POLYOL (SORBITOL-
ALDOSE
REDUCTASE)
PATHWAY:SIGNIFICA
CE AND ROLE IN
DIABETES MELLITUS
8/1/2015 1
Learning outcomes
 Know what polyol pathway is, how &
when it occurs
 Know the pathologies that may occur
with the pathw...
PATHWAY
 Cells use glucose for energy;
however, unused glucose enters the
polyol pathway when aldose
reductase reduces it...
CONT….
 Then sorbitol is oxidized to fructose by
the enzyme sorbitol
dehydrogenase(SDH)
 The oxidation of sorbitol to fr...
8/1/2015 5
RING FORM
REPRESENTATION
8/1/2015 6
PATHOLOGY
In a hyperglycemic state,
othe affinity of aldose reductase for glucose
rises.
ocausing much sorbitol to accumu...
Cont….
 NADPH acts to promote nitric oxide and
glutathione production.
So, its deficiency will cause glutathione
and nit...
Cont…
 As to nitric oxide, deficiency of
NADPH results in less production of
nitric oxide which is one of the
important v...
Polyol pathway and Diabetes
mellitus
 hyperglycemia-induced polyol
pathway hyperactivity has an
important role in the eti...
Cont …
 Some of the complications include
neuropathy, retinopathy, nephropathy,
keratopathy, cataract-formation,
possibly...
Diabetic neuropathy
 Clinically there has been a massive
concentration of efforts on diabetic
neuropathy.
 What happens ...
Cont …
 It is also possible that damage of the
peripheral nerve may result from
depletion of intracellular cofactors,
suc...
Cont …
 This may in turn decrease Na+-K+
pump activity, resulting in changes in
cellular metabolism and the
membrane stru...
Polyol pathway and
atherosclerosis
 It has been hypothesized that a
reduction in Na+/K+-ATPase activity is
the major path...
Cont…
 sorbitol, Na+/K+-ATPase activity and
[Ca2+] were measured using cultured
rabbit aortic smooth muscle cells.
 Epal...
In general
 Fructose metabolism has some
dangers because fructose is
metabolized differently from glucose.
 Unlike fruct...
Cont …
 Fructose on the other hand,
is more rapidly metabolized in the liver,
flooding metabolic pathways and leading to...
references
 Harper's Illustrated Biochemistry
8/1/2015 19
8/1/2015 20
of 20

Polyol 2015

polyol pathway and its relation with diabetic complications
Published on: Mar 4, 2016
Published in: Education      
Source: www.slideshare.net


Transcripts - Polyol 2015

  • 1. POLYOL (SORBITOL- ALDOSE REDUCTASE) PATHWAY:SIGNIFICA CE AND ROLE IN DIABETES MELLITUS 8/1/2015 1
  • 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 8/1/2015 2
  • 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+. 8/1/2015 3
  • 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. 8/1/2015 4
  • 5. 8/1/2015 5
  • 6. RING FORM REPRESENTATION 8/1/2015 6
  • 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. 8/1/2015 7
  • 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. 8/1/2015 8
  • 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. 8/1/2015 9
  • 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. 8/1/2015 10
  • 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. 8/1/2015 11
  • 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. 8/1/2015 12
  • 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. 8/1/2015 13
  • 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. 8/1/2015 14
  • 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. 8/1/2015 15
  • 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 8/1/2015 16
  • 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 8/1/2015 17
  • 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 8/1/2015 18
  • 19. references  Harper's Illustrated Biochemistry 8/1/2015 19
  • 20. 8/1/2015 20