The Sorbitol Blues

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Whether type 1 or type 2, the number one obsession for the diabetic individual is blood glucose. There is good reason for this. The host of complications that await the unfortunates who do not control their blood glucose level is daunting. However, glucose, advanced glycosylated endproducts (AGE), and the activation of the AGE receptor (RAGE) is only part of the problem. The other part is contributed by sorbitol. As it happens the two are tightly linked. High glucose leads to high sorbitol. If we want to understand mechanistically why these complications happen we need to consider sorbitol in addition to RAGE.

Sorbitol is derived directly from glucose in one enzymatic step. When glucose enters the cell there are several enzymes that compete to use glucose as a substrate. One of them, hexokinase converts glucose to glucose-6-phosphate which is the first step on the way to converting glucose to energy via the Krebs cycle. Hexokinase has a high affinity for glucose. What this means is that if glucose binds (which it will do) it likes the fit so well that it stays bound and a millisecond or so later gets converted. The other enzyme, aldose reductase, converts glucose to sorbitol. It binds to glucose with a much lower affinity. This means that glucose is likely to come off of its binding site before aldose reductase has a chance to convert it. So, as you might imagine, usually hexokinase wins, most of the glucose goes into the Krebs cycle, and all is right with the world.

Unfortunately, hexokinase is low capacity. In other words it takes a while for it to get around to converting glucose to glucose-6-phosphate. Meanwhile, aldose reductase is high capacity. If given the chance, it will do the deed very quickly. Now, if glucose levels increase we are faced with an interesting situation. Glucose preferentially binds to hexokinase but hexokinase takes its sweet time catalyzing the reaction. Since there is so much glucose around, all of the hexokinase is occupied. Aldose reductase is happy to take up the slack. It has lots of glucose with nothing better to do so voila, we get lots of sorbitol. The ratio has shifted and now aldose reductase wins.

Now, there are two ways in which sorbitol causes problems. The first comes from one of sorbitol’s functions. Sorbitol is involved in something we call osmoregulation. Osmolarity is the concentration of stuff inside the cell. It needs to be balanced with the outside. If it gets too high, water will flow into the cell causing it to swell and possibly rupture. This is especially important in the kidney where salt levels keep fluctuating as the kidney does its job. To keep things happy, the cell has volunteered 3 molecules to function as osmoregulators: sorbitol, myo-inositol, and taurine. However due to non-intelligent design, myo-inositol and taurine have other functions. If sorbitol levels go up, the concentration of these other two molecules must go down to keep the osmolarity of the cell in some reasonable range. Myo-inositol does all sorts of useful things including maintaining certain aspects of insulin signaling as well as functioning as a precursor for an important signaling molecule in tissues often damaged in diabetic complications. Taurine can function as a protective molecule. It has been implicated in lowering the damage caused by oxidative stress by scavenging free radicals (the chemical type – not the political type). Taurine also has been shown to potentiate energy metabolism in the heart. So, lowering these things is bad. Since we scientists love to give things names this one is called the “Sorbitol Osmolyte Hypothesis”. Sounds impressive.

The second way in which sorbitol causes trouble is that its creation uses up another important resource called NADPH. This is an enzymatic cofactor and one of the other important reactions that it helps catalyze is the conversion of glutathione to reduced glutathione. Reduced glutathione is one of the most important free radical scavengers that we have. Another important reaction that needs NADPH is the conversion of arginine to citrulline plus nitric oxide (NO). NO is necessary for vasodilation. Its loss leads to high blood pressure. So, as we make lots of sorbital we use up this important co-factor and it is no longer available for making those other important protective molecules.

There are lots of other details that fill out this bad scenario but I think you get the idea. Increased glucose, leads unintentionally to increased sorbitol, which unintentionally leads to decreased levels of other stuff which unintentionally leads to a decrease in the synthesis of protective molecules. In mountaineering, it is often noted that fatal accidents (apart from catastrophic avalanches of the great peaks) usually involve a series of bad choices with unintentional consequences.

We simply are not designed for abundance. Indeed we are not designed at all.

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Makelesi DriuMaheenDiabetic Retinopathy and Aldose Reductase Inhibitors | A Sweet LifeRobert ScheinmanJason Voss Recent comment authors
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Makelesi Driu
Makelesi Driu

Thank you so much, very interesting information.

Maheen
Maheen

Thank you so much! Exactly what I needed. 

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[…] Dr. Mark Petrash is Professor and Vice Chair of Research in the Department of Ophthalmology at the Rocky Mountain Lions Eye Institute at the University of Colorado Denver and  is a leader in the field of aldose reductase research.  Never heard of aldose reductase?   Here’s a primer:  Aldose reductase is the enzyme that converts glucose to sorbitol. Aldose reductase activity increases in the body as the glucose concentration rises, so in diabetics with high blood sugar levels,  more and more sorbitol gets produced.  Sorbitol, while good in small amounts, is bad when overproduced and contributes to many of… Read more »

Jason Voss
Jason Voss

Hi Robert,

Just wanted to see if you were willing to answer my above question. The info you’ve posted about Sorbitol is new to me and I’d love to see what your thoughts were on oral consumption of Sorbitol.

Thanks!

Jason Voss
Jason Voss

Fascinating information on Sorbitol that I wasn’t aware of. What are your thoughts on ingesting Sorbitol in both diabetics and non-diabetics?

Would that contribute to some of the problems you have outlined?

Thanks.

Coach Mike

“Indeed we are not designed at all.”  Wonderful!  Quite made my day.  I love the answer on sorbitol too, and the factor(y) floor analogy. :)

Jan
Jan

I seems to me the reactions you’re talking about here all take place inside the cell. In fact your article states, “When glucose enters the cell there are several enzymes that compete to use glucose as a substrate.” I’ve always understood that the job of insulin was to move glucose from the blood into the cell,  which is why in the absence of sufficient insulin, glucose ends up hanging out in the blood, picking fights and causing trouble. So what do the inside-the-cell reactions you describe have to do with diabetic complications? Or am I missing something here?

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