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Searching online I see numerous studies and references that say that excess glucose in the body will trigger the polyol pathway which converts glucose to fructose. Example link.

How much of a carbohydrate bolus is required to activate metabolism through this pathway?

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    Hello Plasty, and welcome to Medical Sciences. Questions about general nutrition are off-topic here, so I have taken the liberty of refocusing your question on the metabolism. I also edited out some editorializing.
    – Ian Campbell
    Sep 14, 2023 at 17:00

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This is a very complex question, despite its apparent simplicity. To help you understand its complexity, it is, in a way, the equivalent of asking how much rain it takes to flood a city.

Well, cells of your body are, pretty much, akin to little cities. They have as many differences (if not more) between them, as actual cities. If a city is close to the sea, it will flood more easily. If the city contains many dry fields, it will absorb more water, and it will take much more water to flood it. Cities with better drainage infrastructure obviously "tolerate" much more water than others without such infrastructure. Even microscopic details may be important, the yard of each home, its soil composition, the plants, everything matters in the end.

If we simplify things, there is a relatively "mathematical" way to deal with the issue. Glucose enters the cell through GLUcose Transporters. Then, the standard pathway starts with the "escort" called Hexokinase. To "flood" the cell with glucose, the rate, at which glucose enters the cell must be high enough, so that Hexokinase does not have enough time to convert (phosphorylate for further processing) all this glucose, and much is left "standing there", so that another "escort", Aldose Reductase can grab it for processing down the road to Fructose.

Enter enzyme kinetics. The maximal velocity Vmax of an enzyme is its maximal rate of conversion, i.e. how much substrate (the thing the enzyme "takes by the hand", i.e. what it works on) it can handle per unit of time. The affinity of an enzyme for a substrate is expressed through the Km, i.e. the Michaelis constant. This tells us how much of a substrate (in terms of concentration) is necessary for the enzyme to work at a rate equal to half of its maximal velocity.

Is it really that simple? Of course not. There is another parameter to that, namely, the quantity of the enzyme. Cells can make more (upregulation) of some protein if they need to, or less (downregulation). But it's really much more than "just" mathematics. In order for such things to be determined, actual experiments would have to be made either in vitro or in vivo (not so easy).

Let's take a look at how extracellular glucose affects intracellular Aldose Reductase activity (to establish, first of all, that glucose abundance can actually trigger the polyol pathway, regardless of mechanism).

In [1](https://iovs.arvojournals.org/article.aspx?articleid=2122997), the authors studied how human retinal pigment epithelial cells behave when (among other things) they take a "bath" in higher-than-normal glucose concentrations. One of the things studied was the activity of aldose reductase (the enzyme that "escorts" glucose down the fructose alley, by converting it, first, to sorbitol), and how it changes when the surrounding glucose concentration rises from 5 mM to 20 mM* (normal serum blood glucose ranges are equal to 3.5-5.5 mmol/L). In short, take a look at Figure 3:

AR activity vs glucose concentration in medium

To cut a long story short, the figure indicates an almost triple activity of Aldose Reductase (AR) when the surrounding glucose is 4 times the normal serum blood glucose.

In [2], the authors studied another cell type, Peripheral Blood Mononuclear Cells (PBMC), of patients with diabetic nephropathy, versus normal controls. The authors state in their Discussion chapter:

This response was specific for D-glucose and was not due to differences in osmolarity, as demonstrated by the lack of response to L-glucose and mannitol. However, the major finding from this study is the quite striking and unexpected lack of a response of the ALR2 gene to D-glucose in the PBMCs of the uncomplicated patients (no microvascular complications after 20 years duration of type 1 diabetes) as well as the normal controls

So, higher glucose did not really upregulate Aldose Reductase in these cells in patients without diabetic nephropathy. What this tells us is that things are not that simple, dozens of parameters are at play, and the perturbation of any one among dozens and dozens of equilibria may be able to lead to upregulation of the Aldose Reductase pathway.

Now, what about the glucose transport itself... Well, in [3], the authors exposed bovine retinal capillary endothelial cells and pericytes to increased glucose concentrations and tried to figure out how fast they absorbed glucose. According to them:

Exposure of pericytes to 20 mM glucose for 8 days decreased the initial maximal rate of glucose transport by 30%, compared to pericytes cultured in 5 mM glucose (187 to 7 versus 133 to 9 fmol/20 s/g DNA, P < 0.01), but had no effect on glucose transport activity in endothelial cells.

In short, retinal capillary pericytes downregulated their GLUT1 transporter quantities (i.e. reduced total transporters), so that they could absorb less glucose. Retinal capillary endothelial cells did not do that. It is reasonable to presume that, in vivo, it may be important for pericytes to not allow too much glucose through, perhaps as a mechanism of retinal protection from the effects of hyperglycemia.

As a final note, to answer your question directly, no specific bolus can actually divert glucose substantially to the polyol pathway; most studies focused on chronic hyperglycemia. If you are interested on the subject, I hope this answer gave you some insights on how to expand upon a search to understand the intricacies behind your question.

*mM == mmol/L

1 Douglas N. Henry, Robert N. Frank, Seth R. Hootman, Sandra E. Rood, Charles W. Heilig, Julia V. Busik; Glucose-Specific Regulation of Aldose Reductase in Human Retinal Pigment Epithelial Cells In Vitro. Invest. Ophthalmol. Vis. Sci. 2000;41(6):1554-1560.

[2] Hodgkinson AD, Søndergaard KL, Yang B, Cross DF, Millward BA, Demaine AG. Aldose reductase expression is induced by hyperglycemia in diabetic nephropathy. Kidney Int. 2001 Jul;60(1):211-8. doi: 10.1046/j.1523-1755.2001.00788.x. PMID: 11422753.

[3] L J Mandarino, J Finlayson, J R Hassell; High glucose downregulates glucose transport activity in retinal capillary pericytes but not endothelial cells. Invest. Ophthalmol. Vis. Sci. 1994;35(3):964-972.

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  • Thank you! As a layperson, I find this extremely helpful. Chronic Hyperglycemia does tend to exacerbate AR as far as I can tell, but I will need to search and see if there are any studies done on people with just temporarily high blood glucose levels (consuming large amounts of refined sugar in a very short period). It also seems that the main problem is caused if the sorbitol doesn't get converted to fructose fast enough and this will cause damage to the kidneys and the eyes. But I need to read more to see what happens with the fructose further downstream. Again, thank you very much! Sep 28, 2023 at 2:35
  • @PlastyGrove you are welcome! Don't neglect to read about Sorbitol Dehydrogenase as well. Again, it's not that simple, there are experiments, where Sorbitol Dehydrogenase overexpression potentiates glucose toxicity instead of what you would think. It's not only sorbitol itself, if you read this, sorbitol does cause an osmotic shock, but fructose is also a potent glycating agent, leading to cellular damage in respective ways. Sep 28, 2023 at 11:20

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