Monday, January 10, 2011

Eating Fat and Diabetes -- Response to Bix Weber

by Chris Masterjohn

Melissa McEwen recently brought to my attention a blog post by Bix Weber, the Fanatic Cook, "Diabetes is a Disorder of Fat Metabolism."

Weber cites a 2009 study published in The Journal of Clinical Investigation entitled "Mitochondrial H2O2 emission and cellular redox state link excess fat intake to insulin resistance in both rodents and humans" that purports to show that eating too much fat contributes to insulin resistance not only in our furry little lab rat friends but also in humans.

The paper contains an animal study and a human study.  The animal study is useful and informative, while the human study is poorly designed.  This paper is important and does shed some light on the causes of insulin resistance, but to conclude from this paper that humans will become diabetic from eating too much fat is a serious misuse and misinterpretation of the paper.

The researchers fed rats a control diet or a 60% lard diet from Research Diets.  The authors don't state what the control diet was, but if it was similar to the standard control diet that Research Diets offers, the 60% lard diet would yield not only a high content of saturated fat, but a 50% increase in total PUFA.  They fed this diet with or without an antioxidant that targets the mitochondria, scavenges reactive oxygen species, and prevents the oxidative destruction of PUFA.

The high-fat diet did not produce any oxidative destruction of PUFA in rats:
No evidence of mitochondrial dysfunction or oxidative stress, at least with respect to the levels of the lipid peroxide derivative 4-hydroxy-nonenal (data not shown) was found in muscle of high-fat diet-fed rats with or without SS31 [the antioxidant] treatment.
However, when they isolated the muscles from these rats and provided them with energy sources, there was a 2-3-fold increase in the maximal production of hydrogen peroxide, which is used as a signaling molecule but can induce oxidative damage at high doses or when combined with certain metal ions.  This effect was abolished when the rats were treated with the mitochondrial antioxidant.

The high-fat diet also reduced concentrations of the master antioxidant of the cell, glutathione, and led to impaired glucose tolerance.  It is typical for this type of high-fat diet to produce these metabolic effects in rats, so this is not surprising.  Treatment with the mitochondrial antioxidant helped prevent the decrease in glutathione and completely abolished the impairment of glucose tolerance.

When they repeated the experiment in mice, they genetically engineered some of them to produce more of the enzyme catalase, which converts hydrogen peroxide to water.  Overproduction of catalase completely prevented the negative metabolic effects of the high-fat diet.

Quite obviously, this paper shows that high-fat diets are not inherently harmful to rodents.  Simply providing an antioxidant nearly abolishes all their negative effects.  

Health-conscious humans do not eat high-fat diets made of refined, purified ingredients or obtain 60% of their calories as lard.  A diet based on organ meats such as liver, shellfish, muscle meats, fish, fruits, vegetables, starches, and animal fats from healthy animals or selected traditional plant oils bears no resemblance to this type of diet and is instead loaded with antioxidants.

Nevertheless, I actually really like this paper.  In the discussion section, they point out that glutathione is not just an antioxidant, but is actually a master control switch responsible for regulating the activity of a whole host of different proteins and that insulin resistance is not so much a result of damage to the organism, but a way of homeostatically regulating energy balance.  I'll write more on this topic in the future.

Their hypothesis is basically that the supply of fat exceeds the metabolic demand for fat, and that the cell responds by creating a more oxidized environment in order to deliberately reduce its sensitivity to insulin, which will stop the flood of more incoming fuel in the form of glucose.

By providing an antioxidant, they increase the mitochondria's ability to process the fats, and thus increase the cell's tolerance for incoming fuel.  So the cell will take up more glucose in response to insulin.

The only problem with the paper is they never explain why fat would constitute "excess" whereas carbohydrate would not. It's possible that fats just burn a little less cleanly than glucose.  For example, a large excess of energy provided to mitochondria will tend to cause glucose to get converted to fat, but could tend to increase the burning of fatty acids in the endoplasmic reticulum, which generates a lot more oxidative stress than the mitochondria.  They provided no evidence of this, however.

But it's also quite possible that the 50% excess PUFA made all fuels burn less cleanly by increasing the mitochondrial content of vulnerable PUFAs.  Since they didn't find oxidative destruction of PUFAs, this hypothesis is not very well supported.

It's also possible that this simply reflects an adaptation to fat-burning.  As the cell adapts to fat, it stops taking up glucose. 

Regardless, the antioxidant improved mitochondrial efficiency enough to handle the fat and to be able to respond to insulin sensitively.

The big problem with this paper is that they try to extrapolate this to humans with an incredibly poorly designed study.

Here is what they report for methods:

Nine healthy lean (BMI, <25 kg/m2) men (aged 18-25 years) of a variety of races participated in an acute high-fat diet study.  Subjects reported to the laboratory following a 12-hour overnight fast.  After muscle samples were obtained, subjects consumed a single high-fat meal (35% daily kcal intake; >60% kcal from fat), and a second muscle biopsy was taken 4 hours later.  Subjects then consumed a high-fat diet (isocaloric; >60% kcal from fat) for 5 days and returned 12-hour fasted on the morning of the sixth day, when a final muscle biopsy was obtained.

Hmm, can you spot the control group?

Picture borrowed from here.
I think Waldo might be in there, but there's no control group in this study.  Nor is there a control trial where the people consumed a low-fat diet.

Nor is the diet described.

Their animal study would seem to suggest that the effects of the high-fat diet — if in fact there were any effects — could be mitigated simply by including appropriate antioxidants, perhaps the type that are included abundantly in traditional, nutrient-dense fatty foods.

Read more about the author, Chris Masterjohn, PhD, here.


  1. Nice article. I don't know much about the profile of antioxidants "that are included abundantly in traditional, nutrient-dense fatty foods" because I haven't optimized my diet for antioxidant intake. I imagine most sources on the web would be hyping a vegan diet. Do you have a good summary?

  2. Hi Chris,

    interesting, just yesterday I was wondering how to interpret studies Bix mentions, as I love to eat some fat with my meals and find it hard to believe humans are designed to not eat it at all. But Bix does put forth some food for thought. If you find time, would you care to read/comment on later posts as well? This one is esp. interesting:

  3. I eat a high fat, low carb diet, and my latest blood tests show I that have no insulin resistance. In fact, my tests are off the chart low in this area.

    Move on, nothing to see here.

  4. Just curious what would be a good antioxidant to use for a situation like this. i.e high amount of existing insulin resistance

  5. This is slightly off-topic from your post, but thought I'd mention it to you. I recently came across a presentation that suggested a connection between high fat diets and the endocannabinoid system's role in appetite and obesity.

    I hadn't heard of this before and haven't had time yet to delve into it deeply, but arachidonic acid is/can be a precursor to one or both cannabinoids. One of these, anandamide, is apparently somewhat similar to THC, the substance in marijuana responsible for the high (and pot-induced munchies!).

    It looks like there has been a lot of research into cannabinoid receptor antagonists via pharmacology (which is not turning out to be the obesity panacea just yet), and/or the effect of omega 3 supplementation on the system. But even as a lay person, I couldn't help but wonder if this was another role that the high levels of dietary omega 6s played in the standard American diet as far as disrupting appetite and leading to weight gain. And presumably, whether this was yet another reason why a minimizing veggie oils is worthwhile. Curious!

  6. Stephen Guyenet has covered this pretty extensively. If you feed a rodent a diet high in linoleic acid, it gets diabetes. They've done this with corn oil. I was looking at the Research Diets website last night, and the feed that they sell explicitly to cause diabetes (there's a link to various studies that use the feed) includes both soybean oil and varying amounts of lard. Lard contains a good bit of linoleic acid, especially when it comes from an industrially-produced animal, as does soybean oil, and has it's not surprising that it has pretty much the same effect as corn oil does on the poor critters.

    Your note about the antioxidants is pretty interesting, however.

  7. Responses to Jeremy, blob, Jake, Anonymous, and Beth.

    Jeremy and anonymous, coenzyme Q10 and lipoic acid are important mitochondrial antioxidants, which would be abundant in foods like liver and heart. Heart is by far and away the best source of CoQ10 I've seen listed. I'll try to post something more extensive on the antioxidant nutrients found most abundantly in animal foods.

    Blob, I'll try to check out that post soon.

    Jake, excellent.

    Beth, the studies on endocannabinoids are hilarious. The weight loss trials with drugs that interfere with this system were abysmally conducted and horrifically reported and cannot be considered respectable science. I do think endocannabinoids play some positive roles, and I discussed a hypothesis that they might play important roles in mental health here:

    I do not think that excess linoleic acid increases arachidonic acid (AA) levels much, because tissue levels of AA plateau very quickly at low intakes. I do think they cause other problems, and are likely to diminish tissue levels of the omega-3 DHA, and that might lead to dysregulation of the endocannabinoid system.

    It's important to realize, though, that production of anadamide and the others is very regulated, so it's not the precursors that matter so much as the regulation, as long as the precursor levels are saturated, like they should be (as tissue levels of AA are highly regulated).

    Hope that helps,

  8. I just added this sentence:

    "It's also possible that this simply reflects an adaptation to fat-burning. As the cell adapts to fat, it stops taking up glucose."

  9. Thanks Tuck. I think Stephan and I are very much in agreement in our takes on the effects of these diets.


  10. I agree, I've often thought that you and Stephen might be the same person. ;)

    I also came across some interesting research that certain primate species had diets that were pretty high in linoleic acid. I wonder if, as you've demonstrated with fatty liver, the linoleic acid is not the problem, but malnutrition really is... Wound linoleic acid be OK if we had the right nutrients to allow the body to safely process it in larger quantities?

  11. Chris,

    Excellent post; I've been following Bix's blog for a while now, out of pure curiosity. I'm glad it was brought to your attention for dismantling. Some of my comments on his side of the fence have been deleted in the past.

  12. Most studies of "high-fat diets" concern diets that are high in fat on top of usual carb intake.

    As Richard Feinman says, “The deleterious effects of fat have been measured in the
    presence of high carbohydrate. A high fat diet in the presence of high carbohydrate is different than a high fat diet in the presence of low carbohydrate.”

    If they don't specify the exact diet, one can't evaluate.

  13. Skeletal muscle in the mouse have no Farnesoid-x-receptors (FxR); nor do humans (some are in smooth muscles of coronary artery & aorta). This is a nuclear transcription factor and humans have 4 genetic forms working in different tissue groups, immune cells and the placenta.

    We eat fat and all four genetic FxRs go to work in our duodenum and small intestine. The different bile acid conjugates are the variable activating ligands for FxR in vivo. Yet, the liver and colon differ between them on expressing which paired sets of those genes are found in their tissues.

    Low FxR expression is caused by high glucose and high insulin. Other research shows that administering bile sequestrants, a ligand of this transcription factor, act to drive down blood glucose. Also, insulin resistance seen in faulty fatty acid metabolism occurs with elevated insulin receptor substrate-1 serine phosphorylation; this dynamic is also seen when FxR expression is lower.

    Since skeletal muscles are very insulin sensitive (humans don't have FxR working there) an in vitro projection for all tissue's glucose response is extrapolation. When we, in vivo, eat a lot of fat our bile is significantly involved.

    (( As for diabetic's morning "fasting" hyper-glycemic blood glucose levels; this is gluco-neo-genesis released from the liver. Glucagon and gluco-corticoids are hormonally involved with rate limiting enzymes like glucose-6-phosphatase and fructose 1,6-bis-phosphatase. After breakfast (post-prandial) our insulin level rises and normally inhibits FxR. Lowered liver FxR transcription allows a switched metabolic cycle that then normally causes less liver made glucose (redundant since we've eaten) to be put out. Unfortunately, once a person is clinically type II adult onset diabetic their FxR mechanisms are epigeneticly altered from the normal non-diabetic responses. ))

  14. Here's a link to the probably diet:

  15. Might-o'chondri-AL would you mind putting in a dumbed down summary of your posts for those of us without a degree in biochem? :)

  16. Nice post. That's why I periodically supplement with milk thistle. It substantially increases glutathione production and SOD, both of which are much more powerful than your standard dietary flavanols, polyphenols, etc. Metabolic enzymes are the best route for increasing antioxidant status.

  17. Chris,

    Cool post. I am curious what effect ascorbic acid synthesis has on a study like this? AA is an anti-oxidant and rats can make huge amounts if necessary, where as human cannot make any and have to get all from diet. Although we are very efficient recyclers of AA.

    Do you know if they make rats with a L-gulonolactone oxidase knock out or some other method of stopping endogenous ascorbate production to better mimic human physiology?

  18. blob, I just responded to Bix's other post:

  19. Hi Chris:

    After exhaustive reading, I have come to the conclusion that a paleo style of eating is the way to go. I'm a research tech in a cancer research lab. I am surrounded by incredibly intelligent people who refuse to see the forest for the trees. I recently became frustrated when I was telling a co-worker about a friend who effectively cured her type ll diabetes by switching to the Atkins diet. He told me that was a dangerous move and that the Atkins diet had been marginalized as a fad diet. Of course he couldn't give me specifics about the source of his information, but I suspect the research you mention in this post may have something to do with it. If I could send out one convincing web site with lots of irrefutable info (it will have to have a high impact to grab their attention) what would it be? One of my favourite sayings applies here "bullshit baffles brains." Thanks so much for your excellent posts.

  20. I gave up on reading Bix's Fanatic Cook blog a long time ago. Bix's choices of and interpretations of studies is washed with bias for high fiber, low fat diets. Bix censures perfectly civil commenters who dare to disagree, so the reader comments were more like a Bix fan club. There are far better blogs to read ;-).

  21. Responses to everyone.

    Tuck, I've wondered that too, but when I run a hypothesis by Stephan and he says "Uh, I think you're going to need a lot of data to support that" it reassures me that we are in fact different people, which makes his friendship more valuable. I do think that the human body is very resilient, so while I think excess linoleic acid is generally a tax on the body, I think if everything else is optimized, the human body can probably withstand such a tax and be healthy. However, "as long as everything else is optimized is somewhat like the economist's famous statement "assume a can opener."

    Mike, thanks! Too bad he's apparently not a fan of open discussion, according to you and some other commenters. But glad you found your way over here!

    Gretchen, I do not think that's true. Most high-fat diets contain carbohydrate, but they substitute fat for carbohydrate rather than adding it.

    ...AL, thanks for your thoughts. How do you relate this back to the conlcusion of the study or to my blog post?

    Davide, cool, I've used milk thistle before.

    Paul, good point. There is at least one such rodent model, mouse I believe, but it's not too popular. A much easier way would be to use guine pigs, which also have the advantage of having similar lipoprotein metabolism as humans, whereas lipoprotein metabolism in rats and mice is very different.

    Olga, you're welcome. I agree that can be frustrating. I'm glad you see through the fog. Thanks for your comments and compliments.

    againstthegrain, I never started reading it. ;-)

  22. Study over looked what I detailed; original post shows conclusion flawed. My comment is to show that none-the-less, fat metabolism is inter-connected with insulin (glucose metabolism).

    For examining these types of studys, I thank you for reporting your efforts here.

  23. Chris,

    This study seems flawed in a much more fundamental way, as are virtually all similar such studies. You'd think that in a study like this at involves antioxidants that they would measure the ascorbate production levels in the mice/rats.

    For all we know, AA levels may have gone way up and thus had a significant effect.


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