POLYOL (SORBITOL-

ALDOSE

REDUCTASE)

PATHWAY:SIGNIFICA

CE AND ROLE IN

DIABETES MELLITUS

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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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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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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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RING FORM

REPRESENTATION

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PATHOLOGY

In a hyperglycemic state,

othe affinity of aldose reductase for glucose

rises.

ocausing much sorbitol to accumulate, and

using much more NADPH.

o leaving less NADPH for other processes

of cellular metabolism.

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Cont….

NADPH acts to promote nitric oxide and glutathione production.

So, its deficiency will cause glutathione and nitric oxide deficiency.

A glutathione deficiency, congenitalor 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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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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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.8/1/2015 10

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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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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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.8/1/2015 13

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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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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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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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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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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references

Harper's Illustrated Biochemistry

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