Glucose transporters (GLUTs)

Y Coleman,

August 13, 2024
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Glucose transporters (GLUTs) and sodium–glucose linked transporters (SGLTs) are the regulatory pathways essential for glucose homeostasis. Glucose is important as -

  • an energy source for most cells,
  • a substrate in many biochemical reactions, and
  • as precursors for cellular building blocks, including lipids and amino acids.

This post focuses on the GLUTs.

GLUTs -

  • transport glucose, galactose, mannose, glucosamine, and dehydroascorbic acid; and
  • as precursors for cellular building blocks, including lipids and amino acids.

Alterations in the function, location or expression of GLUT transporters results in -

  • aberrant use of energy substrates; and
  • health disorders including many in the dysfunctional mitochondria category such as obesity, diabetes, insulin resistance, neurodegenerative diseases, metabolic syndrome, etc.

The GLUT family comprises 14 members (GLUT1-GLUT14) that are grouped into 3 classes –

  • Class I - GLUT1, 2, 3, 4. GLUTs 1, 3, 4 transport glucose, GLUT2 transports glucose and fructose;
  • Class 11 – GLUT5, 7, 9, and 11. GLUTs 7 and 11 transport fructose and glucose, GLUT5 is a fructose-only transporter; GLUT9 transports fructose, glucose and uric acid; and
  • Class 111 - GLUT6, 8, 10, 12, and 13. GLUTs 6, 8, 10, 12 transport glucose, and GLUT13 transports myoinositol.

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 –

  • should vitamin C supplements be recommended to compensate for hyperglycaemia-induced inhibition of the GLUTs that transport DHA? This is particularly relevant to the closed loop scenarios such as between neurons and astrocytes.
  • what is the timeframe from drug administration to inhibition of each of the GLUT transporters?
  • what is the duration of inhibition of each of the GLUT transporters?
  • given the number of prescribed medications with side effects that include hyperglycaemia, why don’t we already know this? And when will this information be included in the Product Information documents?
  • if a person’s hyperglycaemia is drug-induced, then what is the most appropriate management strategy?

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 -

  • recommend qid monitoring for three days to try and establish a pattern?
  • if a pattern is apparent then will you attribute the hyperglycaemia to being a side effect of one or more of the prescribed medications?
  • contact the pharmaceutical companies directly and ask the duration of expression of the hyperglycaemia and best management strategies?

Conclusions

Glucose transporters (GLUTs) are essential to our metabolic processes and their disruption causes both short and longterm physiological havoc.

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