Health Science #2: How Polyol Pathway Screws You
Well, I'm a housewife, and I read a lot. The most interesting article that I read in a science magazine today is about diabetes, and after scrolling down some articles on the internet, I have found some interesting fact about how diabetes screws your body. I was so fascinated by the fact that people (particularly an obese) still ignored the potential harm of eating food with a high level of sugar. Obesity is pandemic and has been one of the medical issues that people in a public health sector are struggling with. In 2015 alone, it is estimated that 30.3 million people which include all age range had diabetes and most of them are obese.
There are a few theories which are proposed to explain the damage that a diabetic patient experienced:
- Polyol pathway
- AGE (Advanced Glycation End) product
- Protein Kinase C isoform
- Hexokinase Pathway Influx
In this series, I will be focusing more on the polyol pathway and explained to you guys in the most straightforward term on how they caused damage to our body.
Polyol pathway
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People who had been diagnosed with diabetes mellitus has a high blood glucose concentration. The increase in blood glucose level is attributed to insulin resistance or the incapability of pancreas to produce enough insulin for processing glucose after a high carbohydrate meal. Polyol pathway is activated when the amount of glucose in the cell (intracellular glucose) elevated beyond its average level. Glucose is highly damaging. It cannot stay long in the blood circulation as it can form a detrimental molecule called AGE as a result of an interaction with circulating protein. So when the amount of glucose available in the cell increases, the polyol pathway will be activated.
Polyol pathway is a two-step metabolic process which involved a rate-limiting enzyme called aldose reductase (AR). This vital enzyme would trigger the conversion of glucose into sorbitol which uses a coenzyme called nicotinamide adenine dinucleotide phosphate (NADPH). This is a reduction process in which the NADPH would contribute one hydrogen ion to convert glucose into sorbitol. The process of releasing hydrogen ion is oxidation, and the process which received hydrogen ion is called reduction thus we can say, glucose is reduced to sorbitol, while NADPH is oxidised into NADP. Sorbitol will then be converted into fructose in the second step of Polyol pathway by the enzyme sorbitol dehydrogenase (SDH). This process will release one hydrogen ion which will be utilised by Nicotinamide Adenine Dinucleotide (NAD) to NADH. So now, the sorbitol will be oxidised into fructose, while NAD will be reduced to NADH. It's a redox reaction (red: reduction, ox: oxidation).
So, based on the reaction illustrated above, four critical reactions could harm our body in the process which include:
- Sorbitol production
- Fructose production
- NADP production
- NADH production
How sorbitol and NADP affect the body
So what's the big deal about this 2 compounds which are formed through the first step of polyol pathway? Sorbitol is strong hydrophilic compound. It's an alcohol which is polyhydroxylated so it can't diffuse readily through the cell membrane. So where would the sorbitol go? It will go nowhere. It will accumulate inside the cell which can lead to osmotic damage.The utilisation of NADPH to produce sorbitol bring about adverse consequences to the body as well.
NADPH is an essential compound which is used in the production of an antioxidant called glutathione (GSH). The concept is, after fighting an oxidant which can potentially cause damage to the cell, this glutathione would be converted into an oxidised form. It will only become activated (ready to protect a cell from oxidative damage) when glutathione is in reduced form. The hydrogen ion needed to reduce the glutathione came from NADPH. If NADPH is used up from the sorbitol production due to high glucose level, the body store of NADPH will become depleted. It has been estimated about 30% of glucose would enter polyol pathway during hyperglycemic state which will cause a less production of reduced glutathione. This can potentially expose the diabetic patient to oxidative stresses which ultimately cause microvascular complication.
How fructose and NAD affect the body
The effect of fructose on the body is not well-known. Fructose can produce two compounds which contribute to the formation of advanced glycation end product. The compounds are:
- Fructose-3-phosphate
- 3-Deoxyglucosone
Sorbitol will be converted into fructose by the action of an enzyme called sorbitol dehydrogenase. This enzyme would remove one hydrogen ion from the sorbitol and this hydrogen ion would be used to reduce a NAD compound into NADH. Fructose will then become phosphorylated into fructose-3-phosphate and eventually broken down into another compound called 3-deoxyglucosone. Both of this molecule is important in the production of AGE.
NADH which is produced in the reaction can be a substrate to produce a superoxide molecule. Superoxide molecule is a free radical which can impose an oxidative damage to a cellular structure. This can be achieved by the electron transfer from NADH to a molecule of oxygen. We've discussed how the first part of polyol pathway can cause the reduction of a reduced glutathione, well in the second step, it can produce more oxidant which can increase oxidative damage. This is practically an "oh, crap" moment.
References
- Tang, W. H., Martin, K. A., & Hwa, J. (2012). Aldose Reductase, Oxidative Stress, and Diabetic Mellitus. Frontiers in Pharmacology, 3, 87. http://doi.org/10.3389/fphar.2012.00087
- Santos, J. C. de F., Valentim, I. B., de Araújo, O. R. P., Ataide, T. da R., & Goulart, M. O. F. (2013). Development of Nonalcoholic Hepatopathy: Contributions of Oxidative Stress and Advanced Glycation End Products. International Journal of Molecular Sciences, 14(10), 19846–19866. http://doi.org/10.3390/ijms141019846
- Giacco, F., & Brownlee, M. (2010). Oxidative stress and diabetic complications. Circulation Research, 107(9), 1058–1070. http://doi.org/10.1161/CIRCRESAHA.110.223545
- Jürgen Steffgen, Katrin Kampfer, Clemens Grupp, Christoph Langenberg, Gerhard A. Müller, R. Willi Grunewald; Osmoregulation of aldose reductase and sorbitol dehydrogenase in cultivated interstitial cells of rat renal inner medulla, Nephrology Dialysis Transplantation, Volume 18, Issue 11, 1 November 2003, Pages 2255–2261, https://doi.org/10.1093/ndt/gfg397
- Howling Pixel. Polyol pathway. Retrieved March 7, 2018, from https://howlingpixel.com/wiki/Polyol_pathway
- Wikipedia. Polyol pathway. Retrieved March 7, 2018, from https://en.wikipedia.org/wiki/Polyol_pathway
That was an extensive explanation. Kudos
Thank you
Interesting one @mawarmerah
Well, it reminds me one of my biochemistry class.... :)
Although I am interested in the biochemistry involved in the pathway of glucose intake by the cell. Factors responsible for the GLUT transporter activation and at which point of its pathway modification can be done to enhance the insulin binding or what can be done to open the channels without insulin.
Cheers
Is it really possible to open up GLUT 4 without an insulin?
Yeah, It is one of the approach.....
Still people are working on it.
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