Is Glucose Toxic to Cells? Answers from the LIRKO Mouse and More ...

I briefly interrupt Thermodenialgate reports to revisit the LIRKO mouse.  But first, a little fun blast from the past.   A few years ago now I did a series on fat tissue regulation that involved various receptor and gene knockout mice.  I had a little fun making (low graphics tech) characters out of Star Wars Lego figures.  

First came C3KO, a mouse deficient in acylation stimulating protein, ASP, production.  Shortly thereafter came Obi No Leptinobi.

These mice are dueling fat receptor knockouts.  On the left is C5L2KO who lacks the ASP receptor on its adipocytes, and to his right is Kit FIRKO, FIRKO standing for fat insulin receptor knock out.  

I could swear I had one more using R2D2 but darned if I can find him.  Well, I've discussed the LIRKO mouse often enough now that I think it's time to bring on the Lego and dub thee Princess LIRKO.

The Princess is somewhat of a legend here at the Asylum because she slays so many of the TWICHOO (Taubes Wrong Insulin Carbohydrate Hypothesis of Obesity) myths.   The "L" in LIRKO stands for Liver, so this mouse is normal in every other way except that its liver doesn't "see" the insulin.   I've discussed LIRKO several times here, the two more extensive posts being Lessons from LIRKO and the earlier Bloggo Science ~ LIRKO Wars Edition.  To summarize briefly, the LIRKO mouse has total hepatic (liver) insulin resistance -- heck ... it's not resistant, it's insulin blind!  Characteristics of this mouse when young (around 2 months) are:

• Hyperglycemia - both fasting and postprandial
• Hyperinsulinemia - both basal and postprandial glucose-stimulated
• Normal to low body weight (and adiposity)
• Normal to low circulating NEFA (free fatty acids)

As the mice age (in the 6-12 month range):

• Hyperglycemia trends to hypoglycemia, particularly in the fasting state.  The livers of these animals are quite "sick" and are undersized compared to normal mice.  As such they begin to fail the mouse in their glucose generating capacities.  
• Hyperinsulinemia continues virtually unabated and pancreatic β-cell mass increases if anything.
• NEFA rise in LIRKO and controls but remain lower if anything in LIRKO

OK, with that background out of the way ... 

I return briefly to something that came up -- once again! -- during Thermodenialgate.  That is that Ian at "Science" of Fat Loss wrote the following after discussing how alcohol consumption inhibits fat and carb metabolism:

This actually serves as pretty interesting evidence on behalf of my hypothesis that the body preferentially oxidizes certain substrates over others, depending upon their inherent toxicity.

My feeling is that, if there are fatty acids, glucose and ethanol around at the exact same time, the body will first oxidize the ethanol and excrete its metabolites, while storing carbs, fats and proteins, since it’s the most toxic to us out of the three. The next most important fuel to get rid of would be the glucose; evidenced by the fact that carbohydrate metabolism directly causes a decrease in lipolysis (fatty acid mobilization from the adipocytes), due to the presence of insulin, and the immediacy of regulating blood glucose concentrations is imminent, so as to avoid tissue damage, organ failure and eventually coma and death. (Oh yeah, did I mention that glucose is toxic to human cells?[15] Open any biochemistry textbook ever written to confirm this. Or, just ask your local diabetologist what happens when our cells aren’t constantly oxidizing our extracellular fluid glucose, and it rises above ~120 mg/dL for any length of time…)

Oh wait!  I noticed that Ian has put up a newly revised, revised version of that post in which specific heat and magnesium are no longer mentioned.  Also, no longer mentioned is any acknowledgment of the prior errors that he has corrected or expressions of gratitude to the insightful readers that pointed them out.   Ahh well.  As long as science is corrected, that's really the point, and as I took him to task over sending readers to "any biochem book" and his hyperbole over glucose toxicity, he seems to have left out all of that.  The second paragraph now reads:  

My feeling is that if fatty acids, proteins, glucose and ethanol are floating around the bloodstream, at the same time, the body will first oxidize the ethanol and excrete its metabolites (while storing carbohydrates, fats and proteins), since it is the most toxic to us out of the four. The next most important fuel to get rid of would be the glucose; evidenced by the fact that carbohydrate metabolism causes a direct decrease in lipolysis (fatty acid mobilization), due to the presence of insulin, and the immediacy of regulating blood glucose concentrations is imminent, so as to avoid tissue damage.[10]  {formerly 15}

Which raises the question, what exactly is this evidence for glucose toxicity in our cells?

Toxicity

We are only a week or so out from yet another functional medicine summit, this time on detoxifying.  There are several terms I wish would be eliminated from the diet and fitness world vernacular.  Toxic and its various related terms are near the top if not at the top of that list.  Yep, I've ranted about this before:  Toxic.  So just to be fair and spread the knuckle rapping around, we have this Tweet from that post to demonstrate that Ian is by no means alone demonizing glucose:

I guess Lundell doesn't consider alcohol toxic, but this nonsense is truly over the top.  The term is used far too indiscriminately in this community.  

Is glucose toxic?  On the surface it most certainly does not meet the definition above.  I'm sure that, as with water we drink and oxygen in the air we breathe, there exists some toxic dose of glucose, but a standard OGTT involves 75 grams of the stuff.  In 1960, in an attempt to determine the insulin secretory capacity of a human, Yalow & Berson submitted several subjects (non-diabetic and diabetic) alike to a 250 gram "assault" of glucose administered over 150 min.  This was done 100 g initial dose followed by 50 g doses at 90, 120 and 150 min afterwards.  As discussed in this post of mine, no sustained hyperglycemia occured in the non-diabetics.  That 250 grams would be 1¼ cups of "sugar" or basically a 2L bottle of Coke (sweetened with glucose ).  

I think from a dietary point of view, especially in light of people like Michael Phelps and Mark Sisson (who claims to have consumed 1000 g carb/day during his days as an elite competitive endurance athlete).

If Fill-in-the-blank were Toxic, Why Would the Body Make It?

This is actually a very good question, but it is not enough to counter all claims regarding possible toxicity.  For example, our bodies will make small amounts of acetone naturally, but we don't make a habit out of drinking nail polish remover!  (I always get a kick out of the MSDS, lab precautions and such for acetone when women routinely will soak their nails in the stuff to remove false nails and such!  But I digress ... )  

But no matter the extreme fasted examples and such of ketones replacing glucose for fuel, there are certain cells in our bodies that are designed to run on glucose -- our brains for example.  A major impediment for aggressive management of blood glucose in diabetics is the risk of far-more-potentially-life-threatening hypOglycemia.  

from this study
blogged on here

But here's a thought -- IF glucose were toxic to cells, why would the liver continue to produce glucose after a meal, and why would insulin stimulate uptake of glucose into the cells?    This makes no sense, especially when cells in the blood -- e.g. glucose dependent erythrocytes (red blood cells) -- possess "always on" GLUT1 transporters.  By that I mean that unlike GLUT4 transporters that can be insulin stimulated, GLUT1 is insulin independent.  It would seem far more efficient to protect the RBC from excessive glucose influx and leave it swirling around in circulation and clearing slowly into the cells of all types, rather than sweeping it out of circulation and into cells it would damage, and eventually needing to ramp up endogenous glucose production again.

If glucose were so toxic to cells, why is it that only about one-quarter of it gets shuttled to glycogen for storage.  Why not store most of it and break that down on an as needed basis?   If metabolizing glucose was somehow harmful to the cells -- being a sugar burner -- why does the increase its rate of oxidation when there's more around instead of storing it to burn off at a steady slower rate the cells an handle?  

Heck ... let's go one step further.  If glucose is so toxic, and yet it is required to sustain life, why isn't dietary glucose "bundled up" in some glycogen blob equivalent of chylomicrons?  

The thing is, the body makes way more effort to avoid hypoglycemia than hyperglycemia.  Endogenous glucose production in the liver is regulated not just by stimulus (pressing the gas = glucagon) but also by inhibition (pressing the brake = insulin), where insulin also suppresses glucagon secretion as it rules the circulatory roadways.  

Taken together, it is difficult to imagine that glucose is toxic to cells or that there is any need to burn it up really really fast to get it out of the way per Ian's suggestion.  Rather EGP would be shut off entirely, glucose stored in non-reactive form, then used when needed.  Only when stores got very low would EGP resume.  We know this is not the case.

But How About In Uncontrolled Diabetes?

image link

Glycation -- some say it with a "k - hard c", some with a "s - soft c" (I'm the latter for whatever reason).   Nowadays it is fairly common to use the glycation of hemoglobin to assess the average level of glucose in the blood.  Risk of any number of things, especially as concerns cardiovascular diseases, goes up quite rapidly as HbA1c rises over around 8%, for example complications in the plot at right.

So this seems to be pretty compelling evidence for chronic glucose toxicity.  The problem with this is that, like so many other things, we cannot separate the underlying pathology (the cause of the hyperglycemia) and concurrent conditions (e.g. elevated free fatty acids) from the singular agent (glucose).  This is me talking here, and I don't have the time to flesh this out with various studies, but it appears to be the relative lack of insulin that is at the root of the problem.  It is something that begins long before one becomes overtly diabetic, but other dysfunctions have already progressed -- things like ectopic and visceral fat deposition and altered lipid profiles.   

It is important to keep in mind that this excess glucose is not coming from the diet, and if glucose were so toxic, why doesn't the body respond to it like alcohol -- which I think we can all agree *is*.  One would expect this toxicity to be noticeable much earlier on than once diabetes becomes full-fledged.  Folks can be mildly diabetic for years without knowing it.

Macronutrient Hierarchy is Established by Storage Capacity

I don't really wish to harp too harshly on Ian here, but a far simpler rationale, as has been set forth by the scientists who did the work in this area, for fuel selection has already been established.  It also makes common sense.  We metabolize what we can to produce energy.  We metabolize that which we cannot efficiently store first.  There is no direct route to store alcohol so it is burned off first.   

image link

Next in line is protein.  Again there is no formal storage depot for protein.  During growth some net amount of ingested protein is added to the lean tissues in the body, but even growing humans still metabolize significant protein.  We know this because we excrete urea all the time which is the "amino" part of the amino acid.   Amino acids are joined together to form proteins using that amino group, as shown at right.  

Therefore, excreted nitrogen is from amino acids that have been metabolized for energy.  The limit on how much protein we can consume is dictated by the liver's capacity to convert the ammonia produced into urea.  In a way, a case could be made for any excess protein being at least potentially toxic as its breakdown necessarily produces a substance that is lethal in large doses.  Things that make you go hmmm... 

But, dietary protein not required for immediate use as a source of amino acids for building various proteins in the body, must be metabolized as it cannot be stored.  As discussed in this short post, the best we have for protein "storage" is a circulating pool and a recycling plant.  Contrary to software manager turned nutritional "science" gurus, protein can be used by the body for energy by feeding into various places in the Krebs Cycle, and is NOT converted to glucose in obligate fashion before it can be broken down to produce energy.

Now we get to carbohydrates.  Unlike ethanol or protein, there are no toxic compounds produced here.  Well, let me take that back, one could argue that the lactate produced in anaerobic glucose metabolism is toxic, and yet lactate can feed into other metabolic pathways and is a wonder fuel for the heart!  Lastly the fatty acids are tapped.  Why?  To repeat myself ...

• In general, excess mass is detrimental to an animal that must be able to move around to find food and water to sustain itself,  and avoid death by predator.
• Every gram of energy containing glycogen is associated with 3-4 grams of non-energy containing water.  Therefore stored carb has an energy density of only around 1 Calorie per gram!  

For this reason, animals store excess energy primarily as fat.  Stored triglycerides contain around 9 Calories per gram, but there is some obligatory water associated with this lipid, etc., so let's say 8 Calories per gram or roughly 8X the energy per pound.  This isn't rocket science.  

But ... Mah Liver!

One more common meme about toxicity.  It seems that many, like Fructophobe In Chief Robert Lustig, will point to the role of the liver in metabolism to assess and assign toxicity.  To wit:  Ethanol is toxic, therefore the liver metabolizes it to detoxify the body.   So we have:

• Fructose is toxic because the liver metabolizes it.  It converts it to glucose, it stores it as glycogen, and even converts it to fat!  Please point to where any of the preceding endpoints are "bad" for cells.
• Glucose is toxic so the liver absorbs what it can and stores it as glycogen!  Or ... the liver likes to keep glycogen on hand as a ready supply for fulfilling one of its major roles in life, which is maintaining a minimum glucose level, and breaking down glycogen is easier than gluconeogenesis.

Those are our carbs and they hardly seem toxic if we're going to be level headed about this.  But ...

• The liver deaminates amino acids which produces toxic ammonia which the liver must then convert to urea for (lost energy!) excretion.  Is protein inherently toxic?  While the human body seems to do just fine on far less protein than some would advocate, it is ultimately protein "starvation" that kills (as the body cannibalizes organs).
• The liver metabolizes medium chain fatty acids.  We lack the metabolic mechanisms to elongate medium to long chain fatty acids so, as with alcohol, we have no capacity to store these fats.  They are broken down for energy by the liver, often resulting in ketone formation.  Unlikely you could get into ketoacidosis from MCTs, but many also experience negative GI effects from MCTs due to the obligate rapid metabolism, so there appears to be some degree of acute toxicity at play here.

Bottom line:  Involvement of the liver seems to be a no go here.

LIRKO ... Remember?  

OK!!  I'm getting there.  So in the preceding ramble I laid out the case for why toxicity is not some universal benchmark for metabolic preferences, nor is it necessarily an indicator of toxicity.  These can be related, but the hierarchy of macronutrient metabolism is quite clearly on an ability-to-store prioritization basis.

So in the end we're left with this question of whether there is much if any evidence that glucose is, per se, toxic to cells.  To support his point -- in a post formerly citing 28 references, now whittled down to 23 -- Ian provides a single reference.   His revised post only cites this reference as evidence that the body needs to burn glucose to avoid tissue damage, but even that is a bit broad for a single citation.  

But before I go on, I'm going to repeat myself here to drive home the point.  IF glucose were toxic, but knowing that it is essential in some quantities for life, which metabolic scheme sounds more efficient and less life threatening?

1. Rapidly store all dietary glucose, releasing it slowly in order to just fuel the glucose metabolism necessary to sustain life, and perhaps having gluconeogenesis as a pathway only initiated when stores are near empty, or ...
2. Rapidly clearing dietary glucose into cells, where some is stored but the cell is "forced" to burn of the majority, only so that later in the fasted state the body is forced to make even more glucose.

If glucose is toxic then #2, which is how our metabolisms are geared, makes no sense.  But this is the metabolic system that is seen in all animals (though relative partitioning may obviously vary).

But then maybe when the system goes awry it's the problem?  Enter Ralph DeFronzo and Ian's singular reference:  Glucose Toxicity.

Glucose toxicity is a well-established entity that has been shown in animal models of diabetes to contribute to development of insulin resistance and impaired insulin secretion. In type II (non-insulin-dependent) diabetes in humans, a considerable body of evidence has accumulated indicating that a chronic physiological increment in the plasma glucose concentration leads to progressive impairment in insulin secretion and may contribute to insulin resistance as well. The precise biochemical mechanism(s) responsible for the hyperglycemia-induced defect in insulin secretion remains to be defined but may be related to a defect in phosphoinositide metabolism.

Even scientists tend to use this term toxicity more broadly than its meaning in scientific contexts!   Regardless of what the full evidence and conclusions of this paper, it focuses primarily on  β-cells in the pancreas and any sweeping generalizations to other tissues and organs is seriously overstepping.  But if glucose is toxic -- e.g. poisonous -- to β-cells, then hyperglycemia should have a predictable deleterious dose-response effect on these cells.  

In LIRKO it does not.  Somewhat the contrary, actually, as the  β-cell mass is increased in LIRKO, presumably to handle the enhanced production of insulin brought on by the insulin-blindness of their livers and the constant stimulation by unchecked gluconeogenesis.   I repeat ... in LIRKO

hyperglycemia ≠ β-cell death/dysfunction

The only reasonable conclusion from this observation can be that glucose is not, toxic to  β-cells.  When you look at the rest of Princess LIRKO, it is only her liver that suffers.  It may not have been tested for, so it would be interesting, but glucosuria is not seen, therefore kidney function is not likely impaired.  Which leaves neuropathy, a condition that is often blamed on hyperglycemia ... I haven't read where LIRKO has been tested.

The thing is, in human diabetics, you have insulin deficiency, glucose and fatty acid excess, and disruption in protein anabolism/catabolism.  You cannot isolate the glucose levels.  In LIRKO, we are able to do just that.  LIRKO is otherwise pretty normal but its workhorse pancreas is doused continually in glucose to no negative effect.  

If you see A, B, and C along with Factor X, then all three are potential suspects in Factor X.  If you see A but not B and C or Factor X, it is highly unlikely that A is the cause of X.  Further, the case is strengthened that B and/or C is the culprit.

The LIRKO mouse presents compelling evidence that glucose is not toxic.  

The snowball effect where uncontrolled diabetes seems to further damage the pancreas, is most likely due to another causative factor or factors.  My bet is the free fatty acids that accumulate in the  β-cells ... stemming back to relative insulin deficiency and insufficient (healthy!) fat trapping and trafficking in adipocytes.