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.