2. Learning outcomes
Know what polyol pathway is, how &
when it occurs
Know the pathologies that may occur
with the pathway
in relation to diabetes mellitus and
other diseases
Know how the complications could be
treated
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3. PATHWAY
Cells use glucose for energy;
however, unused glucose enters the
polyol pathway when aldose
reductase reduces it to sorbitol.
The reduction of glucose to sorbitol(a
six carbon sugar alcohol obtained by
the reduction of the aldehyde group of
glucose) is accompanied by the
oxidation of NADPH to NADP+.
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4. CONT….
Then sorbitol is oxidized to fructose by
the enzyme sorbitol
dehydrogenase(SDH)
The oxidation of sorbitol to fructose is
paralleled by the reduction of NAD+ to
NADH.
Then after the enzyme called
HEXOKINASE can return the fructose
molecule to glycolytic pathway by
phosphorylating to form FRUCTOSE-
6-PHOSPHATE.
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7. PATHOLOGY
In a hyperglycemic state,
othe affinity of aldose reductase for glucose
rises.
ocausing much sorbitol to accumulate, and
using much more NADPH.
oleaving less NADPH for other processes
of cellular metabolism.
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8. Cont….
NADPH acts to promote nitric oxide and
glutathione production.
So, its deficiency will cause glutathione
and nitric oxide deficiency.
A glutathione deficiency, congenital
or acquired, can lead to
hemolysis(because glutathione is the
protector of cell membrane from
damage its deficiency makes cell
membrane less safe) caused by
oxidative stress.
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9. Cont…
As to nitric oxide, deficiency of
NADPH results in less production of
nitric oxide which is one of the
important vasodilators in blood vessel.
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10. Polyol pathway and Diabetes
mellitus
hyperglycemia-induced polyol
pathway hyperactivity has an
important role in the etiology of late-
onset diabetic complications.
Once sorbitol has been produced, it
does not easily diffuse across cell
membranes; this intracellular
accumulation of sorbitol may be a
factor in the etiology of diabetic
complications.
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11. Cont …
Some of the complications include
neuropathy, retinopathy, nephropathy,
keratopathy, cataract-formation,
possibly infection and atherosclerosis.
The inhibition of aldose reductase
(AR), a rate-limiting enzyme of the
pathway, could become a key element
in the prevention and reversal of
diabetic complications.
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12. Diabetic neuropathy
Clinically there has been a massive
concentration of efforts on diabetic
neuropathy.
What happens during the neuropathy
is,
• increase in intracellular sorbitol levels in the
peripheral nerve.
• results in osmotic damage, and metabolic,
structural and functional abnormalities.
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13. Cont …
It is also possible that damage of the
peripheral nerve may result from
depletion of intracellular cofactors,
such as nicotinamide-adenosine
dinucleotide phosphate (NADPH).
Moreover, accumulation caused by
hyperglycemia induced polyol pathway
hyperactivity have also been
associated with the depletion of myo-
inositol.
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14. Cont …
This may in turn decrease Na+-K+
pump activity, resulting in changes in
cellular metabolism and the
membrane structure of the peripheral
nerve.
the effect of AR inhibitors on diabetic
neuropathy is mainly via the metabolic
changes due to the inhibition of the
polyol pathway activity.
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15. Polyol pathway and
atherosclerosis
It has been hypothesized that a
reduction in Na+/K+-ATPase activity is
the major pathogenic step in the
development of hypertension.
This results in the accumulation of
intracellular Na+ and ultimately leads
to significant increases in cytosolic-
free Ca2+ concentrations [Ca2+] in
vascular smooth muscle cells.
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16. Cont…
sorbitol, Na+/K+-ATPase activity and
[Ca2+] were measured using cultured
rabbit aortic smooth muscle cells.
Epalrestst (100 IlM), an AR inhibitor,
was seen to block glucose-induced
changes in sorbitol and myo-inositol
metabolism.
reducing free cytosolic Ca2+ to control level
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17. In general
Fructose metabolism has some
dangers because fructose is
metabolized differently from glucose.
Unlike fructose
Glucose can be metabolized and
converted to ATP, which is readily
“burned” for energy by the cells’
mitochondria.
Alternatively, glucose can be stored in
the liver as a carbohydrate for later
conversion to energy
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18. Cont …
Fructose on the other hand,
is more rapidly metabolized in the liver,
flooding metabolic pathways and leading to
increased triglyceride synthesis and fat
storage in the liver.
This can cause a rise in serum triglycerides,
promoting an atherogenic lipid profile and
elevating cardiovascular risk.
Increased fat storage in the liver may lead to
an increased incidence in non-alcoholic fatty
liver disease
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