May 28, 2013

Nutritional biochemistry

Is sugar toxic?

Read Time 15 minutes

I remember one of my mentors in surgical residency made a very important distinction for me.  He said, “Peter, never forget what you are getting paid to do, and what you are doing for free.”  You see, there are some aspects of being a surgeon that are not particularly enjoyable.  The hours are long.  Sometimes you’re asked to intervene in a situation where there is no hope, and you feel you may only make things worse.  A lawsuit is just around the corner. But there are many aspects of surgery that are pure bliss.  Though I’m no longer a surgeon, some of my fondest memories in life stem from moments there.   Anastomosing a transplanted kidney into a patient (especially the renal vein anastomosis, which is the easiest to screw up).  Endartarectomizing a plaque-filled carotid artery.  Telling a patient and their family that you were able to remove the entire tumor in their colon, and that the lymph nodes were free of tumor.

What my mentor was saying to me was that those moments of pure bliss are not what we’re getting paid for.  In fact, we’d probably pay to do them!  What we’re getting paid for is the time we have to be away from our family.  The long hours, smelly call rooms, and bad hospital food.  The cost of medical malpractice insurance.

What does this have to do with the toxicity of sugar?  Well, nothing actually.  But I constantly remind myself of this when I feel my personal stress and anxiety mounting.  The past year has been a whirlwind of kinetic energy that makes my days in residency, 80 to 100 hours of work every week, seem tame and almost boring.  Most of what I do today is wonderful, but some is not.  I fly about 12,000 to 15,000 miles a month (in coach, no less) and spend about 8 to 10 nights a month in hotels.  Red-eyes are a regular part of my existence.  My day starts between 4:45 and 5:00 am and goes until 11 pm or later.  I can’t put in words how much I detest traveling and being away from my family.  So, I guess, that is exactly what I get paid to do.  (By the way, do not feel sorry for me.  I’m pretty sure all of this is self-imposed, but I still hate it.)

So, do you want to know what part of my role at NuSI gives me bliss that rivals the finest moments of surgery?  It’s exactly what I did a couple of weeks ago (and, fortunately, something I get to do often).  I spent a day with some of the best and most thoughtful scientists talking about their work and how we can make it better.

Can you imagine (assuming you’re as much a geek as I am) getting to pick the brains of the best scientists for hours on end?  Finding out why they are obsessed with the questions they ask? What keeps them up at night? What are the challenges they face?  What’s preventing them from resolving uncertainty?

I would pay to do this part of my job. This is the bliss described by Joseph Campbell.  And this meeting a few weeks ago was a great example of it.   This particular meeting focused on sugar research, specifically the metabolic impact of sucrose, high fructose corn syrup (HFCS), and fructose.  If you need a quick refresher on the distinctions, this should help. Spending so much time with this group got me thinking about a broader issue, which is actually the focus of this post:  Is sugar toxic?

What does ‘toxic’ mean?

Before we dive into the main focus of this post, we need to get crystal clear on our semantics.  Too much tomfoolery has already taken place for the simple reason that many people don’t understand the words they use.

For the purpose of rigor, let’s turn to the pharmacology literature for a clear understanding of toxicity.  Even though we all have an understanding of what “toxic” means, let’s be sure we’re understanding the nuance.  If you troll the medical textbooks you’ll eventually settle on a definition something like this (from Harrison’s Principles of Internal Medicine):

TOXICITY: The degree to which a substance can harm humans or animals. Acute toxicity involves harmful effects in an organism through a single or short-term exposure. Subchronic toxicity is the ability of a toxic substance to cause effects for more than one year but less than the lifetime of the exposed organism. Chronic toxicity is the ability of a substance or mixture of substances to cause harmful effects over an extended period, usually upon repeated or continuous exposure, sometimes lasting for the entire life of the exposed organism.

The first thing you may notice from this definition is that toxicity is actually subdivided into acute, subchronic, and chronic toxicity, based on how long it takes to progress from exposure to insult and the number of exposures necessary to cause insult.  This constitutes what I call:

Important point #1 – don’t confuse acute toxicity (what most people think of) with chronic toxicity.

Acute toxicity and the LD50

An example of acute toxicity is acetaminophen (abbreviated APAP, but commonly referred to by its trade name, Tylenol) overdose which, if significant enough, requires a liver transplant within days to prevent death from fulminant liver failure. (As an aside, this is particularly tragic because the liver, unlike the heart, lungs, and kidneys, can’t be supported extracorporeally; so if a person overdoses, and the liver is irreversibly damaged, they will need a liver transplant within days, or they will die.)

The question, of course, is what dose of APAP is toxic? (In this case, the toxicity is liver failure, which results in near-immediate death.)  Enter the LD50.  LD50 stands for “lethal dose required to kill 50% of the population.”  How is this quantified for a given substance, including APAP? Obviously, we don’t do randomized trials of increasing APAP doses in people until we definitively resolve this.  Instead, we (I’m using ‘we’ pretty liberally here – obviously I have never done this) do 3 things typically:

  1. Carry out the above experiment in animals to accurately estimate LD50 (in the animal);
  2. Mathematically model the best human data available and try to estimate LD50 (in humans);
  3. Compare the two estimates.

Not surprisingly, the answer to #1 is usually much higher than the answer to #2.  In the case of APAP, the LD50 in rats depends on age, but is probably somewhere between 800 and 1,500 mg/kg, suggesting a 75 kg human would expect toxicity (on average) between 60 and 110 gm (120 to 220 extra strength Tylenol tablets!).  Is this likely? Let’s go to step #2.  Below are data integrating known human toxicity with a mathematical model to estimate LD50, as a function of APAP dose (x-axis) and death versus survival over time (y-axis).  As you can see, this analysis suggests LD50 in humans is closer to 20 gm.  (These are data from humans who did not undergo liver transplant, except in the case of the yellow triangles.)

Acetaminophen Overdose Model

I’ve looked at several other models and they all appear to suggest about the same thing, The LD50 of APAP in humans is about 10 to 20 gm (10,000 to 20,000 mg or 20 to 40 Extra Strength Tylenol tablets), and most sources point to the lower end of that range.

So what’s my point of this?  My point is that there is a statistical distribution (see figure below) of the toxicity, which is why it’s called LD50 and not “LD” (which would imply everyone would experience toxicity from the same dose).  In other words (let’s simplify and ignore weight differences since this is in mg/kg and just assume I’m talking about a 75 kg human), some people will experience toxicity at 6 gm and others not until 16 gm. In the figure above, you can see one person lived, despite a dose of 40 gm (given that he received the antidote early enough) and another at 25 gm, without antidote.

Important point #2 – there is a spectrum of susceptibility to any toxin. 

LD50

What about chronic toxicity?

Sticking with APAP as our example, it turns out that much lower doses than the LD50, if taken day after day, are also toxic to the liver. How much lower?  As you’ll see below, the answer is highly dependent on the timing of these doses and other host factors.  In general, though, some authorities suggest repeated daily doses of more than 6 gm are toxic, while repeated doses below 4 gm daily are rarely toxic.  The point is that much smaller doses, if taken repeatedly, are still toxic.

Important point #3 – just because a dose does not result in acute toxicity does not mean it can’t or won’t cause chronic toxicity.

Complicating things a bit further…

There is no reason to expect physiology to be simple or binary, so adding one more layer of nuance to this already-longer-than-you-wanted-to-read-explanation is the following point. Factors such as alcohol consumption, underlying liver disease, viral infections, and genetic susceptibility are highly influential in both acute and chronic toxicity from APAP.  This shouldn’t be surprising, of course, though it complicates our discussion.  Since APAP taxes hepatocytes (liver cells), taking other drugs that do the same, consuming alcohol (uniquely metabolized by hepatocytes), or having underlying liver disease are invariably going to reduce hepatic reserve.  So, an individual’s ability to tolerate APAP is highly dependent on both measureable (e.g., cirrhosis) and idiosyncratic variations.

Important point #4 – host factors play a significant role in susceptibility to toxins.

Parting shot

I would be surprised if anyone reading this has not taken or used APAP (i.e., Tylenol or some generic equivalent).  In fact, most of us have experienced great relief from it.  That does not change any of the points above.

Important point #5 – the term “toxin” does not imply something is “bad” or universally harmful.

What does APAP have to do with sugar?

There must be some reason I’ve gone through all of this, right?  After all, the question of sugar’s toxicity is a somewhat polarizing one. On the one hand, folks like Dr. Rob Lustig have argued that fructose is harmful at the doses most people are consuming it today.  On the other hand, folks like Dr. James Rippe have argued the opposite.  Having read just about every paper and review article on this topic (I think) over the past year, I can say the debate has many facets, which I’ll outline briefly:

    1. The PRO sugar folks** argue that sugar, while void of any nutritional value, is no more or less harmful than a calorie of any other nature. In other words, it has no unique metabolically harmful consequence.
    2. Depending on affiliation, some of the PRO sugar folks debate back and forth about the advantages or disadvantages of sucrose (natural sugar from beets, cane, etc. composed of a linked glucose and fructose molecule) and HFCS (synthesized sugar composed of 55% fructose, 45% glucose mixture).   (There may be some merit to this discussion, though it would probably qualify as a “higher order” term. To a first or second order approximation, they are biochemically equivalent.) It appears this debate is a convenient way to avoid really confronting question/point #1.  The “natural sugar” producers can point at the corn growers, and vice versa, without really confronting the jugular question.  Both of these groups (sugar and corn) downplay research on pure fructose (which is pretty rare in nature and even our current environment), which is a valid point, though a distraction from the issue above.
    3. The ANTI sugar folks argue that sugar is indeed a “unique” macromolecule distinct from other carbohydrates.  Whether solely due to the fructose content, the combination of fructose and glucose, and/or the kinetics of the fructose (i.e., the speed with which the fructose requires hepatic attention when not accompanied by fiber) is a matter of debate and speculation, but those in this camp do agree that sugar is not “just” an empty calorie. The toxicity of sugar, they argue, is primarily related to its hepatic metabolism.  Specifically, “excess” (see below) ingestion of fructose increases VLDL production which increases apoB or LDL-P due to greater triglyceride load.  Additionally, at least at reasonable doses according to most literature, insulin resistance is worsened which amplifies the harm caused by other foods.
    4. Even among those who don’t subscribe to the idea that sugar is metabolically unique (and harmful), with or without a dose-effect, some argue that fructose consumption impacts subsequent food consumption in a way that glucose does not.  In other words, eating sugar may fail to satiate you and/or make you subsequently hungrier. These data are sometimes confounded, as are many data in this area, by the use of pure fructose, rather than the glucose-fructose mixture found in sugar.  Furthermore, evidence is emerging that sugar is addictive, much in the same way that a drug like heroin or cocaine might be, as suggested by functional MRI. So, while folks in this camp argue that sugar per se isn’t harmful, it does make you eat more (sugar and non-sugar, alike), and that is the harm.
    5. Perhaps the largest debate in this area stems from the dose issue.  The PRO sugar folks argue that at the doses most Americans consume sugar, there is no harm (even if there is a theoretical harm at very high doses).  The ANTI sugar folks argue that there is a dose-dependent (and probably a context-dependent – e.g., the insulin resistant person vs. the insulin sensitive person) deleterious impact of sugar, AND that current consumptive patients are indeed in this zone of toxicity. (This is probably the most comprehensive single review I’ve read on the entire topic, and I’ve discussed it point-by-point with 2 of the 3 authors.)
    6. Speaking of the dose issue, no area of this debate (in my opinion) has generated so much controversy.  How much sugar, defined as added sweetener (so this does not include the fructose found in fruit, for example) do Americans actually consume?  This is important, of course, if we want to know how applicable the above studies are to the question at hand.  Where to begin? (This topic alone is really a 3-part blog post.)  Estimating how much added sweeteners Americans consume is primarily done via two methods:
      1. Taking the difference between food availability data and waste data (ERS); or
      2. Using nutritional surveys (NHANES).

One of my colleagues, Clarke Read, looked into this recently.  Here is what he found (this was in response to a recent NY Times article suggesting sugar consumption is less than typically reported):

The adjustment to loss rates was done by RTI International in this report to the USDA Economic Research Service (ERS).  Section 4-1, which is an example calculation, is most useful.  RTI was asked to calculate estimates of loss, not estimates of consumption, and rather than working down from availability data, they in fact used NHANES 2003-2004 data to estimate consumption, then basically compared this to availability numbers (with a few adjustments) to find amounts of loss.  These loss percentages calculated from 2003-2004 then became the standard, and all other consumption data was calculated by applying this % loss to the availability data.

This means that all consumption numbers are effectively derived from NHANES data.  This is especially relevant for added sugars.  Since NHANES data tracks only consumption of foods, not ingredients, this availability-versus-consumption comparison initially leads to a 96% loss of cane and beet sugar (seen on page 95 of the 2011 USDA document — the “4 percent” referred to in the NY Times article), since NHANES data only reflects sugar added to foods directly, rather than used as an ingredient.  The judgment of a panel of experts was then used to determine the percentage of available sugar used as an ingredient, which led to their 34% loss estimate for sugars.  For HFCS, which is never consumed as a food and always as an ingredient, they simply gave it the same value as honey (15% loss between availability and consumption).  The ERS, however, overruled them (as described in the NY Times article — see the end of the Losses at Consumer Level section in the link for ERS evidence) and used the 34% loss estimate instead.

Page 10 of the 2011 USDA document shows who these 6 experts are.  The NY Times article asked 2 of these 6 about these sugar estimates, who don’t recall making them, though it’s implied that they simply don’t remember what happened back in 2008. In other words, while the overall trend in sugar data is determined by availability data (since % loss is assumed to be constant over time), the absolute amount consumed on any given year, as estimated by these loss-adjusted numbers, is entirely dependent on this RTI loss estimate which, for added sugars, is almost entirely dependent on an expert’s estimation.  All foods that are primarily consumed as foods rather than as ingredients have consumption levels that are based on an extrapolation of 2003-2004 NHANES data.

Translation: this is a complete cluster.  If you triangulate between the ERS and NHANES data, you wind up with an estimate of about 90 pounds of added sweetener per person, per year, or about 110 gm per day which, on average, works out to about 15% of total caloric intake.  Of course the actual consumption is much more nuanced (what isn’t?), since consumption varies a lot by age, gender, and socioeconomic status.  Furthermore, this estimate doesn’t include the fructose in fruit juice or fruit, though the latter probably isn’t nearly as high, or relevant, as the former.

Another very interesting point uncovered by colleague, Clarke, was that in a 2009 paper in The Journal of Nutrition, Dr. James Rippe (one of the leading proponents of sugar) noted the following:

“…fructose, as a component of the vast majority of caloric sweeteners, is seen to be particularly insidious.”

“It has also been shown to increase uric acid levels, which in turn promotes many of the abnormalities seen in the metabolic syndrome including hypertriglyceridemia.”

“There is considerable evidence of a detrimental effect on metabolic health of excess fructose consumption.”

Whether by accidental omission or otherwise, this paper is not listed on Dr. Rippe’s CV on his website.

**Sadly, it’s difficult to really interpret the data objectively from those in the PRO sugar camp because of the conflicts of interest.  Most of the PRO sugar scientists are heavily funded by the sugar industry.  For those interested in the historical context on science and the sugar industry, you’ll find this article particularly interesting.

Take home messages

What I find frustrating about this debate is that most people yelling and screaming don’t fully define the terms, perhaps because they don’t appreciate them (forgivable) or because they are trying to mislead others (unforgiveable).  The wrong question is being asked.  “Is sugar toxic?” is a silly question.  Why?  Because it lacks context.  Is water toxic? Is oxygen toxic? These are equally silly questions, I hope you’ll appreciate.  Both oxygen and water are essential for life (sugar, by the way, is not).  But both oxygen and water are toxic – yes, lethal – at high enough doses.

What did the APAP example teach us?  For starters, don’t confuse acute toxicity with chronic toxicity.  Let’s posit that no one has died from acute toxicity due to massive sugar ingestion.  But, what about chronic toxicity?  Can eating a lot of sugar, over a long enough period of time, kill you (presumably, through a metabolic disease like diabetes, Alzheimer’s disease, cancer, or heart disease)?

Even among a healthy population (i.e., people without overt liver disease), toxicity is a distribution function.  What’s toxic to one person may not be toxic to the next.  This is true of APAP and it’s true of sugar.  It’s true of most things I can think of, actually, including tobacco, alcohol, cocaine, and heroin. Ever wonder why “only” about one in six smokers dies of small cell lung cancer? Maybe it’s the same reason some people (e.g., me) get metabolically deranged from even modest doses of sugar, while others (e.g., Jill, my wife) can mainline the stuff and not appear to suffer many adverse effects.

I posit that Jill and I are both outliers on the distribution of susceptibility, probably driven mostly by genetic difference (rather than, say, exercise as we both exercise a lot).   So, I offer you a framework to consider this question.  I know some of you just want an answer to the question, Is sugar toxic or not? But I hope this slightly more nuanced response can help you figure out what you should be asking: Are you like me? Like Jill? Or like an Average Joe somewhere in between us?

This is what you will need to figure out on your own.  You could play it safe, assume you’re like me and eliminate all sugar from your diet (I eat no more than about 5 gm of sugar per day, almost exclusively in 85%+ dark chocolate – so less than 4 pounds per year).  But if you have Jill’s genes, maybe this is overkill.  (Though, I would argue, and may do so in a later post, that even Jill has noticed a change in her energy levels and a number of biomarkers by reducing her sugar content somewhat over the past 3 years.)

Sugar toxicity

It’s pretty easy (conceptually) to figure out where you are on this spectrum, but it does involve a few deliberate steps:

  1. Without making any adjustment in your current eating habits (i.e., fight like hell to avoid the Hawthorne effect), record everything you eat for a week and, using a database like this one (or something fancier like Nutritionist Pro), calculate exactly how much sugar you consume.
  2. Collect blood work (paying special attention to lipoproteins, triglycerides, glucose, and insulin among other things) and other measurements (e.g., DEXA if you want to assess body composition, waist measurement).
  3. Get intimately familiar with all the places sugar shows up that may seem counter-intuitive (e.g., “healthy” cereals, sauces, salad dressings, bread).  To do this experiment, you need not restrict your complex carbohydrate intake, but you’ll have to substitute products without added sugar.  For example, before I was in ketosis but beginning to discover my own susceptibility to sugar, I had to make my own spaghetti sauce from scratch rather than pour it out of jar.  I had to make steel cut oatmeal rather than eat Quaker oats.  I had to buy bread made with zero sugar (at $7 a loaf!) rather than my usual “whole wheat” bread.  You get the idea.  It takes time, and you should expect to spend a few extra dollars on food. But, it’s actually possible to find foods that contain minimal to zero added sugar.
  4. With this information in hand, begin the intervention: aim for a reduction of at least 50% from step #1. (In my first experiment I did 6 days per week of zero sugar, and one day of all I wanted.  Ultimately, this became too difficult, and it actually became easier to just go zero every single day.)
  5. Repeat the measurements (i.e., step #2) after about three months.  If you’ve seen minimal effect, assuming you were methodical and consistent, you’re probably in the Jill camp.  If you’ve lost fat, seen a reduction in your triglycerides, fasting glucose and insulin levels, increased your HDL-C, and decreased your apoB or LDL-P (assuming you were able to measure them), you’re probably in the Peter camp.

Last point I’ll make, as I suspect at least some of you are wondering.  How do two genetic outliers treat their genetic hybrid (i.e., our daughter)? I’ve written about this previously.  In short, we limit the sugar she eats in our house, but not so much outside of the house (e.g., birthday parties).  I estimate she eats about 25% of the sugar a “normal” kid does.  There is no doubt she loves it, and even a week ago when we went on a daddy-daughter date, I got her ice cream with sprinkles for dessert (the irony of me carrying a bowl of sprinkle- and Oreo-covered ice cream through a crowded restaurant was not lost on me).

What does amaze me is how it seems to override her senses.  That night, she had a big plate of salad, a bowl of soup, and even a large slice of pizza (if you’re wondering, I had 3 large plates of salad with chicken). She claimed to be absolutely full, and I believed it.  But when I brought that ice cream out, it was like she had never seen food in her life.  She simply devoured it.  The best part?  When she looked like she was done, I said, “OK sweetie, looks like you’re done, time to get going…” only to have her say, “No daddy!  I’m still finishing the chocolate broth!”  She literally left not one drop of melted ice cream (“chocolate broth”) or one single sprinkle or one single crumb of Oreo behind.

This does not seem “normal” to me, and for this reason I guess I refuse to accept, personally, that sugar is just a benign empty calorie.  But, one day our daughter will have to decide for herself where she lies on the distribution and how much she cares to do anything about it. Until then, we’ll save the chocolate broth for special (and not too common) treats.

Sarah's wedding

So, in response to the question, “Is sugar toxic?” it seems to me the answer is, “yes, sugar is probably chronically toxic to many people.”  And so is water. And so is oxygen.  My sincere hope, however, is that you now understand that this is probably the wrong question to be asking.  The better question is probably “What dose of sugar can I (or my child) safely tolerate to avoid chronic toxicity?”  The goal should be to figure out your toxic dose, then stay well below it.  (It’s probably not wise to consume 95% of the toxic dose of APAP just because you have a really bad headache.) What makes this important, of course, is that with water and oxygen, the toxic doses are so far out of the range of what we normally consume, it’s not really necessary to expend much mental energy worrying about the toxicity.  But with sugar, at least for many of us, the toxic dose is easy to consume, especially in world where sugar resides in almost everything we eat.

Photo by Joanna Kosinska on Unsplash

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323 Comments

  1. I think some of the anti-sugar opinions and studies deserve a ** footnote too, as that camp is probably more fanatical and devious than the industry itself.

    Sugar or indeed fructose is seldom consumed alone, and the RCTs looking at differential effects of different sugars in the context of the whole diet don’t really seem to show any significant difference in outcome, do they ?

    How do we handle the fruit paradox. Lustig says that the vehicle is irrelevant, so how does the 16% sugar solution that is Welch’s grape juice fit into the picture compared to the 10% HFCS or sucrose sweetened full fat cola ? Sure, there a vitamin or two in the juice but I might not need them, maybe some beneficial polyphenols I already get from red wine, who knows. Is fruit juice toxic ? For that matter, as fruit is just juice soaked into fibre – is fruit toxic ?

    All of a sudden the argument is two orders of magnitude more controversial and less acceptable by society.

    • Well, the difference is probably that the anti-sugar folks are generally (though some might be) not funded by an industry that wants to see a specific outcome. I’m only pointing this out because it complicates the science. Maybe I’m missing your point, but I think Lustig would be the first to point out that grape juice and Coca Cola are, from the standpoint of the liver, very similar. He’d say eat grapes, but don’t drink grape juice.

    • “Well, the difference is probably that the anti-sugar folks are generally (though some might be) not funded by an industry that wants to see a specific outcome.”

      The anti-sugar folks *are* an industry that wants to see a specific outcome.

  2. Dr. Attia,
    I heard your presentation last week at the IHMC in Pensacola and found it to be profound. I have had a nerve issue in my foot for a number of years. Two years ago I had a nerve bisection in hopes of terminating the pain. Instead of curing the pain, it resulted in a hypersensitivity to sugar. Any sugar intake in my diet results in severe nerve pain in my foot that lasts for hours and usually results in loss of sleep.

    So my question is: How can sugar intake result in nerve pain?

    Richard H. McSwain PhD PE

    • Stephen and Peter:

      So why wouldn’t we rather say sugar or fructose in refined form is more “stressful” to the system when in isolation (why fruits don’t have the same impact b/c of their antioxs, polyphenols and fiber buffers the stress of the sugar/fructose —- Oxidative stress drives VLDL, not to mention insulin resistance, metabolic distress, etc) Would that be equally (if not slightly more) scientifically and technically accurate? Although it would have the same lack of nuanced defintion and understanding from both general and scientific communities, which is the same problem with the word “toxic”. We tend to have an “outside” linear impact instead of the more nuance nonlinear internal systems interaction balancing act starting with the “host factors”. Which are aptly (and impressively, way to go Peter) not only significant but essential for the delineation of impacts. So host factors are the way in which one handles stress and typical coping pathways (the distribution curve). Which depends on which systems (based on experience, expressed in epigenetic mechanisms) are engaged and what other stressors (and resources) are present. So while toxic is adequate (sorry Stephan I think “harmful” and/or “unhealthy” are without the meaning and would be variations-on-the-tune of “when are they stressful and how is that stress balanced” which takes a conserted effert to tease out cost/benefit situations). I would think “stress” although currently lacking proper definition by our general and even more professional audience is the most accurate term.

      So I’m very curious why we do not use the word stress?

      “Palatable foods” also have a complex stress interaction depending on the system. On one hand they counter stress, on the other they can create stress. Depends on the system and the other resources required at that time. Palatability of high density caloric resources are great for handling stress, but if they don’t actually contain resources or counterbalances (ahem, junk food) they create stress… depending on the antioxidant systems, jobs, counteractions, system engagement, alterations, level of adaptation (to respond in more “toxic” degrading fashion) etc. involved or otherwise engaged. Since Peter mentioned Tylenol that would be the CYP2E1, tylenol, alcohol, glucose all overlap this same pathway and interact with the same type mechanisms, stress/toxicity mechansims.

      So “stress” would be some kind of “dirty” (?) word (or oblivious hidden gorilla maybe?) that nobody uses because……

      Effects of early life interventions and palatable diet on anxiety and on oxidative stress in young rats.
      Marcolin Mde L, Benitz Ade N, Arcego DM, Noschang C, Krolow R, Dalmaz C.
      Physiol Behav. 2012 Jun 25;106(4):491-8. doi: 10.1016/j.physbeh.2012.03.025. Epub 2012 Mar 30

      Consumption of a palatable diet by chronically stressed rats prevents effects on anxiety-like behavior but increases oxidative stress in a sex-specific manner. Krolow R, Noschang CG, Arcego D, Andreazza AC, Peres W, Gonçalves CA, Dalmaz C. Appetite. 2010 Aug;55(1):108-16. doi: 10.1016/j.appet.2010.03.013. Epub 2010 Mar 27.

      Chronic ethanol and high glucose inducible CYP2E1 mediated oxidative stress leads to greater cellular injury in VL-17A cells: a potential mechanism for liver injury due to chronic alcohol consumption and hyperglycemia Kavitha Swaminathan,a S. Mathan Kumar,a Dahn L. Clemensbc and Aparajita Dey*a
      Toxicol. Res., 2013, Advance Article

      Combination treatment of epilepsy with ketogenic diet and concurrent pharmacological inhibition of cytochrome P450 2E1. Palmer M.Med Hypotheses. 2013 Apr;80(4):481-5. doi: 10.1016/j.mehy.2013.01.011. Epub 2013 Jan 28.

      UT Southwestern Medical Center (2011, April 19). Limiting carbs, not calories, reduces liver fat faster, researchers find. ScienceDaily. Retrieved June 4, 2013, from http://www.sciencedaily.com­ /releases/2011/04/110419003651.htm

      • Lori, I can only speak for myself. I don’t find semantics to be my forte. I like to describe processes, as best I can, and uncover the nuance. I leave it to the smart folks to come up with the perfect nomenclature. While I don’t have any philosophical opposition to the word “stress” and I agree it’s better than “not healthy,” I’m more interested in trying to define and test this hypothesis.

        Is smoking a pack of cigarettes each day unhealthy? yes. Toxic (chronically)? yes. Physiologically stressful? yes. Bottom line…you’re more likely to live a longer, disease-free life, if you don’t smoke a pack of cigarettes a day than if you do (all other things equal). That’s what I want to understand.

    • Oxidative stress and diabetic neuropathy: pathophysiological mechanisms and treatment perspectives.
      van Dam PS. Diabetes Metab Res Rev. 2002 May-Jun;18(3):176-84.

      Combination of alpha lipoic acid and superoxide dismutase leads to physiological and symptomatic improvements in diabetic neuropathy.
      Bertolotto F, Massone A. Drugs R D. 2012 Mar 1;12(1):29-34. doi: 10.2165/11599200-000000000-00000.

    • What is interesting about the body is that pains in certain areas aren’t necessarily emanating from that area. The feet and hands are full of nerve meridian endings and recurring pains and discomfort in the feet can often correlate with issues elsewhere in the body.

      For instance, for some years I have had a very itchy left heel. Checking the reflexology chart, it equates with the colon. I have had some issues in my colon, so that ties in well. Also, not long after I dumped gluten and most carbs over 5 years ago, my liver suddenly had a big clear out. I could feel lots of stuff going down my hepatic tubes in my right side, it became very sore, and immediately it started a very sharp and intense regular pain started in my left foot. Lo and behold, checking the chart, the area of the pain equated with the liver.

      For many years prior to dumping gluten-based grains I would get raging restless legs, kicking about the bed uncontrollably for hours. If I get ‘glutened’ the restless legs resurface with a vengeance. Why? Because the gluten and other foreign proteins in the modern wheat triggers neurological issues in my gut. It’s basically a form of ‘gluten ataxia’.

      Our feet (and hands) can tell us a lot more about what is going on than we realise. The reason you developed sugar intolerance after the surgery was probably because the nerve pain in your foot was actually telling you there was an issue elsewhere, possibly in your gut (not knowing where the pain actually was). Surgery trauma like any major stress or trauma depletes the body of a huge amount of nutritional elements and that can have a long-term effect on people that in the main are already very nutritionally deplete. Surgery is also often followed by antibiotic or other drug courses, and that all has a major impact on the health of the bowel, and therefore the person.

      Whilst I do believe that a lower carb diet is always going to be beneficial for most people, it’s as much about what is removed, as what it is replaced with. Most low-carb regimes remove grains. It is well documented how modern grains, especially wheat can rob the body of far more nutrition than they give – the joke that with many cereals you’d probably be better off eating the cardboard box is sadly not really a joke at all. A lower carb or ketogenic diet concentrates mainly on all-natural real food so people are always going to be getting more nutrition. The more nutritious the food, the healthier we will be. Much emphasis is placed on probiotics these days to help the gut. However, it’s not the microbes per se that are the important thing, but what they do. Lactic bacterial fermentation makes food far more nutritious. It draws more nutrition out of the food, and adds more too. B vitamins are increased, which helps digestion, and things like vitamin K2 are generated.

      Life really is all about nutrition. The better and more abundant the nutritional elements – the elements we are made from, the healthier we are. Unfortunately these days, much of the food out there, including much of the commercially grown fruit and veg may look like food, and taste like food, but isn’t food at all. You can’t Improve on perfection. The more mankind fiddles and meddles with their food the less beneficial it becomes. How far will they go before its too late to change it back? Has it already reached the point of no return???

  3. Hello Botros,

    I’m desparetely waiting for ur post on caffeine. I’m very appreciative of all the work your doing in the field. Thank you

  4. Peter stated: “Is smoking a pack of cigarettes each day unhealthy? yes. Toxic (chronically)? yes. Physiologically stressful? yes. Bottom line…you’re more likely to live a longer, disease-free life, if you don’t smoke a pack of cigarettes a day than if you do (all other things equal). That’s what I want to understand.”

    Semantics is not my forte either, I’d say physics and neuroscience is more my thing. You are unfortunately in this statement making the same mistake as most and looking at stress as a variable. Something that is stressful. I am referring to it as a model. HOW stress works, which is through complexity dynamics that require us to think differently about the questions we ask, the evidence we see and the evidence we seek (framework to put it together).

    I’m not fighting here for semantics, but language is important (as it leads to research terms and pathways). When is smoking cigarettes “healthy”? Depends on the system right? What are you trying to accomplish and what is being accomplished on that individual. You have to break down the stress (balancing) mechansims and trade-offs. And how and on who stress would re-regulate a system that would make potentially unhealthy resources a viable healthy brain balancer (and address this balance so the “unhealthy” balancing crutch is no longer necessary). When you take a systems thinking stress approach you look at how stress has impacted the system and also how nicotine may become a regulator of that stress for some (which can be caused by multiple different things, a nonlinear stress mechanism means there is overlap and cross-over).

    One exposure (or combination of exposures and lack of nutrients or resources at that time, in particular individuals) can create problems we may not seem to think are associated (or were mediated by ‘choice’). when if we address from a systems approach via stress mechanisms of nonlinearity we may find getting the outcomes, and understandings, we are looking for, may become more feasible.

    I can give you thousands of examples and the starting points (genetic-neuroendocrine) i currently suspect (needed for chaos patterns). If you’d like to discuss sometime Peter, please give me a call, my website is “The Meal Matters Most” on wordpress.

    http://themealmattersmost.wordpress.com

    Smoking, Genetics and Schizophrenia: Evidence for Self Medication. Sherry Leonard, Sharon Mexal, and Robert Freedman. J Dual Diagn. 2007 November 1; 3(3-4): 43–59

    Oxidative stress might be a mechanism connected with the decreased alpha 7 nicotinic receptor influenced by high-concentration of fluoride in SH-SY5Y neuroblastoma cells.Gao Q, Liu YJ, Guan ZZ.Toxicol In Vitro. 2008 Jun;22(4):837-43. doi: 10.1016/j.tiv.2007.12.017. Epub 2008 Jan 15.

    Alpha7 Nicotinic Acetylcholine Receptors Modulate Motivation to Self-Administer Nicotine: Implications for Smoking and Schizophrenia. Darlene H Brunzell, J Michael McIntosh. Neuropsychopharmacology. 2012 April; 37(5): 1134–1143. Published online 2011 December 14. doi: 10.1038/npp.2011.299PMCID: PMC3306875

    .

    • Appreciate your thoughts, Lori. I guess my issue with the term “stress” to denote something negative is that stress is actually quite beneficial in many circumstances. I’m somewhat myopic/obsessive in my view of exercise, for example, where I constantly focus on stress and the adaptive response it brings in strength, endurance, and explosiveness. This is true in many other instances also, so I’m also not sure stress is the best word choice. My original point still stands, of course.

  5. Love your blogs. My comment is a personal one unrelated to the sugar essay. I’m a 55 year old male; exercise 6-10 hours per week with moderate intensity resistance training and moderate-to-high intensity aerobics; follow a low carb diet (meat and veggies, primarily; there are periods when I consume fruit and nuts; no starch; no sugar (other than in the fruits, veggies, nuts); several cups of coffee per day; have always had very good lipid panel results. Baseline toal chol is 135-140; trigly ~25; HDL >55; VLDL <25; calc'ed LDL 175.

    What the heck happened to me?

    • My msg above somehow got truncated….
      Component//11/2009//5/2012//3/2013//5/2013
      CHOLESTEROL, TOTAL/137/ 144/ 257/ 280;
      TRIGLYCERIDES/24/67/81/73;
      HDL CHOLESTEROL/52/50/66/55;
      VLDL CHOLESTEROL CAL/5/13/16/15;
      LDL CHOLESTEROL CALC/80/81/175/210.

      I’m not after your medical advice, although I’ll take it. Just trying to figure out if there were/are other variables at play beyond a simple dietary change. Bryce

  6. Dr. Attia,

    Another excellent post. I saw where you mentioned that this might turn into 3 posts. Look forward to it if that is the case as I could read a new post of yours everyday it seems. On sugar tolerance I actually have a question that hopefully you can help with or possibly point me in a good direction (book or person). Can carbs and insulin affect people only in certain smaller ways while everything else seems fine? My wife, like yours, is very sugar/carb tolerant when it comes to the obvious symptoms like fat gain, and not as obvious symptoms when it comes to blood pressure, apoB count, etc….. She is a pure Ectomorph and doesn’t have any of those problems.

    There is one issue though that she has that correlates heavily with carbs and insulin resistance, and that is Polycystic Ovarian Syndrome. To actually be more correct, she does not have PCOS as she doesn’t seem to have insulin resistance, is nowhere near overweight, and has normal cycles. But she does have hirsutism, back acne, and polycystic ovaries (which her doctor refused to believe she could have since she was not insulin resistant till the scan came back showing polycystic ovaries, at which time the doctor seemed to be irritated because she was wrong). So since my wife was constantly having these problems associated with polycystic ovaries but she did not seem to be able to get any help other than being told to get on birth control, I decided to look into it.

    I read the parts Gary Taubes wrote about in Good “Calories, Bad Calories”, looked up what I could find on Dr. Michael D. Fox, looked up studies where those with PCOS tried VLC and their symptoms disappeared and came across this scientific article http://www.medscape.org/viewarticle/562712_3 . I then had her get on a keto diet with me and for her last 3 cycles and the results so far have been her back acne has been going away, hirsutism disappearing, and she has not felt any growth of cysts the past 3 cycles.

    The best diagnosis that I could come up with is that she must be genetically predisposed to have very insulin sensitive theca cells on her ovaries that cause the cysts, hirsutism, and acne, while at the same time not experience any other insulin problems such as weight gain, bad lipid profile, insulin resistance, or anovulation. While most who have polycystic ovaries tend to have anovulation as well, she does not and the I think the reason is that she is not insulin resistant, therefore has a constant source of calories for her body to feed off of and so the body never feels as though it’s starving in any way so it keeps her having normal cycles. Yet she still had cysts on her ovaries and all the side effects and pain that goes along with it.

    I know that was quite a bit to read, but what I would like to know first is, do you plan on posting about PCOS anytime soon? Do have any additional sources on the subject you could point me to? Lastly, as stated at the beginning can she really have problems with the insulin affecting her theca cells (which seems to be the problem as I can diagnose it) but not the rest of her body? Basically could the rest of her body be insulin sensitive and not react negatively to carbs and insulin, with only the theca cells on the ovaries reacting badly, or do you think there could be something else causing it? Also what do you think of the hypothesis I came up with? Sorry if I asked too many questions, I’m just so damn curious. Look forward to your response. Thanks.

    • I know miniscule about PCOS as well. But I do know a bit studying Autism and PCOS does come up in the inflammatory pathways of those predisposed on the estrogen side of the spectrum. So a reasonable hypothesis, for that side, would be of estrogen-insulin relationship with epigenetic modification with stress regulating exposure (endocrine disruptors and estrogen resources like sunlights, aka Vitamin D). So I am PURELY theoretical science, but if I were to nudge your investigation for a spell, it’d be toward Paleo Diet trends that include the elimation of gluten-casein, addition of probiotics (the HPA skin) and of course the relationship of Vitamin-D (sun, butter, antioxs), insulin and androgen modifications (avoiding endocrine-disruptors and adding nutrition contributing to it’s balancing, aka phytoestrogens). But again, I know really nothing about it, just hypotheses generating.

      Effect of soy phytoestrogen on metabolic and hormonal disturbance of women with polycystic ovary syndrome
      Behnaz Khani, Ferdous Mehrabian, Elaheh Khalesi,c and Azadeh Eshragh. J Res Med Sci. 2011 March; 16(3): 297–302. PMCID: PMC3214337

      Vitamin D in the aetiology and management of polycystic ovary syndrome. Thomson RL, Spedding S, Buckley JD.Clin Endocrinol (Oxf). 2012 Sep;77(3):343-50. doi: 10.1111/j.1365-2265.2012.04434.x.

      The role of HPA axis in metabolic derangements in PCOS. Djuro Macut. Endocrine Abstracts (2009) 20 S1.3

      Genome-Wide Methylated DNA Immunoprecipitation Analysis of Patients with Polycystic Ovary Syndrome
      Hao-ran Shen, Li-hua Qiu, Zhi-qing Zhang,2 Yuan-yuan Qin, Cong Cao, and Wen Di.
      PLoS One. 2013; 8(5): e64801.

      Pervasive developmental disorders in children of hyperandrogenic women with polycystic ovary syndrome: a longitudinal case-control study. Palomba S, Marotta R, Cello AD, Russo T, Falbo A, Orio F, Tolino A, Zullo F, Esposito R, Sala GB.Clin Endocrinol (Oxf). 2012 Dec;77(6):898-904. doi: 10.1111/j.1365-2265.2012.04443.x.

      Autistic Traits in Women with Polycystic Ovary Syndrome. Herguner, Sabri; Harmanci, Hatice; Hergner, Arzu; Toy, Harun. Research in Autism Spectrum Disorders, v6 n3 p1019-1022 Jul-Sep 2012

      Inflammation in response to glucose ingestion is independent of excess abdominal adiposity in normal-weight women with polycystic ovary syndrome. González F, Sia CL, Shepard MK, Rote NS, Minium J. J Clin Endocrinol Metab. 2012 Nov;97(11):4071-9. doi: 10.1210/jc.2012-2131. Epub 2012 Aug 17.

      Vitamin D is a membrane antioxidant. Ability to inhibit iron-dependent lipid peroxidation in liposomes compared to cholesterol, ergosterol and tamoxifen and relevance to anticancer action.
      Wiseman H. FEBS Lett. 1993 Jul 12;326(1-3):285-8.

    • Thanks Lori, I’ll take a look into those sources and see what else I can find out. Hate that there hasn’t been many true scientific inquiries into PCOS because between 1 in 10 and 1 in 20 women of childbearing age has PCOS.

    • I really am one of those people who believes that modern grains are pretty evil. Before you even get into GM, they, and particularly wheat, have been subjected to incessant hybridisation. It now contains foreign proteins that interfere with hormonal functions in the body. Personally, although I am no doctor, I am very analytical, and I see no reason why IR and PCOS have to be bed-mates.

      We are all individuals. Each of us comes from different ‘genetic’ and nutritional directions. My body’s weakness or vulnerability isn’t necessarily going to be your body’s weakness or vulnerability. Whilst I have IR, I don’t have PCOS.

      The medical profession always strives to fit us into neat little boxes. When we don’t fit, instead of changing the box, they send us packing. Um. Last time I looked, none of us were clones….

      Although nutrition is considered of little importance, we are actually made of the elements that are in the food we eat. So what we eat is always going to have a good or bad effect. If we remove the insidiously damaging ‘food like substances’ as Michael Pollan succinctly describes them, and replace them with REAL food, the body then has the tools with which to sort itself out. It really isn’t rocket science. Or maybe it is – if we want to rocket!

  7. Thank you again Peter for another platinum grade post, based on science, carefully considered, and relevant i.e. not normally what you find in an article linked to nutrition. I see how much you have thrown yourself into this and the sacrifices you are making and it is incredibly inspiring. I have completely backed your approach close to 100% (my fiance thinks I have taken up some crazy ‘fad’) adopting as much as I can subject to a few practical constraints. The main reason I did this is your credibility, your lack of preachyness and the fact you have nothing to gain from me doing so.

    Sugar can have so much impact on day to day quality of life, it is hard to watch loved ones sometimes suffering the effect of this especially when you feel unable to really influence their behaviour. My fiancé ironically is concerned about my own health since changing my diet and to try and reassure her I have asked for a basic lipid profile from my GP (this will be the cheap version referred to above as NHS in UK – I tried to ask for ApoB but my Doctor stared at me blankly). I have no idea how to even interpret the results and am even more worried my Doctor might misinterpret or over interpret them especially if he subscribes to conventional wisdom (which I am sure he probably does).

    I know the basic lipid stuff tells you very little but is there anything I can look for, any ratio or meaningful indicator at all?

    • JJ, if only having access to conventional labs, non-HDL-C (= TC less HDL-C) is probably a better predictor of risk than LDL-C. Also, TG to HDL-C ratio and fasting glucose and insulin pretty helpful to understand insulin resistance.

  8. All of these individual variations in peoples’ response to nutrients makes me wonder if general health advice is possible at all. Doesn’t this high variability make most “controlled” trials worthless? If the response of half the people in the trial just cancels out the response of the other half, how can one learn anything at all from the trial?

    • I hate to use smoking as an analogy again, but I think it helps. Many people who smoke will not go on to develop lung cancer, emphysema, or heart disease, yet a great number to, presumably because they are genetically or epigenetically susceptible. So how should we handle this? Well, I think what we do right now is exactly the way to handle it. We explains the risks clearly and unambiguously. Everyone is free to smoke, but if you choose to, you know you’re taking a risk. Will it cost you? Hard to tell. Once “nice” thing with sugar is that you can get quicker feedback on your susceptibility than you can with smoking.

      That said, you do make a VERY important point about the utility of most clinical trials: they are almost without exception focused on mean response with little attention paid to variability. This is one more reason to read any study very carefully and try to see the data whenever possible.

    • This concept crossed my mind 20 years ago in school when I asked the innocent question of my stats professor “where does the bell curve come from and how is it it exists”. The answer “no idea”. At the time I thought, “whoa dude, you mean we base our entire scientific premise on an assumption we have no idea how or why it exists?” Sounded fragile to me, but I let it go. However, 5 or 6 years ago studying the mind (information processing) and physiology I suddenly thought “holy crap, what if we got it wrong?: So erase everything you think you know, change your thinking and rebuild it.

      To answer your question Clair Nielson, I would say they are not useless. RCT are clinical snapshots, singular points that assume the system could be controlled out or that our systems are static. They are valid “points” of information. So we now need to put those studies together (instead of thinking they ‘cancel’ each other out like you say), knowing they do not apply to everyone, but particular patterns under certain circumstances. Linear science is fact finding (and our current model) its an outside action that will repeatedly come up with the same outcome because we hold all other variables constant. The problem with the human body is that the variance isn’t random (where we could take an average distrubution) but rather particular patterns for particular reasons. So in nonlinear science it’s about the system it is put into, nonlinear science is about interactions, the interactive dynamics of those singular facts put into active systems. So instead of the outside action as the primary focus on outcome (our current model), rather the system becomes the focus (systems dynamics). And the system can change. It can be different people, but even your physiology can change your response at different times. Our current medical science assumed we could factor that out, we now know we can’t. The problem is is that changes the scientific thinking we have to use. It’s difficult for people to do that, but it can be done because the science we have to use instead using very specific spelled out rules and you still follow very well trooded out physiological facts. So no they aren’t useless, but we do need a new model to understand them.

  9. The take-home message seems to be that nobody can go wrong following a low-carb diet for life (maybe with one day a week off). Otherwise, one must constantly monitor the effects of hire carb consumption through life. Or is it uncharitable to lump all carbs (wheat, spelt, oatmeal, high GI fruit) if you’re looking to maintain/lose weight and be in good health?

    • Sylvie, a rigorous answer to this question would require at least a (long) blog post. Maybe a book. I’m sorry I can’t provide either at the moment, because it’s a fair question.

  10. The story about your daughter and the ice cream reminds me of my niece when she was a child. She would push her meal away saying she was full. She would then ask for dessert, and when we would say, ‘we thought you were full’, her answer was, ‘my food stomach is full, not my dessert stomach!’.

  11. Hi Peter:

    Wonderful work you are doing! I’d like to add a source of invaluable information to your nutrition research. The book, “Nutrition and Physical Degeneration” by Dr. Weston A. Price documents just how devastating the introduction of sugar (and other refined westernized foods) to healthy, remote peoples of the world was to their health and well-being. The non-profit Weston A. Price Foundation publishes fully referenced outstanding articles on the very topics you are interested in. A return to the nourishing traditional foods of our great-great grandparents is what they advocate. Here’s a link to an article from their most recent journal that shows the quality of their research: http://www.westonaprice.org/environmental-toxins/violent-behavior-a-solution-in-plain-sight. Although this article concentrates on behaviour and nutrition, it applies broadly to the fact that we are what we eat. BTW, Dr. Price was born and raised a Canadian, too.

    Linda Morken
    Volunteer Chapter Leader
    Weston A. Price Foundation
    Vancouver Island

  12. Great work there Peter. As a pharmacist I’m reminded of the adage that came up often during my training – the only difference between a drug and a poison is the dose. As this can be the case with nutrients such as the fat soluble vitamins, it looks to be true for sugar. I think Stephen really hit on it in one of his earlier replies regarding fruit consumption.

  13. So while we are debating whether sugar is toxic or not, we are overlooking the other catastrophe bearing down on us, to wit the rising epidemic of degeneration of the brain.

    http://people.csail.mit.edu/seneff/EJIM_PUBLISHED.pdf

    And to add insult to injury, we have been told to remove saturated fat from our diet, despite the fact that the lipid hypothesis of CVD has been thoroughly debunked.

    I do wonder whether medical doctors remember their Hippocratic Oath: “Never to do HARM to anyone”.

  14. Hi Peter,

    I am curious if you recognize the dripping irony in the following statement:

    >>>**Sadly, it’s difficult to really interpret the data objectively from those in the PRO sugar camp because of the conflicts of interest. Most of the PRO sugar scientists are heavily funded by the sugar industry. For those interested in the historical context on science and the sugar industry, you’ll find this article particularly interesting.<<<

    The article in cited is: Big Sugar's Sweet Little Lies How the industry kept scientists from asking: Does sugar kill? — Co-authored by none other than Gary Taubes. Gary's bio there, http://www.motherjones.com/authors/gary-taubes, includes this line: "He is currently writing a book about sugar". He is being paid to reasearch and write that book by the Robert Wood Johnson Foundation and his bias against sugar is longstanding.

    Would this not be a blatant example of conflict of interest on the ANTI side as well?

    One of the problems here as well is saying that any science that doesn't support the sugar=toxic side of things is thus "pro" sugar consumption. This is a good way to polarize the debate because it allows one to paint anyone who "defends" sugar as someone suggesting we should all live on Pixie Stix and Sierra Mist. That's just silly, would you agree? There can be a happy medium there somewhere … one where the term toxic really has no rightful place. It is a needlessly inflammatory term and clouds the issue. If you are serious about personal toxic limits, I hope you extend that to all foods and components that are isolated and consumed in high levels. After all, we can induce far greater toxic effects in rodents with lower doses of various fats than sugar (and not just trans fats).

    The ANTI science, when held up to the light of scrutiny, doesn't stand up very well. Make no mistake there are financial stakes in that game too.

    • Interesting point, Evelyn. I think the real question is if Kimber Stanhope, Peter Havel, George Bray, and others in the ANTI camp have the same degree of conflict — financial conflict — as John White, James Rippe, and others in the PRO camp. There is no doubt that bias will always play a role in science. We are all biased despite how hard we might try to not be biased. But a conflict of interest may be a separate issue.

      Perhaps the more important question ought to be, what can be done about it, if our goal is to know the truth? How can science overcome its inherent bias due the fact that people, not robots, do the work?

    • (I did not see a way to reply to your response Peter, so I am replying to my comment and hoping it goes in the right place. )

      In my past life I researched both in academia and industry and I’m well familiar with how funding works. I am really not sure that just because funding is from a public source or purportedly non-interested private source doesn’t mean it won’t influence the outcome. Moreso, it may influence the study that gets done at all. Try getting funding for a study not designed to show man-made global warming for example.

      So since you mention Stanhope and Havel, the study design of the one where they took obese subjects and intended to replace 25% of calories with glucose or fructose sweetened beverages is questionable to me. Since nobody is drinking fructose-only beverages, the 125g/day of pure fructose (with no balancing glucose) is physiologically aberrant (this alone renders the results to be of questionable relevance off the bat.) Secondly, if the goal was to replace calories with fructose or glucose, why didn’t they attempt to control for calories in the rest of the diet? These subjects did not compensate fully for the liquid calories and as such were in a chronic hypercaloric state and gaining weight. Considering that the effects of fructose have been hard to elicit in isocaloric states might that have been considered?

      I don’t see how this science is any more OR less suspect than had the same study been paid for by PepsiCo. In other words, the science is what it is, and there are problems with this study that could be due to bias by the researchers and/or could have been influenced by the funding source and needing to get a predicted result.

      What if Pepsico had done the same study, replaced 50% of calories with Sierra Mist (sweetened with sucrose) or UCAN (grin) and controlled the rest of the diet so that 25% of their weight stable calorie intake was fructose or waxy maize Superstarch. Had this shown no difference, everyone would be shouting bias because PepsiCo funded the research. Would that change if Jeff Volek did it? How about Richard Feinman? How about if NuSI had funded the study?

      This study would be an improvement in that it tested physiologically relevant “foods”, but it would still be of limited relevance in the “real world” where mostly I see numbers like 10% bantied about in terms of calories from SSBs. So lets say PepsiCo chooses instead to use 20% or even 25% Sierra Mist (and keep total calories constant) and they can compare to 20-25% glucose-superstarch mix. The results of such a study would have far more relevance to the causes of metabolic dysfunction, don’t you think? And again, if PepsiCo vs. NuSI or NIH or whatever sponsored such a study, would the results have any different meaning? Havel v. Volek? I don’t think so.

      The science is the science, so the issue becomes one of study design, implementation and interpretation. Stanhope & Havel provided extensive supplementary information with the first publication from the study I’m talking about here. Even as extreme as it was, there were some very surprising “no differences” that went not noted in the publications. Were PepsiCo to pay some researchers to publish that analysis up, would it now become tainted?

      • Not necessarily, but the probability is greater. There are solutions to this. These questions that remain unanswered can be answered. To quote the late Basil Rifkind, “the data are gettable.” How to do so is what I suspect is the most important set of questions to be asking. And, yes, I agree with your comment about the lack of utility about fructose-only interventions. While they may be mechanistically interesting, they don’t appear clinically relevant.

    • I agree, the data are gettable. In some cases we do already have it. I’m not sure there’s a solution to the problem of “no result” being seen as an outcome not worthy of investigation/publishing. It certainly influences what studies get done to begin with, and it’s not conducive to further funding to find nothing conclusive.

      Thanks for allowing me to comment here Peter, and your considered responses. It’s refreshing and much appreciated.

      • I think all data should be published, including so-called “negative” data (I’m not sure this term makes sense). I’ll share an anecdote. Early in my post-doc/fellowship I did a series of experiments on human cancer and immune cells looking to modulate reg T cell response. This was follow up work to something I did that was very promising and I expected this to work (and to be published in a high-impact journal). The experiment didn’t work. The toxin I was using to modulate the immune system didn’t work. I repeated the experiments two more times. Nothing. I was bummed and didn’t want to go through the trouble of writing it up, only to publish it in a 2nd or 3rd tier journal. My mentor, who is simply a giant in the field, said, “Peter, this must be published. One of the biggest problems in science is people not publishing negative work. If your publishing this alerts others to the problems, that is as valuable as had it worked.”

        Talk about a valuable lesson in scientific integrity. I went on to publish many more papers in that field — some ‘negative,’ some ‘positive’ — but I never forgot what Steve Rosenberg taught me. I think this culture can expanded to all of science, and certainly nutrition could benefit from it. I think it would also raise the bar on the types of experiments people would do. Pre-registration is one step in this direction, but ultimately, it has to be driven by the scientists themselves.

    • Preregistration might work if all that is required is to make the data public. Otherwise I think the unintended consequence of research not being done at all may occur.

  15. “some argue that fructose consumption impacts subsequent food consumption in a way that glucose does not. In other words, eating sugar may fail to satiate you and/or make you subsequently hungrier. ”

    The study you quoted actually shows that glucose stimulates eating more than fructose
    Gender Fructose Water Glucose Glucose-aspartame
    Female 703 960 1328 1088
    Male 1035 1231 1474 1501

    And later “pooling across sex, subjects in the fructose condition ate, on the average, 225.9 calories less than subjects in the water condition, who in turn ate, on the average, 252.7 calories less than subjects in the combined glucose conditions” and “It is noteworthy that subjects ingesting 197 keal of fructose showed almost perfect regulation, reducing food intake by about 225 kcal relative to subjects who had the 0 kcal preload of water. On the other hand, subjects with the glucose preload showed potentiation of intake, leading to about 450 more calories overall than water subjects, after ingesting both the preload and the buffet meal”.

    “So, while folks in this camp argue that sugar per se isn’t harmful, it does make you eat more (sugar and non-sugar, alike), and that is the harm.”

    We now have confirmation from the authors themselves (via the letters published in the Journal of the American Medical Association) that the much misquoted study “Effects of fructose vs glucose on regional cerebral blood flow in brain regions involved with appetite and reward pathways” from January 2013 with regards to fructose and hunger – has been largely misrepresented.

    http://www.ncbi.nlm.nih.gov/pubmed/23632711
    “We underscore that the study found no statistical difference between glucose and fructose ingestion on hunger, fullness, or satiety. Thus, while we also reported pre-drink vs post-drink changes in fullness and satiety for each drink separately, we did not interpret this as demonstrating a difference between treatments.”

    We also know from the supplementary data from the Stanhope 2009 study, that although MASSIVE doses of fructose resulted in a similar levels of fat gain (admittedly it was the more problematic visceral fat) that people taking in 25% of their calories from fructose vs glucose, didn’t eat any more calories under free living conditions. http://www.jci.org/articles/view/37385/sd/1

    With regards to Dr Lustig and his fringe views on fructose, while theories and evidence may seem convincing to the general public and reporters, the real test is how well he performs with his fellow scientists!

    He was certainly called out for overstating the evidence and poorly extrapolating rat research at a conference he spoke at last year – check out the Q and A video in the attached article by David Despain (as well as the other lectures)!

    http://evolvinghealthscience.blogspot.com.au/2012/04/sugar-showdown-science-responds-to.html for a full review and links to all lectures – if not just watch the Q and A at http://www.youtube.com/watch?v=ypWe6npULUQ and http://www.youtube.com/watch?v=cnGhfX2yaU4

    What research shows that it is fructose that causes addiction? The study that you quoted certainly doesn’t show that ” Furthermore, evidence is emerging that sugar is addictive – http://ajcn.nutrition.org/content/95/4/810.long

    At the Q and A at the Sugar Symposium, Dr Lustig was called out on this and one researcher showed that rats liked glucose based carbohydrates over sucrose, and another questioned the applicability of rat research to be extrapolated to humans!

    Also a recent rat studied suggests that it might be the sweet taste and NOT the fructose (as they used an artificial sweetener) although this article has been largely misquoted also!
    http://www.plosone.org/article/info:doi/10.1371/journal.pone.0000698

    • David, excellent catch. A friend pointed this out last week (that I had linked to the wrong paper), but I need to revise it. A better study to illustrate the potential (though conflicting) role of fructose vs. glucose on subsequent appetite and feeding behavior is probably the 2004 by Karen Teff et al in The Journal of Clinical Endo & Metabolism. But even this study doesn’t look at what needs to be studied (if you know of such a study, please send link, but I’ve been looking for a month…). The “ideal” study would pit isocaloric levels of glucose vs. sucrose (or HFCS), which is far more interesting in my mind than isocaloric glucose vs. (pure) fructose for the obvious reasons.

      To your point about the Stanhope and Havel data, including 2009 and 2012 data using 25% is understandable, but still represents ‘efficacy’ data (though not necessarily ‘effectiveness’ data). A big part of the problem is what I address in the sidebar about NHANES and ERS databases. I have seen numbers reported as high as 140 pounds per year per capita of added sweetener! When one uses more conservative numbers, 73 pounds per year per capita seems to be the convergence, which is about 14-15% of total calories, not 25%. However, and this is crazy part, while the AHA recs (2009, Johnson, Appel, et al.) recommend no more than 150 kcal/day, the DGAC (“The report of the Dietary Guidelines Advisory Committee) in 2010 recommended up to 25% of total energy from added sugar! I had to read it to believe it. That’s quite a range, 5% to 25%. So, in this setting, I think the work of Kimber S and Peter H is warranted to explore the boundary conditions.

      To your last point, I have seen data in press (but still in review) that show the impact of glucose + aspartame vs. HFCS vs. glucose (all isocaloric) on all biomarkers available including TG, TG AUC, apoB, etc. There was a some difference between glucose vs. glucose + aspartame, but HFCS stood out very clearly. However, since unpublished, best to wait until they are out to really comment.

  16. Hello again Peter,
    Are you familiar with the books: Body by Science? Or Slow burn? Or Power of Ten?
    Or the literature about strength training to reduce visceral fat and reverse incipient metabolic syndrome?
    Specifically, Is high intensity necessary? And how can we tell If we have allowed enough time for recovery?

    I am particularly interested in reversing the metabolic damage of IR, but also injury prevention, to avoid surgeries for joint problems.

    Thanks again.

  17. More Qs, prompted by comments to me from a dietician.

    Why do not feel any need to supplement with B vitamins?
    And, what about pastured meats, chicken, dairy, . . . .? Do you believe your fish oil supplement provides adequate balance?

    Do you know of a good online site, or book, that would provide more guidance, valid guidance, for aging women trying to reverse metabolic syndrome?

    Your website is fantastic.
    Again, thanks so much.

    • I think supplements should be person specific, and based on some baseline. Some people need B supplements, others don’t. Same with EPA, DHA, folic acid (which can be based on MTHFR mutations), etc. Point is, I don’t think there is a one-size-fits-all approach.

    • Jane:

      I’m an aging woman (nearly 60!) that has had success in reversing pre-diabetes, obesity, IBS, and GERD by learning and applying the information I found on the following sites. I believe that our ancestors had food right and if we want to regain our health we have to go back to eating whole, unprocessed, nourishing foods. My food list includes pastured meats and eggs, plenty of animal fats, naturally fermented homemade kefir and sauerkraut, bone broths, organic veggies and some fruit – mostly berries, and a little real sourdough rye bread. It’s basically the food we would find on our great-great grandparents’ small farm, before food became industrialized processed concoctions. Eating like this is working (4 years now) for me and many others. Here are the links to sites that have helped me so much:
      http://www.westonaprice.org/basics/dietary-guidelines
      http://www.dietdoctor.com/how-to-cure-type-2-diabetes-2

      I wish you wellness.

    • Thank you, Peter. That makes sense, of course.

      Linda, thank you very much for reminding me about Jay Wortman’s excellent story, and about the helpful website by Andres Eenfelt.

      The westonaprice.org approach certainly has a lot of appeal, and has a ring of truth to it, but I have not yet learned to enjoy all that food prep. I am still working, always, toward the optimum personal balance.

      Cheers.

  18. Hi Dr. Attia,

    Great article.

    Since we are still unravelling how cells work and how nutrients affect them, I realize the unknowns about nutritional science are enormous. From my conversations with my friend Urgelt, I know we have absurd amounts of sugar in the modern diet. This , I think, is likely a very bad thing.

    Take care,
    Raz

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