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How many different facilitative glucose transporters are there?
13; GLUT1-GLUT13; they are carrier-mediated but do not involve the expenditure of energy
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What does GLUT1 do?
- It has a high affinity for glucose (Km= 1-2mM); it is responsible for glucose uptake in erythrocytes and the uptake of glucose into
- the brain across the blood-brain barrier
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Where is GLUT1 most commonly found?
Ubiquitous, but most commonly found in red blood cells and at the blood-brain barrier
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What disease do mutations in GLUT1 cause?
GLUT1 deficiency syndrome; this results in impairment of glucose delivery into the brain
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What are the symptoms of GLUT1 mutations?
Early onset encephalopathy (syndrome of global brain dysfunction), seizures, developmental delay, hypotonia, a complex movement disorder, hypoglycorrhachia (decreased glucose levels in the cerebrospinal fluid) with normal blood levels of glucose
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How are GLUT1 mutations treated?
Children with the disorder are treated with a ketogenic diet
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In what cells is GLUT1 over-expressed?
Tumor cell; it is over-expressed to support the increased energy demands of tumor cells
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How is PET scan being used for tumor detection?
Regions of a tissue with cancer have a higher capacity to accumulate 2-deoxy-D-glucose, a non-metabolizable glucose analog recognized as a substrate by GLUTs, because of the differential expression GLUT1; this technique is known as 18FDG-PET
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GLUT2
- This transporter has a low affinity for glucose, but has a high capacity for glucose, therefore, it is used to sense when there are high levels of glucose in the small intestines and insulin needs to be released; it
- increases its transport activity in response to high levels of glucose
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Where is GLUT2 most commonly found?
In the liver, the β-cells of the pancreas, the intestines and in the kidney
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How does GLUT2 cause β-cells to secrete insulin?
- When plasma glucose increases, GLUT2 in the pancreatic β-cells allows more glucose to enter the cell, this increases glucose metabolism and ATP production; when the ATP levels raise, K+ channels are shut down
- which depolarizes the cell; once the cell is depolarized the voltage-sensitive Ca2+‑ channels are activated, allowing an influx of Ca2+; this influx of Ca2+ triggers the release of insulin
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What do mutations leading to the inactivation of sulfonylurea receptor cause?
These mutations are the cause for the genetic disease Familial Persistent Hyperinsulinemic Hypoglycemia of Infancy (PHHI)
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What disease do mutations in GLUT2 or glucokinase cause?
Mutations which lead to inactivation of GLUT2 or glucokinase cause hypoinsulinemia and diabetes
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What drugs are used to treat non-insulin-dependent diabetes mellitus?
Sulfonylureas; Oral hypoglycemics which inhibit the ATP-sensitive K+ channel in β-cells; this inhibition causes depolarization, which triggers the voltage-sensitive Ca2+ channel to allow an influx of Ca2+ which trigger release of insulin
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Where is GLUT4 most commonly found?
Most commonly found in adipocytes, skeletal muscle and heart muscle
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GLUT4
GLUT4 is an insulin-sensitive glucose transporter regulated by insulin; when the insulin receptor in the cell is activated, GLUT4 rapidly moves from intracellular pools into the plasma membrane
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What negative side effect can result from the activation of GLUT4?
Because of the sudden influx of glucose into muscle or adipose, insulin-induced hypoglycemia can occur; exercise also recruits GLUT4 so it can hypoglycemic episodes can occurring during or soon after exercise as well; this particularly can happen to type 1 diabetics who control their blood glucose levels with insulin injection
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How does the sodium coupled glucose transporter 1 work?
The sodium coupled glucose transporter 1 (SGLT1) transports D-glucose and D-galactose; it utilizes the Na+ gradient generated by the Na+/K+ pump for energy; if there is an inhibition of the Na+/K+ pump or a decrease in ATP production there will be a decrease in glucose absorption in the intestines
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What happens to individuals with genetic defects in SGLT1?
Leads to the disorder called glucose-galactose malabsorption; children born with this cannot absorb glucose and galactose but can absorb fructose, so they frequently suffer with glucose-galactose malabsorption, osmotic diarrhea; they can be treated with fructose
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Where is SGLT1 predominantly found?
In the intestines
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Where is SGLT2 predominantly found?
In the kidney; it is the major contributing transporter for renal absorption of glucose
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What is Hartnup disease?
Defect in the intestinal and renal absorption of neutral AAs; absorption of free AAs is the major transport mode in the kidney b/c circulating levels of small peptides are very low; there is no significant impairment of proper nutrition
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Why is Hartnup disease relatively benign in developed nations?
- Because developed nations have a relatively nutritious diet; there may be symptoms of niacin deficiency caused by low levels of tryptophan and cerebellar ataxia (lack of voluntary coordination of muscle movement
- originating from the cerebellum)
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What is cystinuria?
A disease associated with a defect in the intestinal and renal absorption of cationic AAs (lysine and arginine) and cystine; extretion of all other AAs is normal; kidney damage due to cystine-containing stones in the urinary tract is a major complication
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How is cystinuria treated?
Alkalinzation of urine or stimulation of urine production; alternatively, the use of penicillamine to form mixed disulfides with cystine in the nephron would enhance cystines solubility thus decreasing stone formation
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