Polyol 2015

polyol pathway and its relation with diabetic complications

1. POLYOL (SORBITOL-ALDOSE REDUCTASE) PATHWAY :SIGNIFICACE AND ROLE IN DIABETES MELLITUS 6/12/2015 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 6/12/2015 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+. 6/12/2015 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. 6/12/2015 4

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6. RING FORM REPRESENTATION 6/12/2015 6

7. PATHOLOGY In a hyperglycemic state, the affinity of aldose reductase for glucose rises. causing much sorbitol to accumulate, and using much more NADPH . leaving less NADPH for other processes of cellular metabolism . 6/12/2015 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 . 6/12/2015 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. 6/12/2015 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. 6/12/2015 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. 6/12/2015 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 . 6/12/2015 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. 6/12/2015 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. 6/12/2015 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. 6/12/2015 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 6/12/2015 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 6/12/2015 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 6/12/2015 18

19. references Harper's Illustrated Biochemistry 6/12/2015 19

20. 6/12/2015 20 Thank you