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?


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.


charles grashow said…
JULY 14,1934

charles grashow said…
The value of whole potato in human nutrition
The Sweet Potency of the Sweet Potato

Sweet Potato: A Review of its past, present, and future role in human nutrition
Sanjeev Sharma said…
thanks for sharing your hits. I've gotten some good stuff out of these.
charles grashow said…

Start with page 323
Professor H. P. Himsworth: Diet in the Etiology of Human Diabetes.

"During wars the diabetic death-rate tends to fall. Closer analysis reveals that this is related, not to actual war, but to food shortage, for no such decrease occurs in belligerent countries whose food supplies are unaffected while it falls significantly in neutrals subject to privation."
"Overall, these studies show that very high fructose intakes can worsen insulin resistance in people who carry excess fat, but they do not offer strong support to the idea that normal intakes of fructose cause insulin resistance in those who are lean (particularly when the sugar comes from natural sources). It is possible that insulin resistance would develop over a longer period of refined sugar consumption, particularly if visceral and liver fat continued to accumulate, but this has not been demonstrated to my knowledge. Although some uncertainty remains, the evidence I've seen does not convince me that sugar intake within the typical range causes insulin resistance through an inherent metabolic effect of fructose, and I have seen nothing that suggests we should avoid eating whole fresh fruit. However, since added sugar increases the energy density and palatability/reward value of food, it can contribute to insulin resistance indirectly via increased food intake and body fatness in susceptible people. To be clear, I still think refined sugar is unhealthy and should be largely avoided."
John Smith said…
Sometimes it takes a few centuries for the toxicity of glucose to take effect. But sooner or later every single last one of those people on high carb diets will be dead as fried chicken.
charles grashow said…

Dry rice of 250 to 350 grams daily forms the basis of the diet. Any kind of rice is used as long as it contains no milk or salt. The rice is boiled or steamed in plain water or fruit juice, without salt, milk or fat. (One cup of dry white rice weighs about 200 grams, and contains about 13 grams of protein, 150 grams of carbohydrate, 1 gram of fat, and 700 calories.)

*Calorie intake is usually 2,000 to 2,400 calories daily. Intake varies based upon the patient’s condition: underweight people are fed more calories, and vice versa.

*Fruit and fruit juices are allowed.

*Dried fruits can be used as long as nothing but sugar has been added.

*White sugar may be used as desired (ad libitum); on average a patient takes in about 100 grams daily (400 calories) but, if necessary (to maintain body weight), as much as 500 grams (2000 calories) daily has been used.

*No avocados, dates, or nuts.

*No tomato or vegetable juices.

*Supplementary vitamins are added in the following amounts: vitamin A 5,000 units, vitamin D 1,000 units, thiamine chloride 5 mg, riboflavin 5mg, niacinamide 25 mg, calcium pantothenate 2 mg. (However, none of the Rice Diet patients during five months of treatment showed any signs (epithelial, neural or metabolic) to make one suspect any vitamin deficiency.

*Adaptation to the diet takes about two months.

*Exercise is encouraged. Bed rest is only advised with severe conditions.

*Water intake is restricted in some severely ill patients to less than 1.5 liters (6 cups) a day to prevent water intoxication and electrolyte imbalances.

*A few patients with kidney disease cannot tolerate the diet because of their inability to retain minerals.

*Once the patient’s health has returned, then small amounts of non-leguminous vegetables, potatoes, lean meat or fish (all prepared without salt or fat) may be added. However, if these additions result in adverse consequences (elevated blood pressure, enlargement of the heart, abnormal EKG changes, worsening kidney or eye conditions, etc.), then the basic Rice Diet, without modification, must be continued.

*A physician competent in diet therapy should follow anyone in need of the Rice Diet. Sicker patients need closer supervision.

The nutrient breakdown is about 2,000 to 2,400 calories per day (depending on the patient’s body weight): 95% carbohydrate, 4 to 5% protein (20 to 25 grams), 2 to 3% fat (rice is relatively high in the essential fat linoleic acid), 140 milligrams of calcium, and 150
milligrams of sodium daily. For more rapid and effective weight loss, the calories are restricted."

Nigel Kinbrum said…
I've blocked Lane, so I don't have to see his bollix ever again.

What with VLC'ers going bat-shit left, right & centre, and Peter D going on about possible (but highly improbable on a whole foods diet) reverse electron flow through Complex I caused by glucose, I think that the commenters here are the only sane people left in this neck of the blogosphere. :-/
Thanks for the share.

This was actually referenced in the comments section of this blog a while back. Perhaps fall of last year? I am not sure if it was you who shared the text, but there was another piece along with this one. This particular piece was about the 'Randle Effect'; how elevated blood fats can have a resonant affect on glucose tolerance and lipids that could last a good few weeks before normalising.
billy the k said…
Yeah, that was probably my earlier posting.  Which I also mentioned in my exchange with Nige.  The surprise for a lot of folks is to realize that the blood fats are elevated notbecause you've added some butter but rather because when you've cut your carbs down to ≤50g/d, you can't expect to have sufficient insulin around to inhibit lipolysis.  Unless you're injecting it, like Dr Bernstein.

While photocopying Randle's classic study that gave the world the
"Randle Cycle", I saw that the very next article in that same volume of the Lancet [April 13, 1963] was also a Randle paper, and for my interests, a rather important one:
"Effects of Low-Carbohydrate Diet and Diabetes Mellitus
On Plasma Concentrations of Glucose, Non-Esterified Fatty 
Acid, and Insulin During Oral Glucose-tolerance Tests"

"Five normal men (ages 23-36), whose daily intake of carbohydrate was more than 200g., were given 50g and 100g oral glucose-tolerance tests after an overnight fast.  The same men had repeat 100g tests after five days on a diet containing less than 50g of carbohydrate daily (fat and protein unrestricted), and two further tests two and five weeks after returning to a high-carbohydrate diet."

So after five days on <50g/d carbs, results:
a. Elevated fasting BG levels [an average 22% increase, i.e., from 86mg/dl to 105mg/dl]
b. Elevated post-glucose load peak BG rise [peak of 188mg/dl vs previous peak of 134mg/dl]
c.  Elevated fasting NEFA's [from 350μ-moles to 768μ-moles]
d. Elevated fasting insulin levels [from 16 to 67μ-units/ml]

The kicker was that after just five days of such restriction, these men resumed their previous "normal" carb intake [>200g/d]; after two weeks, and also after five weeks, more tests were given: [Randle wrote]:
"In our experiments five days of carbohydrate deprivation led
to abnormalities of plasma glucose, NEFA, and insulin during
a glucose-tolerance test which persisted for at least two weeks
after return to a normal diet...After resumption of the normal diet
the plasma concentrations returned slowly towards normal, ,BUT
[italics & emphasis mine]

As I said to Nige: Thanks to Randle, I became concerned about unwelcome--and possibly permanent--physiological adaptations that may occur as a result of a long-term ketogenic level of carb restriction.
MacSmiley said…
Enlightening post, Evelyn.
charles grashow said…

Start with page 105 to see Taubes' take on Himsworth
charles grashow said…
charles grashow said…
MacSmiley said…
Will somebody please drill this into Jimmy Moore's head?
Thanks for that as well.

I generally agree. Added fats don't mean insulin resistance by proxy, since the idea of 'added fats' themselves has a wide range of contextual implications. There's nutritional ketosis levels of adding butter, and then there's adding a pat of it to one's rice -- world's apart. Generally, one should avoid a state of metabolic adaptation that induces dylipidaemia/glycaemia. How they go about doing this can vary from individual to individual and the best adhered approach will always be the best, but since we're on that topic, whole food low fat diets also rather effectively avoid this state.

I do favour the school of thought that in the context of maintenance and excess energy intake, certain saturated fats can induce insulin resistance, but again, this would go back to what was being said in the above paragraph about amount and context.
MacSmiley said…
Found this image on Twitter.

More fun on Nigel's blog:

Evidence that Dihydrogen Monoxide is ineffective and toxic. I'm gonna' kill your buzz.

Mitochondria. Proton pumps.

*Mic drop!*

My blood glycated from the mere reading of this article! LOL!
Kevin Klatt said…
Obviously, water is the most toxic to your body - that's why your kidneys filter it and you pee so much!!
billy the k said…
Evelyn has pretty much covered the topic of overconsumption from all angles; often reminds me of the following, where we learned the formula for happiness:

"Annual income twenty pounds, annual expenditure nineteen six, result happiness. Annual income twenty pounds, annual expenditure twenty pound ought and six, result misery.” [Dickens. David Copperfield]

Similarly, we might write the formula for metabolic mayhem as:

                              E in >E out →hyper *YNI
[*you-name-it: ↑FBG, ↑PP-BG, ↑TG's, ↑LDL-C, ↑ NEFA's, etc.]
That is, all those blood markers you'd want to be normal now ain't.
The fix for metabolic mayhem?  Reverse direction!: caloric deficit       [which needn't be forever--see the "Newcastle Diet."] 

"Welcome all seeking refuge from low carb dogma" is the Carbsane heading,  and visitors here will find plenty of evidence that the demonization of carbs is a mistake.  I favour the school of thought that thinks the same applies to dietary fat.

Evelyn has, for instance, written that she is a butter-phile [but it doesn't follow that butter must therefore be regarded as its own food group!
 While a gram of fat has of course more than twice the E [kcal] than a gram of the other macros--making it perhaps the easiest to overdo, all the macros contain E and so the fat we eat is not per se THE dietary culprit responsible for metabolic mayhem.

Kade said: "...certain saturated fats can induce insulin resistance..."
I'm persuaded that the evidence shows that you are correct--and I don't think this effect occurs only in the context of excess energy intake.
BUT!  I'm also persuaded that the matter of 
nutrients is even more important for healthy-longevity than is the matter of temporary IR [which can be addressed by attention to the E in vs E out factor].

Milk, for example.  The sat fat in whole milk increases to some degree, let us say, one's IR.  So then: is skim milk therefore a better choice? It doesn't increase IR, and, after all, the Gov't requires fortification of the missing nutrients [the Gov't actually defines a food which has any of its nutrients removed as being adulterated!]  Let's consider the replacement of these lost nutrients [ a wikipedia search plus various links will turn up the following]:

 Vitamin A palmitate (also known as Retinyl palmitate) is added to low-fat milk products to make up for the vitamin A lost in fat reduction, and also acts as an antioxidant. Palmitate is attached to retinol (part of Vitamin A) to make the vitamin stable in milk. Palmitate is a major part of palm oil, and you get it by treating palm oil/ fats with really, really hot water (more than 200 degrees celsius) and distilling the whole thing.  Hmmmm… SO: they take the natural fat out of milk, and the vitamin A of course goes with it, so they take new synthesized vitamin A, mash it together with an acid from palm oil to make it bind better and put it back in the milk.  And this is what you get in exchange for avoiding artery-clogging IR-elevating saturated dairy fat?

  Hmmm...[no o o o thanks! --I'll take the sat fat in un-homogenized, pasteurized whole milk, for its healthy-longevity promoting naturally occurring & indispensable nutrient benefits --fat soluble vitamins A, D, E, & K--[not merely for its fabulous taste] and compensate for its ↑IR potential by my routine pre-dawn jogging.
Melly Crane said…
Evelyn, would you kindly finish this sentence? You're leaving me hanging as to your conclusion.

"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)." ...
Nigel Kinbrum said…
2, 4, 6, 8, everybody urinate! 😂
billy the k said…
Good find, Charles.  
I think, however, that Himsworth's papers from the 1935 Clinical Science (v2) are more pertinent in that they're focused on the glucose tolerance and insulin sensitivity of humans rather than rabbits.
     I know that Evelyn has wanted to get a copy of that classic 1935 paper, and she'd appreciate it if you could find a link to it.
(If anyone can, you can!)
Nigel Kinbrum said…
"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?"
'Cos it (and our kidneys, which also secrete glucose) hate us?
billy the k said…
Cleave's big Theory-of-Everything is that all carbs are great, 
except when refined, in which case they now become killers.
I don't buy it.
Evelyn has written previously about the misleading slipperiness in the term "refined foods."
I don't see how, for example, C₁₂H₂₂ O₁₁ is fine and dandy when it's 
inside an apple but suddenly becomes evil and unhealthy when it's outside.
charles grashow said…

"Diabetes mellitus is a disease that can now be treated as efficiently in general -practice as in the clinic or hospital. The whole treatment can be summed up in two simple rules: (1) Eliminate and keep entirely absent -from the urine every trace of acetone (ketone) bodies. (2) Remove or reduce to the smallest proportion loss of sugar in the urine. These rules are carried out by giving sufficient
carbohydrate to prevent the production of acetone bodies and, if necessary, insulin to enable the patient to utilize this carbohydrate."
charles grashow said…
Fair enough, although I am aware of your advocacy of saturated fat food sources from your many other posts.

Considering that we were having an exchange about insulin sensitivity and resistance, I thought I'd bring up that point regarding resistance and that it isn't just down to level of carbohydrate intake. That is all.

If one prefers to favour a whole food source of saturated fat where a mild degree of insulin resistance would be the pay-off for nutrient density -- that's well and good. I can see a sensible case for someone favouring whole milk over skim, on the other hand, people basing their diets on butter--not even milk--as an outright lion's share staple presents us with something substantially different... blatantly drastic, in my informed opinion. That's the point I was addressing and also distinguishing from yours, earlier.

Also, I don't buy entirely into the Weston A. Price Foundation's implicit theory that most of us in the developed world are suffering from some kind of chronic 'factor x' (fat soluble vitamin) deficiency. It in itself is rather reductive. Furthermore, this statement of mine shouldn't be taken to mean that I am against factor x either; I just don't think it is meant to be a lion's share issue or the missing solution to all of our problems as implied by another poster who's been losing their marbles about steaks and butter and the rise in US obesity statistics.

The talk about the benefits of whole milk kind of reminds of this time that I decided to annoy our resident research hunter, Charles, a bit on Andrew Kim's blog. Andrew posted up an entry about his menu for the day with a cron-o-meter screen cap of the food and nutritional targets. Charles questioned Andrew's choice to favour skimmed milk over the more vitamin rich A, D, E, K, whole milk. Andrew's response was that he didn't have a desire to gain more weight, without mentioning the other obvious points. So I decided to poke fun at the question by referencing the fact that all the daily vitamin and mineral allowances were beyond maxed out on every single front with more than enough fat--of which we don't nearly need as phenomenal an amount--to absorb or convert certain vitamins.

Yes, whole milk is a superior and non-denatured form of whole vitamin A, D, E, K, nutrition compared to skim milk. So is a generally diverse diet that might not prioritise large quantities of dairy or more reduced forms of SAFA for daily intake.
Ray Peat, dude!

Paving the way for the future with ice cream and orange juice!
charles grashow said…
Epidemiology of Coronary Heart Disease: The Framingham Study
Jane Karlsson said…
Why don't you buy it? The point is that refined carbs have had micronutrients removed which are needed for processing the carbohydrate. I don't think Cleave talks about that. He was a doctor, not a biochemist, and probably knew very little about carbohydrate-processing enzymes and what activates them.
Jane Karlsson said…
Nigel, Peter is probably right about that. He's talking about the G3P shuttle which links the electron transport chain in mitochondria with glycolysis in the cytoplasm. It's very clever, because it produces hydrogen peroxide which goes to the nucleus and activates transcription of genes for carbohydrate metabolism. So the more glucose you eat, the more you can process. I'm not sure Peter knows about this aspect of it.

The hydrogen peroxide is made by manganese-dependent SOD. Extra copies of MnSOD make flies and worms live longer. The activated genes are exactly those which are found to have lower activity in ageing animals. Glucose prevents ageing!

'...Transcriptional profiling indicated that the expression of specific genes was altered by MnSOD in a manner opposite to their pattern during normal aging, revealing a set of candidate biomarkers of aging enriched for carbohydrate metabolism and electron transport genes....'

So glucose will only stop you ageing if you have enough manganese. Do not eat rice which has had its manganese removed unless you want to get Alzheimer's. The enzyme PP2A which prevents Alzheimer neurofibrillary tangles is a manganese enzyme.
I should've clarified in the previous post. When I refer to
ADEK in the context of dairy, I explicitly mean K2. Otherwise, K1 is trivially
more abundant in some of the least calorically dense plant matter. I've engaged
in discussions about Vitamin K2 and its various forms (MK4; 7; 8; 9); in fact,
it was a chat with Nigel that won my interest. So my last response was to
address the benefits of the vitamin array in distinct terms of their K2
contribution, which I don't deny but I don't hold in as high a regard as some
of those WAP references you just shared.

There are plenty of thriving Blue Zone cultures that do not rely on
substantial amounts of dairy or K2-specific fat sources and do not have
elevated blood calcium or arterial calcification, bone degeneration, plaque
deposit issues or dental caries – quite the opposite, actually. So, while I
don't deny some of its understood benefits, I don't hold up K2 as the missing x
factor in human health and longevity. Reasonably favouring whole milk over skim
milk while having a sensible grasp on one's health is not at odds with this
perspective as those benefits are not being rejected.
Nigel Kinbrum said…
Aw, man. I don't read :-/

Am I missing-out on life?
Well, if you count head aches as a desirable part of life that you're missing. ; )

Not all that bad, but needs to be taken with serious contextual consideration.
Nigel Kinbrum said…
~50g/day dry weight Basmati rice contains ~39g of low-GI (mostly amylose) starchy carbohydrate. It takes me hours to om nom nom my way through a casserole dish full of Broccoli (~300g raw weight), mixed veggies (~250g raw weight), legumes (~50g dry weight) and Basmati rice (~50g dry weight).

If you seriously believe that the above food is going to damage my body in any way, shape or form, you really should consider getting your orthorexia seen to. It's bad for your serum cortisol to freak out over homoeopathic quantities of foods that have had some of their nutrients refined out.
Nigel Kinbrum said…
As I'm currently working my way through a casserole dish full of cooked broccoli (~300g raw weight), mixed veggies (~250g
raw weight), legumes (~50g dry weight) and Basmati rice (~50g dry
weight), I think I'll pass!
Mmm... headache.

Well, you're loss, bro.
Simple series of questions, for my end.

Does Jane's theory accept the RDA for manganese or do we need more?

If so, then how much more?

If so, then what are the chances that Nigel's whole food diet's already meeting this targets?
Nigel Kinbrum said…
See :-(
Nigel Kinbrum said…
If you're speaking literally, I was getting some mild headaches on my previous diet, but they're not so bad, now that I'm eating the above foods during the day.
Bloody hell... in 2012, you two were have the exact same argument over the single slice of white bread you were having, to which I posited the same question--i.e. what if manganese and copper for that meagre, insignificant, 100 calorie slice of bread are being met through other sources--only to end up with something about how Mark Sisson is avoiding damage by drinking wine... which kinda' support the contention within the question.

I'm starting to believe that I am trapped in a Matrix.
Likely because your magnesium requirement is being met and exceeded rather generously on such a diet, along with glucose.

Nah... I was just messing around.
carbsane said…
I'm going to put this up here although I'm woefully behind keeping up with my own comments section here! (Don't let that stop you all though :-) )

Just wanted to chime in on the micronutrient thing. I haven't looked in depth at this but have seen some interesting research on the role of minerals. However my sticking point vis a vis carbohydrate metabolism per se, is that here the high fatties are somewhat right: once it gets into your body it's all sugars, mostly glucose in the end. So how can the micronutrient content of the "package" vary so widely if XX mineral is required, depleted, etc. etc. Are these critical micros present in relatively similar concentrations in all starch sources? I don't see that. Similarly, how can the same human form thrive on such wildly different diets -- diets I might add, that until very recently (in the scheme of things) were largely seasonal, and rather unvaried?

Personally, I still favor varied omnivoury to cover the bases, but it's hard to dismiss reports of cultures basically subsisting on one or a few staple foods and not much more.

Also ... have come across tons of research on associations between mineral excesses/deficiencies and various conditions. We don't know the direction of causality (with VitD, there seems to be evidence of sequestration in adipose causing the deficiency for example), and correcting the imbalance doesn't always correct the associated condition.

So those are just some thoughts I thought I'd throw in! Carry on ...
billy the k said…
What--no hot sauce?
Rosie May said…
In this current U.K. heatwave Nigel (nearly over?) what you need to do is forget about the magnesium and take a leaf out Jack K's book . Get thee into a bathtub full of ice cubes and stay in the buff for at least an hour upon emerging to pick up your free leptin reset.
billy the k said…
Howdy Jane
"...Cleave...probably knew very little about carb-processing enzymes and what activates them."

Good point about the enzymes needed to process the carbs.
Indeed, this often overlooked factor is another of the reasons why folks on VLC diets see their BG's go through the roof when they  re-introduce  carbs.  The first reason is the "physiological IR" which kicks in to spare nitrogen [and save the bacon of the VLC dieter].  As Cahill explained:

"One mechanism [to spare nitrogen] is to prevent tissues not
needing glucose, such as muscle, from using glucose, and the low 
insulin accomplishes this by being inadequate in concentration
to permit glucose entry.  A second process also occurs, namely
  a functional atrophy of the glucose-using enzyme inside the 
so that even if insulin should rise, a diminished glucose 
        uptake persists until the enzyme hexokinase has been        
        resynthesized.  These phenomena explain the diabetic-type 
        glucose tolerance in any individual deprived of dietary 
It should be added that  adipose tissue likewise 
undergoes functional atrophy in the prolonged absence of     
ELEVATIONS in insulin levels..."

The part of that Fuji apple that I had yesterday that's responsible  
for "activating" the present functionality of the glucose-using enzymes needed to process the carbs in it is not those welcome beneficial micronutrients [which I'm all in favor of] but the 11.68% total sugars + 0.05% starch content.  Because, as you know, the glucose-using enzymes--hexokinase and glucokinase--are inducible enzymes--ones whose production requires a specific molecule, the inducer, which is a substrate of the enzyme.

It's the carbs in our foods that keep our carb-processing enzymes up-and-running.

But T.L. Cleave was no dope, and his book is a worthy read, especially the first chapter's analysis of evolution and hereditary defects.  A part I found especially noteworthy was at the very end: his "Natural Diet for Health" [p188-192 of the 1974 John Wright edition of The Saccharine Disease].  Rule No.1 was, and remains, to my mind worthy enough that I photocopied it to stick on the fridge:

1. Do not eat any food unless you definitely want it.—Eating 
food that is not wanted is a most unnatural act, yet frequently
takes place today.  One reason lies in eating routinely, especially when one is overtired or worried and does not really fancy any food at the time; another reason lies in eating a meal because someone
has taken the trouble to prepare it, or in eating food to avoid     
wasting it; whilst yet another reason lies in eating food on social
or business occasions, when it is taken for motives of politeness
or policy.  On all these occasions 'if you don't want it, don't eat it'.
   This decision is always made most accurately before coming to
the table.
[italics his]
StellaBarbone said…
Mark Sisson has given up the demon grape.

I don't need to worry about the manganese in an occasional bowl of rice because I am protecting my brain with regular consumption of manganese-rich dark chocolate. I recommend this solution.
I am curious about a couple of points.

Is fasting and 24-hour insulin guaranteed to be lower in long-term ketosis, or will the body keep fighting back as can be seen in certain cases where fasting glucose and glucorticoid-induced glucose and insulin stimulation start to creep back?

If functional adipose tissue atrophy does take place in prolonged absence of insulin, then why isn't this necessarily translating for everyone (Jimmy Moore, for example)? It would seem that from my reading--and this is all purely anecdotal--some individuals spontaneously lean out from long term ketosis, like a LOT, while others develop a skinny fat physiology with an increased adiposity around the waist region. In fact, someone recently commented on one of Evelyn's posts with a similar personal story.

StellaBarbone said…
My grandfather had a stroke in his early 50s. He went on the rice diet and died 20 plus years later in a bicycling accident. My grandmother gained quite a bit of weight after that since her rallying cry was, "My last meal won't be plain rice!" It wasn't.
Rosie May said…
Oh those Ornish confounding factors. I wonder what the response would be to someone who approached those confusionists and said " Hey I get tons of exercise and I do Yoga five days a week, I have a really loving family and really close friends but my cardiovascular risk factors are dismal - I just don't know what to eat, has any diet or way of eating shown any promise for someone like me?"
charles grashow said…
Well - as for me - I drink raw goat milk as well as goat milk kefir and occasionally sheep/jersey cow milk yogurt - they're all A2 as opposed to A1 which can cause problems
John Smith said…
Are you aware that storing the dark chocolate at temperatures below 65 degrees F or above 78 degrees F makes the manganese totally inaccessible to humans, assuring a prolonged and quite painful death to anyone relying on its consumption for proper manganese dosage?

Based on written reports it really is a terrible way to go.
Nigel Kinbrum said…
I forgot to mention the squirt of sweet chilli sauce into the wet rice & legumes mixture before adding the frozen veggies!
Nigel Kinbrum said…
I'll "Get thee into a bathtub full of ice cubes and stay in the buff for at
least an hour upon emerging to pick up your free leptin reset." YOU, in a minute! ;-) :-P
billy the k said…
Are you aware that a 100g Lindt 90% Cocoa chocolate bar (Peter
D's current lunch) contains 7.5g of total added sugars--refined white sugar C₁₂H₂₂O₁₁--having NO micronutrients whatsoever in them?
Nigel Kinbrum said…
I didn't know that Jane had an OCD, back then :-/
Nigel Kinbrum said…
"7.5g of total added sugars"
I can almost hear him spontaneously combusting right now...
StellaBarbone said…
I live in San Diego where the temperature varies from a frigid 65 degrees in the winter to a torrid 78 degrees in the summer, so I'm in luck!
Nigel Kinbrum said…
'Cos I'm crap at judging whether or not someone's messing around, I prefer to err on the side of caution and assume that they're not messing around.
Nigel Kinbrum said…
Mel posted a link to the following video on Twittard:-
Dr. Greger. Such vegan. Wow.
Lighthouse Keeper said…
Having today downed a pudding named ' Death By Chocolate' in a local pub one now regrets being thermometerless at the time (there's never an ardent Matt Stone devotee around when you most need one)
StellaBarbone said…
I hope that there is some magic, health giving property in delicious, delicious cheese. If so, I'm good to go. Whole milk yogurt is nice too, but I could not drink whole milk as a kid. Skim was fine, but whole milk was just icky. I haven't had it in more than 40 years.

Hitch blew the Iraq thing.
Rosie May said…
Nigel Kinbrum said…
You jammy dodger!

Hasn't San Diego got a large occasional downside, what with there being a fault named after it?
Yeah, but I'd hope that this wasn't one of those cases. I was obviously messing around. Wasn't I? ; )
One can try to reason, Nigel. I commend your patience in many regards.
Nigel Kinbrum said…
As Negative Feed-Back (NFB) loops regulate every process in the body, I think that the level in the body of each mineral, is also controlled by a NFB loop.

Although there are problems at the bottom end of intake (deficiency symptoms) and at the top end of intake (toxicity symptoms), everything works correctly over a wide range of inputs. Therefore, small variations in intake level caused by consuming small quantities of overrefined foods make no difference.
Yeah about Hitchens and Iraq, and I don't want to hijack anything here, but this is something I'm compelled to comment upon.

He has always argued for a post-Saddam era in the Middle East for reasons much more bigger picture and long term than the WMD angle. Certain tyrants were the direct mistake of world power interventionism and these mistakes needed rectification at some point. Hitchens' arguments link back to colonial imperialism and autocratic linchpins that have, in the longer term, kept the region fundamentally unstable.

In other words, global politics paralysed the region's ability to explore the slow but essential steps of democracy, and so the world powers bandaged that issue up by leaving autocratic dictators who are indeed some of the most cruel and sadistic individuals known to history. It was always a powder keg ready to go off and we did ascertain some benefits from this intervention with the rest of the follow up being a collosal disaster. Hitchens himself has been critical about the post-mortem of the Iraq invasion.

I say all of the above as someone who was rather stridently critical and cynical about the entire Iraq war as well as the political talk points--WMD hype included--used to manipulate the American public into supporting this war.
Nigel Kinbrum said…
"We don't know the direction of causality (with VitD, there seems to be
evidence of sequestration in adipose causing the deficiency for
example), and correcting the imbalance doesn't always correct the
associated condition."
I know that this is anecdotal, but:-

1) My Mg level has been maintained in the normal range, by using Mg supps since 2003.

2) I was severely IR between 2003 and 2007, based on fasting TG's.

3) I started supplementing with Vitamin D3 at 2,000iu/day + UVB lamp in 2007 and changed it to 5,000iu/day in 2008.

4) In September 2008, I got the BEST OGTT result EVER, and low fasting TG's. I was no longer IR.

Nigel Kinbrum said…
I've only just noticed that one of your comments has a ; ) in it.

So yes. It's obvious, now! 😜
Jane Karlsson said…
What theory?

The RDA for manganese is nonsense because how much you need depends on how much iron you have. If you eat meat every day, you'd better not eat white flour/rice/sugar in any quantity. Nigel told me he eats a lot of liver and kidney, which have a very high Fe-Mn ratio.

Nigel's mother died of DLB, a brain disease resembling Alzheimer's + Parkinson's + (perhaps) prion disease. There is evidence suggesting that manganese deficiency is an important cause of all three.

Obviously, eating a tiny amount of white rice is not going to kill him, or probably, even give him DLB. But Alzheimer's is thought to start several decades before symptoms do. If he ate a rubbish diet when he was younger, he may have rubbish in his brain which needs clearing out. He needs to find out about autophagy, and what micronutrients are needed for it.
Thanks for the response. I was referring to your theory re: manganese, copper and iron.

Next question: Given that intake of some of the most unprocessed and whole plant food--until and unless one is simply consuming mono-meals of brown rice--will contain substantial amounts of non-haem iron, what kind of realistic ratio would one be looking at for manganese to iron intake.

And on the subject of autophagy, are we talking about overall caloric restriction, or just protein restriction, or intermittent fasting, or some kind of variable combination of all of the aforementioned?
Jane Karlsson said…
I do not have theories. All I have is what I have read in the literature. If there are theories here they aren't mine. People claim to have theories because they need funding for their work, or power. I don't.
I'll call it Ray Peat's idea in that case. I have to call it something when every discussion on a certain topic comes down to one party reducing most problems to the role of a certain factor rather passionately.

Nigel had a theory about the carbohydrate-insulin hypothesis. Money grabber.
Jane Karlsson said…
No, power grabber. And you?
billy the k said…
Right ON.
Jane Karlsson said…
Hi Billy
The 'physiological IR' is probably due to low intracellular magnesium. Insulin makes cells take up magnesium, which increases their insulin sensitivity.

'Magnesium, the second most abundant intracellular divalent cation, is a cofactor of many enzymes involved in glucose metabolism. Magnesium has an important role in insulin action, and insulin stimulates magnesium uptake in insulin-sensitive tissues.'

This is important because it explains Himsworth. He found glucose increased insulin sensitivity, and it most likely did that by raising insulin which raised intracellular magnesium.
Jane Karlsson said…
Glucose is made in plants by photosynthesis, which needs Mg for chlorophyll and Mn for water splitting. So if you eat plants which contain glucose or starch, you are eating Mg and Mn as well, unless you remove them. You would be insane to do that, because they activate enzymes of carbohydrate breakdown as well as carbohydrate synthesis. Glycolysis is Mg dependent. Gluconeogenesis is Mn dependent, and so are glycosyltransferases.

And guess what, ATP synthesis is Mg dependent. No Mg, no ATP.

The big mystery is why so many people like their carbohydrate without the Mg and Mn. What's the attraction? To me it tastes awful.
charles grashow said…
The Cause of Atherosclerosis
William C. Roberts

"If it is useful for the LDL cholesterol to be <100mg/dL after a heart attack, surely it must be useful for the LDL cholesterol to be <100 mg/dL before a heart attack! Therefore, in my view, the goal for all populations—not just those with heart attacks or strokes, diabetes mellitus, or non–coronary atherosclerotic events—must be LDL cholesterol <100 mg/dL and ideally <70 mg/dL. If such a goal was created, the great scourge of the Western world would be essentially eliminated, “primary” and “secondary” prevention would be the same, and >100 million Americans—rather than the present 13 million—would need to be on a statin drug with or without ezetimibe or be pure vegetarian fruit eaters."

"Thus, although not clearly established at this time, to prevent atherosclerotic plaques, the serum LDL cholesterol must be <70 mg/dL, the serum total cholesterol certainly <150mg/dL, and the high-density lipoprotein (HDL) cholesterol >20 mg/dL. The latter surely a surprise to most readers—is in patients with a serum total cholesterol level about 130 mg/dL and a LDL cholesterol level of about 60 mg/dL. Exactly what HDL cholesterol level is required to prevent plaques is unclear at this time, but clearly if the LDL cholesterol is very low (eg, 50mg/dL), then a low HDL cholesterol—as long as it is >20mg/dL—appears not to be dangerous. Ideal may be equal serum HDL and LDL cholesterol levels or an HDL cholesterol >LDL cholesterol. In summary, the recommended guideline numbers—particularly those for primary prevention—are intended for decreasing the risk of atherosclerosis events, not for preventing formation of atherosclerotic plaques."

"The average serum LDL cholesterol level in American adults is about 130 mg/dL. Therefore, if we want to prevent plaque formation in the United States, most of us will need a 50% LDL cholesterol reduction! As shown in Table 1, that goal can be achieved by 3 doses of statin monotherapy (rosuvastatin 20 and 40 mg daily or atorvastatin 80 mg daily) or by adding ezetimibe 10 mg to all statin doses except the lowest level of recommended statin doses. Because titration is often neglected, starting the dose from the beginning, which achieves the preventive goal (LDL cholesterol <70 mg/dL), appears reasonable."
Nigel Kinbrum said…

You need to declare your Conflict of Interest - your OCD about not ever eating refined foods, due to your imagined lack of micro-nutrients in them like Mg, Mn & Cu.

It's not fair on billy the k if you don't.
billy the k said…
"Since insulin sensitivity is absolutely dependent on magnesium, the best explanation is that
[increased] glucose caused insulin release and the insulin caused Mg uptake."

Jane, I do believe you are verging on an error again.

1. Himsworth tested dietary carbs, not "injected glucose."

2. While Mg is important for insulin sensitivity, it does not follow that the Physiological IR secondary to a VLC diet must therefore be due to an inadequate intracellular Mg content:
The efficient proximate cause of the housefire was Jones' smoking in bed; the fire was
"absolutely dependent" upon the presence of flammable bedsheets as well as air-in-the-room, but the newspaper report will not include those as being among the causal factors responsible for the fire.  Rather, the efficient proximate cause--the predominant cause that set into motion the chain of events--was smoking in bed.

Magnesium's role in the Physiological IR that results from substantial carb restriction is like that of the bedsheets in the housefire.  The predominant cause is the glucose fatty-acid cycle (Randle's Cycle).

Nigel K's recent comment [to Carbsane] re Negative Feedback Loops and mineral balance in the body is directly applicable to this matter of the Magnesium-inadequacy factor in IR.  Nige said:

  "Although there are problems at the bottom end of intake (deficiency symptoms) and 
at the top end of intake (toxicity symptoms), everything works correctly over a wide 
range of inputs.  Therefore, small variations in intake caused by consuming small
quantities of overrefined foods makes no difference."

Jane, it's a good thing that increased Mg uptake will not prevent Physiological IR:  despite the elevated ketones on a VLC diet, your brain will still be absolutely dependent on some glucose, and if your Mg supplements allowed your muscle cells  to once again start again oxidizing the little glucose available, your brain would NOT BE VERY HAPPY.
Jane Karlsson said…
Himsworth did indeed inject glucose. Charles gave you the paper and you
called it a 'good find'. Not good enough to read, obviously.

Nigel is almost right about mineral balance but not quite, because of iron. Iron doesn't really get excreted, and it accumulates with age. Free iron is very toxic. Ask Nigel which minerals prevent iron toxicity.
Jane Karlsson said…
Hi Nigel

OCD? I have obsessive compulsive disorder, and that's why I don't eat refined foods? No. I avoid them because of the experiment I am doing. 30 years ago I read about Robert McCarrison's work. I decided to find out whether the diet which produced excellent health 100 years ago in India, in both humans and rats, would do the same today using modern western ingredients. Obviously, I needed to stick to the diet, and have done so.

I have spent 30 years reading the biomedical literature with a view to finding out how this diet works. My experimental work on tissue regeneration together with my reading led me to believe that the repair processes which fail in modern degenerative disease are dependent on minerals which get removed from carbohydrate foods.

My brain is in very good nick. How's yours?
Nigel Kinbrum said…
I'm sorry Jane, but refusing to ever eat a small amount of a minimally-refined carbohydrate is not rational behaviour. It's an Eating Disorder. The reduction in micro-nutrients from eating a small amount of a such a food is insignificant.

I get the feeling that you're not reading my blog. I've recently mentioned Negative Feed-Back loops as regulators of all bodily functions, so that humans can survive over a wide range of diets and environments. Enzymes can up & down-regulate their action, depending on the concentration of input & output substrates. The body doesn't need precise amounts of micro-nutrients - it works over a wide range of input levels.

I don't want to waste any more time discussing this. You put me through the wringer with Burgen Soya & Linseed Bread some time ago. You endlessly-quibbled about nutrient losses in just one slice of Burgen a day. I'm not going through it again!

At the very least, tell people that you never eat anything that's been refined, in any amount, and let them make up their own minds.
Jane Karlsson said…
I put you through the wringer? Sorry. Is that really how you saw our conversation? I was trying to help. I thought you might be interested in what I had found. After all, I have been reading the literature for far longer than you have, and unlike you I am a biologist. That doesn't mean I can't learn from you, of course. What about you learning from me?
billy the k said…
Another error.

Jane, I'm guessing you did not read that most-cited classic 1935 Himsworth paper.
To refresh your memory:  

"The DIETETIC factor determining the glucose tolerance and insulin sensitivity to insulin of healthy men."

True, the term dietetic is  used as well in the title of the paper that Charles linked to, but I assure you that if you read the paper above, you would find that while the sensitivity to insulin was [of course] determined by intravenous injection, all of the administered carbs were dietary ones taken in MEALS.  Not a single test involved injections of glucose in their EARS, as was done to the rabbits in the study you're referring to.

billy the k said…
That is to say:  the ear injections of glucose were how the GTT's were given to the rabbits, but the administered carbs were indeed also dietary ones taken in "meals": i.e.,

"250g fresh cabbage and ~150g oats & bran."

Whereas the GTT's given to the men was 50g glucose in 300cc H₂O and "taken by mouth."
Jane Karlsson said…
What error?

Yes I did read Himsworth 1935, at least I read the part you quoted.
And in the other paper, glucose injections increased insulin sensitivity only in carbohydrate-fed animals, not in fat-fed ones. The fact remains that glucose injections can increase insulin sensitivity. I imagine you would agree that glucose -> insulin -> Mg uptake is a reasonable explanation. This explanation would not have been available to Himsworth 80 years ago.

If insulin makes cells take up Mg, it should be released again during fasting. It looks like this does actually happen. Serum norepinephrine increases, and it makes Mg leave cells.

'Norepinephrine evokes a marked Mg2+ efflux from liver cells'

'Resting energy expenditure in short-term starvation is increased as a result of an increase in serum norepinephrine'

So now we need to know whether eating low carb raises serum norepinephrine. It looks like it does.
'The effect of low-carbohydrate diet on the pattern of hormonal changes during incremental, graded exercise in young men'
billy the k said…
I can see that I've mistakenly left some impressions in need of correction:
With regard to micronutrients: I'm all in  favor of them.
And as for the major elements, magnesium is right up there as one of my favorites.  
Jane, we are closer than you think.
Jane Karlsson said…
I rather thought we might be. Excellent.
billy the k said…
I hasten to add that while being all in favor of micronutrients, I still don't buy 
the claim that refining some of them out of some foods--like rice and pasta--thereby suddenly
turns those foods into killers.

The other foods we enjoy along with them also have micronutrients, and [as Nigel K 
said] as long as the rest of your diet enables you to avoid both the toxicity symptoms at the 
top end of intake as well as the deficiency symptoms at the bottom end, that white rice and 
pasta is gonna be A-OK.

The long-lived Asians (white rice eaters) and the long-lived Mediterraneans (white pasta
eaters) are conspicuous counterexamples that refute the hypothesis that refined foods and 
"processed" carbohydrates are killer foods deserving of demonization.

That's why, despite being all in favor of micronutrients, I regard the blanket claim that refined food are ipso factokiller foods as lamentable and ludicrous.
billy the k said…
That is to say,the claim is--NOT YOU!
Jane Karlsson said…
Of course they aren't killers. People are living longer than ever in spite of eating copious amounts of micronutrient depleted food. They're sick, of course, but they aren't aware of it because their brains don't work properly. So they're quite happy to hang around and bankrupt the health services. Who cares? Not me.
billy the k said…
Jane--Let me address this micronutrient business from another perspective--that of a man I know you regard highly: Sir Robert McCarrison.  From his: "Nutrition in Health and Disease" (1936) [link below]

"...consider the foodstuffs which, when properly combined in the diet, are known to ensure perfect nutrition and a high degree of physical efficiency and health in human beings.  These foodstuffs are: 

1 a good whole grain cereal...or a good whole meal bread 
2 milk 
3 egg
4 green leaf vegetables
5 root vegetables--potatoes, carrots, etc.
6 legumes
7 fruit
8 meat
9 water

"That these provide all elements and complexes, known and unknown, needed for normal nutrition is evident from the fact that they are the ingredients of the natural diet of certain races of northern India whose physique and health, when they make use of their natural diets in their entirety, are unsurpassed by any other races of mankind."

The best diet, he found, was that of the Sikhs, but notice what he said in his earlier Cantor Lectures (Royal Society of Arts) about this Sikh diet: [link below]

"Supposing now we cut out the milk component of this diet or [even just!] reduce it to a minimum, we find that disease soon begins to make its appearance, especially if at the same time we limit the consumption of fresh vegetable foods. I have repeatedly made these restrictions with the result that respiratory diseases, gastro-intestinal diseases and maladies consequent on degenerative changes in mucous membranes and other structures of the body become frequent. It is apparent, therefore, that the diet of the Sikhs is only health-promoting so long as it is consumed in its entirety. Indeed, we know that those of this race who, for whatever reason, do not consume adequate quantities of MILK, MILK PRODUCTS and fresh vegetables, do not long retain the fine physique for which the Sikhs are famous. These food-materials are for them and in their own parlance, takatwar khurak (foods that give strength); nowadays we speak of them [using the expression coined by E.V. McCollum--the man who first confirmed this value these foods possessed] as 'THE PROTECTIVE FOODS', since they make good the deficiencies of muscle meat, REFINED cereals, etc., which enter so largely into the diets of western peoples."  [emphases mine] 

 While whole wheat chapattis do taste WAYbetter than if made with refined flour, McCarrison agrees here with McCollum that milk and milk products will make good the deficiencies of the latter.  But not vice versa. WHOLE wheat chapattis cannot make good the deficiencies of a Sikh diet that's devoid of MILK and its products.

 McCarrrison of course recommends that we choose the whole grain rather than the refined, but as he says [above], we won't suffer a cascade of pathologies from having some refined foods in our diet IF we also enjoy other good foods--namely the protective foods--that make good the deficiencies of not only the refined ones but also of our basic cultural staples--meat & potatoes or beans & rice.

Jane, that's the difference that makes all the difference.  I'm persuaded that McCollum and McCarrison were right about this, and that's why I don't accept the demonization of refined carbohydrates.


[BTW--you may find (as I most certainly did)  McCollum's major work of some interest:  "The Newer Knowledge of Nutrition: the Use of Food For the Preservation of Vitality and Health.©1918.  --an optical reprint of the 1922 Macmillan 2nd ed. is available @ Amazon]
CynicalEng said… says 7.0g of sugar a small amount of which will be from the cocoa itself. No "added sugars" on the label ? Makes the taste and texture work, a reasonable compromise don't you think ?
billy the k said…
From the back of one of the100g Lindt 90% bars taken from the rather large stack of them on our kitchen shelf:

Nutrition Facts:
serving size: 4 squares (40g) 
servings per bar:  2.5
amount per serving:
total fat...............22g
saturated fat.......13g
trans fat................0g
total carbohydrate...12g
dietary fiber............5g
SUGARS.................3g  ☜ (this indicates the total added sugarson
protein....................4g          USA Nutrition Labels; i.e., 3g X 2.5 = 7.5g)

Ingredients: chocolate, cocoa butter,  cocoa powder...,sugar, bourbon vanilla beans.

And yes--it makes the the taste and texture "work"--marvelously well.  Spectacularly well!!! (especially with some home-made dry roasted almonds!)  My point to Stella was [OF COURSE] to, as Stella would put it, "GO FOR IT!"
Jane Karlsson said…
Where does McCarrison say we won't suffer a cascade of pathologies from having some refined foods in our diet? You said this, not McCarrison. The 'protective foods' are protective in the context of one particular diet, which he says must be consumed in its entirety.

Of course milk and milk products are protective in this context, because of the fat-soluble vitamins, and vegetables are too because of the vitamin C. You cannot live on whole wheat.
billy the k said…

McCarrison [here]:
said this:  
"...nowadays we speak of milk and milk products as 'the protective foods', since they make good the deficiencies of...REFINED CEREALS..."

Still no capisce?

[from Webster's 3rd Int'l]:
make good:
to make valid or complete: as a: to make up or compensate for (a deficiency)

Jane Karlsson said…
Of course they can. There are enzymes which are activated by more than one micronutrient, and in these cases an excess of one of them can compensate for deficiency of the other. For instance, vitamin D can partially compensate for manganese deficiency (guanylyl cyclase) and B12 for copper deficiency (methionine synthase).

So people eat white rice and take enormous doses of vitamin D and B12. I don't expect McCarrison would have considered that a good idea.
billy the k said…
Jane, you're forgetting your Freshman Logic.  As applied to McCarrison's own words:

a. Protective foods make good the deficiencies of refined cereal grains.  

b. Milk is a protective food. White rice is a refined cereal grain.

∴ c. Milk makes good the deficiencies of white rice.

Not "can" but does.  And certainly not by providing "enormous doses of D and B₁₂"! 

Two expressions keep coming to mind: 
1. Beating a dead horse
2. Sheesh!
LWC said…
Milk is "protective"if you're not lactose intolerant.

I've been very interested in this discussion, because it suggests that there is more than one way to get nutrients. It's okay if you can't eat one thing... because there are other sources of whatever. I can't have milk (though I tolerate some cheeses - especially non-cow) but if I have other sources of the nutrient, that's okay.
billy the k said…
Thanks for the comment.
Quite so:  "Milk--and milk products"--are the protective foods. I think I did not make this point clear enough.

Cheeses, yogurt, buttermilk, etc.--they're all members of this class,  so it's definitely not necessary to glug milk in order to obtain its protective benefits if milk doesn't "work" for you--or if you don't fancy it. 

[BTW-my own favorites happen to be sheep's milk cheeses: a sheep's milk Feta [from Israel] and a sheep's milk Romano [from Italy].
Jane Karlsson said…
Billy, you told me McCarrison said this:

"...nowadays we speak of
milk and milk products as 'the protective foods,' since they make good
the deficiencies of refined cereals."

This is not what McCarrison said. Please read your link again. I have read it twice and cannot find anything resembling your quote.

McCarrison says the Sikh diet has to be taken in its entirety, and this means whole wheat, vegetables and milk. Remove the milk or the vegetables and the diet does not work. This is very different from saying milk makes good the deficiencies of refined cereals, which appears to be something you made up.
billy the k said…
I see that it's definitely time now to bury that dead horse...

Well, I suppose there is one upside to having been put through the wringer: it's given me a good appetite.  So I shall restore myself with a couple of pieces of peanut butter toast [crunchy, on German whole kernel rye bread] & a pint of whole milk--a little lunch which,  I am pretty sure Jane, will contain our friends the micronutrients.
Jane Karlsson said…
So that's what Nigel meant about putting him through the wringer! Thanks Billy, that's a great help.
billy the k said…
Most welcome, Jane.
 ♪ ♫"...we did have fun, and no harm done..."♪♬♩
[from the song: Thanks For the Memory]
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