regulate airway remodelling in COPD through the NF-κB/ZEB1 pathway.Location
brain, epithelial cells, foetuses, kidneys, mammary, nerve cells, placenta, sperm, and white blood cells.
neurons - especially in pre-and post-synaptic nerve terminals and small synaptic processes, as well as dendrites and axons.Substrates
glucose, galactose, DHA.
Inhibitors
cytochalasin B, glupin, glutor.
GLUT4
CLASS 1
Role
primary function is the insulin-stimulated glucose uptake into adipose and muscle cells.
other functions include -
- activity associated with activation of nuclear transcription factor carbohydrate-response element-binding protein (ChREBP),
- enhanced lipogenesis and production of branched fatty acid esters of hydroxy fatty acids (FAHFAs),
- secretion of retinol binding protein 4 (RBP4).
levels are altered by glycaemic status ie raised when high glucose availability and low if limited glucose availability.
upregulates in response to exercise and thereby increases glucose uptake into muscles.
if faulty expression or translocation to the peripheral cell plasma membrane then glucose entry into the cell for energy production is limited.
insulin and exercise impacts are dictated from separate intracellular compartments.
glucose management strategies could potentially utilise diet and exercise to increase GLUT4 expression, concentrations, and translocation to the cell surface.Location
adipose, brain, bronchioles, heart, skeletal muscle, trachea.
Substrates
glucose, mannose, galactose, glucosamine, DHA.
Inhibitors
cytochalasin B, forskolin, genistein, glupin.
GLUT5
CLASS 2
Role
primary role in the absorption and metabolism of dietary fructose.
Location
adipose tissue, kidney, skeletal muscle, small intestine, testes.
Substrates
fructose.
Inhibitors
flavonoids: apigenin, epicatechin-gallate (ECG) and epigallocatechin-gallate (EGCG), astragalin (a product from the American pokeweed, Phytolacca americana).
rubusoside (Rub) - a natural sweetener from the Chinese sweet tea plant (Rubus suavissimus).
GLUT6
CLASS 3
Role
a low-affinity glucose transporter that is located intracellularly - its translocation to the membrane is not mediated through insulin.
a lysosomal transporter and has a low affinity for glucose and fructose.
modulates glycolysis in macrophages.Location
brain, lymphocytes, peripheral leukocytes, spleen, testis germinal cells and white blood cells.
Substrates
fructose, glucose, DHA.
GLUT7
CLASS 2
Role
postulated - helping to identify which hexoses can be transported.
Location
colon, kidney, prostate, small intestine, testes.
Substrates
fructose, glucose.
Inhibitors
apigenin.
GLUT8
CLASS 3
Role
a high-affinity transporter of glucose that facilitates the transport of sugar through intracellular membranes.
its translocation is hormonally regulated but not by insulin.
mediates fructose-induced de novo lipogenesis.
is involved in trehalose-induced autophagy.
may be important in the maintenance of epithelial glucose homeostasis.
may mediate intestinal DHA transport.
Location
brain, testes, most airway epithelial cell types, mammary gland.
Substrates
glucose, lactose, trehalose.
Inhibitors
fructose, galactose, glucose, quercetin.
GLUT9
CLASS 2
Role
a high-capacity urate transporter that regulates serum urate and also transports glucose and fructose.
mediates renal uric acid reabsorption.Location
kidney tubules, liver, and placenta.
Substrates
fructose, glucose, urate.
Inhibitors
phlorizin aka phloretin (under inflammatory conditions).
GLUT10
CLASS 3
Role
essential for unsaturated fatty acid driven glucose consumption, and the induction of AKT and ERK signalling pathways.
transports DHA through the perinuclear membrane, and the mitochondrial and endoplasmic reticulum membranes.
critical in maintaining the ascorbic acid levels necessary for adipogenesis.
associated with the compartmentalization of ascorbate within arterial cells.
important for regulating/optimising ascorbic acid levels in the nucleus, and consequent optimal functioning of Fe2+/2-oxoglutarate-dependent dioxygenases.
Location
most airway epithelial cell types, brain, heart, kidney, liver, lungs, pancreas, placenta, skeletal muscle, vascular smooth muscle cells.
Substrates
DHA, glucose.
GLUT11
CLASS 2
Role
Four key isoforms in humans - functions are not clearly identified.
Location
GLUT11A - heart, skeletal muscle, kidney;
GLUT11B - placenta, adipose tissue, kidney;
GLUT11C - adipose tissue, heart, skeletal muscle, pancreas;
GLUT11-D - recently discovered, locations not yet fully identified.
Substrates
fructose, glucose, uric acid.
Inhibitors
fructose.
GLUT12
CLASS 3
Location
adipose tissue, mammary gland alveolar cells, skeletal muscle, small intestine, and placenta.
Substrates
DHA, fructose, galactose, glucose.
Inhibitors
cytochalasin B, genistein, phloretin.
GLUT13
CLASS 3
Role
may be important in maintaining the innate immune function of the airway surface liquid through the transport of myoinositol.
Location
adipose tissue, most airway epithelial cell types, brain (hippocampus, hypothalamus, cerebellum and brain stem), kidney cells, neuronal tissues.
Substrates
myoinositol, inositol triphosphate, and related stereoisomers.
GLUT14
CLASS I
Role
specific functions of this transporter are yet to be discovered.
Location
blood, brain, colon, heart, kidneys, liver, lungs, ovaries, placenta, skeletal muscle, small intestine, testis.
Substrates
arabinose, DHA, galactose, glucosamine, glucose, mannose, xylose.
Inhibitors
lactose, maltose, sucrose.
Clinical considerations
The progressive discovery of GLUTs and their functions, substrates and inhibitors raises some key questions for clinical practice, such as –
I suggest any questions such as these be directed to the pharmaceutical companies as a strategy to stack their stats. Stacking their stats means pharmaceutical companies are more likely to notice issues of concern.
If the GLUT transporters are inhibited then glucose will be trapped either in the blood and/or in the cells and unable to escape. It also means blood test results are less reliable.
There seems to be a dearth of information identifying which prescribed medications are GLUT substrates and/or inhibitors.
Clinical questions
What actions will you initiate as you a review a person whose prescribed medications include hyperglycaemia as a side effect, will you -
Conclusions
Glucose transporters (GLUTs) are essential to our metabolic processes and their disruption causes both short and longterm physiological havoc.Enter your text here...
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The information in this article is provided to support Health Professionals. It is not an exhaustive protocol and Health Professionals are advised that adequate professional supervision is accessed to ensure that Duty of Care obligations with respect to safe administration of medicines is met for each consumer.
Yvonne Coleman is an accomplished dietitian with 30+ years of experience in aged care. Her mission is to make information concerning the interactions between medication and nutrition public and easy to access, having created the most comprehensive resource on the matter.
Her areas of competency include food science & nutrition, dietetics and health education. You can find out more about her work on LinkedIn, AusMed, the Enlightened Pharmacist podcast, and The FX Medicine Podcast.