There are a fantastic number of pieces to the jigsaw puzzle of obesity in this paper, many of which are probably very important and I'll run through them as soon as I can get my head around which ones matter most.
The basic concept is that there are excessive fatty acid derivatives in the cytosol of muscle cells (and probably other tissues, the main thrust of the paper is toward muscle metabolism). Why I view this as supportive of the carbohydrate/insulin hypothesis of obesity is yet another post. This particular post is on some of the problems I have with the concept of a simple defect in fat metabolism as the cause of the accumulated fatty acid derivatives.
As so often there will be a series of stolen diagrams, scribbled over using Powerpoint, which probably break every copyright rule in the book... Oops. Here we go.
Okay, here is the basic concept as a straight copy-paste:
Uptake of long chain fatty acids in to the mitochondria is mediated through carnitine palmitoyltransferase 1 (CPT1, green box upper left hand side). This is suggested as the failed step.
But there are problems with the diagram. Look here:
Here we have citrate being exported from the mitochondria and converted to malonyl-CoA via "fatty acyl-CoA". I think it would have been much better to actually specify acetyl-CoA at this point rather than "fatty acyl-CoA", but that may be nit picking on my part. But it is ONLY acetyl-CoA which is liberated by the citrate shuttle. The function of the citrate shuttle is to get acetyl-CoA out of the mitochondria and in to the cytosol for fatty acid production...
Next we have this feature:
I'm not sure whether this arrow suggests that fatty acyl-CoA, straight from triglycerides, facilitates or activates the citrate shuttle (I can't find any suggestion of this being the case) or is being cited as a source of citrate, which it is not. For fatty acids to form citrate they have to under-go beta oxidation:
And this is not supposed to be happening because the malonyl-CoA is inhibiting CPT1 mediated transport of fatty acyl-CoA to the site of beta oxidation. Hmmmmm.
So where might the cytosolic malonyl-CoA be coming from? Is glucose supplying so much citrate that the obese can use it for malonyl-CoA production?
If we flick to this fascinating reference we can look at the TCA cycle itself, to see whether glucose is producing enough citrate to export for conversion to malonyl-CoA as the spanner in the works.
From the paper we can see that if you have a very complex magnetic resonance spectroscopy machine, which you are willing and able to home-modify (read the methods text!), some exceedingly complex computer models and a supply of carbon 13 labelled acetate tracer you can actually work out how active the TCA cycle is in normal vs insulin resistant muscle tissue. This paper is so cool.
Verdict?
The offspring of diabetic parents have crap TCA cycle activity in their muscle tissue. It will not be producing the amounts of citrate which might be exported for fatty acid synthesis. This is not a failure of beta oxidation. It is a failure of the TCA cycle in its entirety. The fact that obese people run their metabolism on glucose does not mean that they run it well on glucose.
Why is the TCA cycle so compromised?
This study has some excellent pointers. Look at this picture, it could be from an obese or diabetic individual:
These folks have odd muscle tissue.
a) They don't have many mitochondria, b) many of their mitochondria look crap and c) many of their mitochondria are dying.
They don't have a simple failure of fat oxidation, they have a failure of mitochondria full stop. It simply shows most clearly in the failure of beta oxidation.
I'll take a break now and put this post up. There are, of course, a whole stack of follow-ons to this. If you have duff mitochondria you accumulate fatty acid derivatives in your cytoplasm. They cause insulin resistance. Once you have insulin resistance you will be chronically hyperinsulinaemic and, in all probability, go on to develop obesity as a direct consequence of that hyperinsulinaemia. Let's make this plain. Mitochondrial dysfunction is present before obesity develops and does not revert to normal on forced weight loss.
Over eating is not causal. Whatever anyone tells you.
If you are an undamaged human being and you force overfeed yourself with FOOD, say in some tribal ritual, I would suggest that you will not do this to your mitochondria. You will continue to burn fat easily. You will not develop chronic hyperinsulinaemia. You will lose weight automatically after that cultural binge is, thankfully, finished and you can get back to life within your normal appetite.
Humans do such weird things to themselves! Culturally and accidentally.
Peter
70 comments:
Although I had some difficulty following all of the information in this article, it did serve as a potential confirmation that somehow, I have permanently damaged my metabolism. I had thought it was somehow connected to the fact that I had low-fat dieted myself all the way to 350 lbs, but this article and the linked study seem to say that the damage was not done by the extreme weight, but by something else (my guess: gluten and HFCS).
It does appear that I'm finally on the right track, with low-carb diet and weight training. But I wonder if I will ever lose that last 50 lbs...
"Mitochondrial dysfunction is present before obesity develops and does not revert to normal on forced weight loss."
I think all that reference shows is that aerobic exercise causes mitochondria to grow, which is pretty well known already.
It doesn't speak to mitochondrial disfunction at all...
But a fascinating post. Looking forward to the rest.
And we know one way to mess up mitochondria...
"Energetic Efficiency and Mitochondrial Function in Rats Fed trans Fatty Acids"
http://jn.nutrition.org/content/114/7/1183.full.pdf
I got really hardcore fixated on sulfur over the last several days due to some conversations I've had with some of my blog followers, who like to bring me interesting tidbits. I don't have your understanding of the science or the related literature but I'm a bit nerdy about it just the same. Anyway, I started getting curious whether it was possible to become sulfur-deficient and whether that would have an effect on glucose metabolism. Or whether excess glucose having to be processed causes sulfur to be used up faster, as it does for (some of?) the B vitamins.
Well, so far (and this may throw my post into moderation, pout), I've found a few interesting tidbits. Check these out.
http://people.csail.mit.edu/seneff/sulfur_obesity_alzheimers_muscle_wasting.html
I poked around Google trying to find more stuff about cholesterol sulfate and vitamin D3 sulfate, and so far all I'm finding is researchers don't think the latter is very important. That tells me chances are good it's an extremely important substance and they should stop overlooking it.
And this:
http://ajpendo.physiology.org/content/287/4/E744.full
IF sulfur deficiency (or poor use of sulfur?) can be linked with insulin resistance, this might explain part of the mechanism involved in the link between vitamin D deficiency and type 2 diabetes. And what a potentially easy fix.
And if sulfur deficiency (or poor use of sulfur) *is* linked with insulin resistance and type 2, and if sulfur deficiency (ditto) is also linked with a certain skin condition called keratosis pilaris (KP) that shows up quite a bit in obese people (myself included--and my skin got worse as I got heavier), KP might wind up being an early warning signal that insulin production and sensitivity are going all wrong in the patient. It was my nattering on about KP and asking my readers who was getting the skin problems that took me off this other direction.
Just throwing that out there. It really is a puzzle, isn't it? Although I have to say, I wish people would focus on hyperinsulinemia-related chronic disease generally, and not just obesity. There are people out there who have never gotten dangerously overweight, or who haven't gotten overweight at all, but who are going type 2. They need to be reached. Right now they think they're safe because everyone's focusing on the fatties. Probably where a lot of these so-called "hereditary" bad cholesterol, high blood pressure and hypoglycemia are coming from.
It raises more questions (about Kwasniewski's PPP hypothesis). So, when mitichiondria are deffective, the excess glucose may be processed through PPP that takes place in the cytosol only.
http://en.wikipedia.org/wiki/Pentose_phosphate_pathway
I am curious if PPP really plays any causative role in diabetic individuals. This article
http://en.wikipedia.org/wiki/Glucose-6-phosphate_dehydrogenase_deficiency
would probably indicate that PPP may be protective against oxidative damage due to its gluthatione reduction. If mitochondria-defficient cells do indeed utilize more PPP than the healthy cells, could that be a protective response to a damage (damage caused by what?) rather than as Dr. Kwasniewski hypothesized - being the cause of the damage?
Wow! I am trying to deconstruct and understand Peter's argument and the referenced studies. Don't know if I get it? I am slim, glucose intolerant and I am a daughter of a Type 2 diabetic. I am attempting low/moderate carb to avoid big Pharma and medicalization. If I have defective mitos or TCA cycle, why does it not impact my energy or ability to engage in physical activity? I rececently did a hike, 15 mile/3000 ft elevation gain.It was comfortable and I was not tired. Why is it some people who are metabolically broken (often glucose intolerant) get fat and lack energy and others stay slim and are energetic?
Peter:
This is why I'm glad you picked up on my article. We now have a lot of smart people looking at the problem, who (unlike much of the scientific establishment) aren't stuck on the idea that it must somehow be caused by cholesterol and saturated fat.
I intentionally didn't speculate on the cause(s) or cure(s) of mitochondrial dysfunction in my articles, because I hoped that people with more biochemistry knowledge than I, such as yourself, would soon be addressing them.
Any knowledge you uncover will be of great help as we work towards understanding the biochemistry of hunger and weight gain - and what we can do about it.
Thank you for digging into the subject! I'm looking forward to your further writings.
Stan:
That's a very interesting hypothesis, and it makes sense.
Tuck:
I suspect that we'll find the usual culprits behind this: trans fats, fructose in excess, linoleic acid in excess, and gluten grains. But our picture may not be complete or correct, so we need to keep working.
STG:
No one "gets it" yet, despite what some claim.
We have a bunch of empirical information about what works and what doesn't. What no one has is a definitive causal chain of events that causes metabolic syndrome. That's what we're all working towards.
(I suspect the problem involves metabolic pathways that break more easily in some than in others...but as I said above, we need to keep working.)
JS - gnolls.org
Peter:
"Obviously the failure of beta oxidation is strongly challenged by the success of low carbohydrate dieting and supported by the success of (extremely) low fat dieting."
While that's the naive reading (and I understand your sarcasm), I don't think it's true.
First, if beta-oxidation is impaired, we'll have difficulty losing fat no matter what source our calories come from.
Second, altering our diet changes our baseline RER/RQ. This becomes even more important when our metabolic flexibility is impaired, and suggests that a higher-fat diet will enable more fat burning. Empirical support for this idea comes from the "low carb flu", which happens even at carbohydrate intakes too high to enable ketosis. (Sources in this article.)
JS
Stan,
I would agree that cytosolic NADPH from the PPP must be used to reduce glutathione, which is probably a Good Thing. But it is also essential as a supply of reducing equivalents for FAS to build LCFAs in the cytosol too. The question really is what the demand is on the PPP if you drink a Big Gulp and have to do something with the fructose, especially if you start as already more than glycogen replete.
Obviously a huge, acute fructose load will send the citrate shunt in to massive overdrive and then require a ton of cytosolic NADPH to deal with the cytosolic acetyl-CoA. Which just might lead to failure to reduce glutathione??? And of course a fructose load like this will undoubtedly produce enough malonyl-CoA to acutely inhibit CPT1. No surprise that the fructose fed rat has insulin resistance.
So it may be to do with what demands there are on the NADPH from the PPP. My problem is that the issue needs a great deal of digging to produce a logical picture and this is far, far more work than is involved in taking a series of papers and seeing the thread that runs through them which might have been missed by the authors.
You probably remember Kurt's comment about "no religion" many post ago. I really should challenge my own received wisdom from JK. But you know, as I do, that he is mostly correct............
STG, there are many more posts to come. The "Usual Suspects" probably progress the problem and relatively LC paleo might well have a significant effect on the development of the phenotype. It comes back to Aravind's question as to whether you can be "cured". Qualified yes might include managing to not progress... The next question is obviously how will the children of a "non progressed" daughter of a T2DM mother fare. Very, very interesting question. I think they are a very rare human with the current diabetes management protocols.
JS,
Yes, I keep digging. The paper is a goldmine. Obviously we must all have our own take on the implications, but there is a lot to have a take on!
Interestingly it may come down in part to glucose being largely controlled by GLUT4 at the cell surface and beta oxidation by CPT1 at the mitochondria surface. This produces the phenotype which 4.5 billion years of evolution (very approximately) does its best to sort out. Much of the "pathology" is actually adaptive but being pushed to the point where there are problems in other systems.
Tuck, my initial thought was that trans fats were CPT1 inhibitors but it could be more structural than that. There are papers showing trans fats INCREASE fat oxidation. Go figure!
Dana, sulphur is complex. There is a nasty rumour that glucosamine sulphate helps arthritis due to its sulphate content. The HCl salt is what big pharma uses to show glucosamine is ineffective in controlled trials. Never really looked in to it.
And, perversely, limiting sulphur amino acids stops metabolic syndrome developing in labrats...
Anyhoo, time to wake the house up
Peter
JS,
I see parallels between glucose usage in in acutely hypoinsulinaemic T1DM volunteers (glucose utilisation is quantitively NORMAL, at the cost of hyperglycaemia) and elevated FFAs pushing fat oxidation towards normal levels at the cost of insulin resistance in the obese. There is a stack of follow ons from this... Not thought through the carb flu aspects.
Peter
Hi Chainey!
JS, I phrased that very badly, I meant that hyperglycaemia allows insulin-independent but quantitatively normal glucose metabolism at the cost, to neurons, lens etc, of that hyperglycaemia... And calories wasted down the loo of course. Oh, and eventual ketoacidotic death too.
Howard, I'd guess you are on the correct track too.
Peter
Diabetes. 1984 Jun;33(6):596-603.
Marked improvement in carbohydrate and lipid metabolism in diabetic Australian aborigines after temporary reversion to traditional lifestyle.
This paper is one of the most heavily cited papers in the history of paleo nutrition.
The author Kerin O'Dea (now a Professor) is the ultimate pragmatist. She has no real interest in the underlying mechanisms of diabetes. She is only concerned with prevention and cure via lifestyle changes.
Hello Peter,
I won't claim to follow all of the biochem details, but this quote really resonates with me -
"Mitochondrial dysfunction is present before obesity develops and does not revert to normal on forced weight loss".
I look forward to your follow-on posts and the implications regarding the "cure" or lack thereof.
Cheers!
Aravind
@STG -
Not sure if this is completely relevant, but an old post from Dr Harris - http://www.archevore.com/panu-weblog/2010/3/6/diabetes-i-vs-ii-and-diet.html
"In type II, the initial damage can be thought of as prior to both the hyperglycemia and the hyperinsulinemia. The initial damage is the suite of early metabolic defects like liver inflammation, steatosis (fatty liver), elevated inflammatory cytokines like IL-6 and TNF-a and likely systemic inflammatory and immune effects that contribute to cancer and immune disorders and atherosclerosis - (you can have these effects as well even if you never develop diabetes and are thin and apparently healthy on the SAD)."
There have been some other comments he's written more recently in other blog comments on being "skinny fat" but I can't seem to find them at the moment. Maybe he will chime in here?
Regards,
Aravind
Aravind:
Thank you for the suggestion to check out the comments from Dr. Harris on his blog. No doubt inflamation must be a contributing factor to pre-diabetes and diabetes. I have never eaten the standard SAD; although I used to eat a vegetarian, high-complex carbohydrate, high-grain, whole-foods diet which I think made my glucose intolerance worse. I know that there are people who can consume high levels of healthy carbs-I can't. I have transitioned to a low/mod carbo, grainless diet, limited fruit and no sugar or processed PUF oils. I hope this will keep the beast at bay--only time will tell.
Peter:
My father who is 92 and still functioning (wrote a book at 90) has type 2 diabetes. My mother, who died at 87 from lung disease, had a great glucose metabolism--never any problems. My question, is the possiblity that I have defective mitos a result of a maternal gene from previous generations? I don't understand the details of mito inheritance and its been a while since I took a biochem class. Lastly, if I do have damaged mitos, why do I have unlimited physical energy? Something is pumping out that ATP?I apologize if this comment is too much about me and not written in a more general content.
Dana - you should look around at Dr. Mercola's site and watch the video in this article (I don't have the knowledge to debunk or accredit it, but I'd love to read anyone elses view on it) http://articles.mercola.com/sites/articles/archive/2011/09/17/stephanie-seneff-on-sulfur.aspx
Mitochondrial Energetics and Therapeutics PDF
Those interested in possible strategies to improve mitochondrial function and biogenesis will find this free full text PDF of the paper worth studying.
Melatonin in Mitochondrial Dysfunction and Related Disorders
If you enjoyed Mitochondrial Energetics and Therapeutics you'll also find this free full text paper worth reading.
Very exciting stuff going on here lately.
Here's another link that traces mitochondrial dysfunction to Parkinson's disease and hypothyroid:
http://www.ceri.com/mito2.htm
"We emphasized the critical importance of impaired mitochondrial function in the development of Parkinson’s disease, but we only touched upon the potential relevance of mitochondria to fatigue syndromes, lack of stamina, psychological depression, cognitive dysfunction, muscular dystrophies, immune impairment, and senility syndromes."
STG,
I think Jane's comment that if your mitochondria are totally stuffed you wouldn't be here at all, is appropriate. Your mitochondria all came from your mother. She had normal blood glucose but I would guess no one ever measured how much insulin was needed to keep her blood glucose normal...
If you go through the paper on non-obese insulin resistant offspring of diabetic parents you will see that they were not particularly hyperinsulinaemic cf a T2DM person. But they were fatter (BMI around 23 vs 21, now there is a post I'm planning) while still "normal". But the problem is progressive and you seem to be doing the correct things to stop that progression. I almost said it before but you are pushing me now so here I go: I'd love to meet your children. When are you going to get... No, I can't say it. Need more wine and I'd better go to bed now.
Peter
Ta Ted, a bit late to click the links here...
Peter:
I am sorry but I didn't get your comment. Perhaps I am too literal. I have a son who is 42 years old and is hyperactive like his mother. I have discussed with him the topic of over consumption of carbohydrates and sugars and have briefly explained my own blood glucose issues. His diet is not as bad as most Americans, but given the family history he should pay close attention to his diet and any changes in his FBG. He is still at that age of immortality, hyper-manhood and super fitness so I think my words fall on deaf ears.
Ted,
Excellent links.
Your Privacy
Also interesting. I've seen thyroid hormone pooh poohed as unimportant to weight control in "healthy" or subclinically (???derrr???) hypothyroid humans. It has clearly got a lot to do with mitochondria and UCPs. You tend to become a bit biased by dealing with massively hyperthyroid cats!
STG, you clearly come from a line of long live-ers, and thanks for the rapid update on the metabolic functionality of your son! Under twenty I too was a metabolically (apparently) excellent skinny athlete. (Quote from a friend from kayak racing days when we re met a few years post team membership:"Hi Peter, still looking like an advert for Biafra I see" circa 1980ish) I started to put on a little middle aged spread and developed unarguable and occasionally quite unreasonable hunger in my 30-40s with the little pot belly at 40+. I was reasonable in my diet but swallowed the wrong advice quite well (without checking it). I avoided sugar but not especially fat, that would undoubtedly have started when I would have put on a little more central obesity...
I do not come from a line of long live-ers, so I guess I started a little younger than your son will with metabolic issues. But I was still playing roller hockey at the fun level in my fourties. You can do a lot by having a diet a little better than average, especially when the average is quite poor. At a population level 64 lb/year of sucrose only hides less than 1% who cannot handle the sugar consumption three SDs above the mean.
Peter
I do agree with all of this, it stands to reason and I have long thought that mitochondrial defect/deficiency/loss underlie diabetes especially but also weight gain particularly later in life.
However, it seems to me that for many obese people carbohydrate restriction is palliative. There are many many anecdotes of improvement on a high fat, low carb diet - whether or not they stick with it long term, virtually all fat people IMPROVE on this diet and start losing weight. The biggest problem is adherence long term, probably due to culture/lifestyle issues, as well as an underlying ignorance, which make following the diet difficult.
You just can't say that about very low fat diets. All calorie restriction is effective to reduce insulin/glucose/body fat in a lab, and very extreme fat restriction is also effective in a lab... but in the real world where people eat when they are hungry, and respond to dips in blood sugar, and do what their bodies tell them to do (EAT DAMN IT)?
Not so much.
This suggests to me the bigger problem is glucose oxidation, and that is also supported by the research you cite above and I referenced, where in which fat oxidation suppression seems directly related to inappropriate high insulin and prolonged high glucose levels. If the obese have abnormally elevated RQs in the fasted state, this suggests they are oxidizing carbohydrate in a fasting state, which then suggests that CPT1 will be inhibited to then limit fat oxidation.
IF the obese also have abnormally low RQs after eating a mixed meal, this suggests they are not able to completely suppress fat oxidation in spite of the presence of an increase in dietary glucose - this suggests glucose intolerance, which we already knew.
If you remove the dietary glucose, you can work around bandaid solution these mitochondrial energy using defects which cause symptomatic hyperinsulinemia. Not completely, but significantly, which again is reflected in research and real world testimonies of obese people and how they feel/lose weight/eat when eating dietary glucose vs not eating it.
More evidence seems to suggest that mitocohdnrial health and number are also a function calorie intake - calorie restriction is noted to increase mitochondrial regeneration. Aerobic respiration is toxic to mitochondria. Another utility of low carb dieting is that it reduces the caloric energy intake, and it does this by ameliorating the extent of hyperinsulinemia by relaxing pressure to oxidize glucose at meals (which they poorly do, creating LARGE increases in blood sugar which mandate compensatory LARGE increases in insulin, leading to drops in electrolytes/minerals/fatty acids/sugar, leading to disproportionate hunger.
This is no different than bolusing up with some too much novolog. That person is going to eat. A lot. Unless they pass out comatose first.
This is another utility of minimizing the insulin production to meals: overall caloric intake is spontaneously reduced which is not just palliative, but curative for mitochondrial insufficiency.
A cycle seems to be in place where people with impaired mitochondria easily develop hyperinsulinemia, particularly to carbohydrate, which then damages mitochondria further by stuffing them up with glucose / fat, which in turn was triggered by that same hyperinsulinemic person eating an excessive amount of dietary energy due to insulin mediate drops in blood nutrients.
A reason LC may be palliative is it relaxes this pressure and may promote mitochondrial biogenesis by reducing intake, which is a downstream effect of stable blood nutrients/lack of insulin mediated glucose/fat drops.
This is also a nod to insulin's role in lifespan.
This is also reflected in long term low carber testimonies. I've heard many personal anecdotes of people remarking their glucose tolerance / diabetes radically improving after years of low carbing, presumably eating far less energy along the way from reduction of insulin.
Peter, have a look at a paper entitled 'Body temperature and thyroid hormone metabolism of copper-deficient rats', here it is:
http://www.sciencedirect.com/science/article/pii/0955286395000625
The people who work on copper say most of us have mild copper deficiency. It causes secondary deficiency of selenium (see paper) which is needed for conversion of T4 to T3.
Remember those trials of antioxidant cocktails? They contained vitamins A, C and E, and selenium, but no copper. Didn't work, did they.
That picture of mitochondria says 'The magnification bar is 0.5 m.' Wow. Those are BIG mitochondria.
The same goes for cats. I have my cats on a high protein, high fat cat food and they are sleek as can be. If we go away for a week, they are stuck eating a higher carb (but still grain free) kibble that is higher in carbs than their normal canned food, and both cats are noticably fatter when we come home. After a week or two of their normal diets, they go right back to their healthy weight. The intersting thing about feeding cats this way, is their absolute lack of appetite. They eat twice a day, and never ask for food. Contrast this to the two cats I had 10 years ago, who ate a much higher carb diet, were constantly eating, and both developed type 2 diabetes around the age of 12. I suspect I more resemble a cat than a rabbit, so bring on the steak!
ItsTheWooo2:
Always appreciate the content of your commentary: good understanding of the physiology and helpful to those of us who have forgotten so much biochem. I also ditto this for others who have posted comments--very informative and educational. Thanks!
Jane,
Vitamin A deficiency also leads to hypothyroidism, and D levels are associated. Do you think the Cu added to the antioxidant cocktail would have made a difference--I would guess still no significant benefit?...
...I noticed increased back pain (which I get sometimes from sitting) from a tocopherol [mostly gamma] supplement over the last two weeks, which brought me back to old posts on worms and ROS, as well as the self-note that every "supplement" has been neutral or negative for me.
@Olga,
I have had very similar experiences with feeding cats. On canned food they only ate at sunrise and sunset and never seemed hungry. On dried kibble they were constantly eating. One of my cats even ripped open a bag of dried food and helped himself.
However I think the overeating of dried cat food isn't due just to the carbs. Dried food has high levels of glutamate which make the food very tasty. The concentrated food also allows a cat to eat a lot of calories before it feels full.
Al this research is simply an attempt at reinventing the wheel. It is a total waste of time and money.
We already know what humans need to stay healthy - a diet very in low refined carbohydrates, plenty of animal protein including organ meats and a lot of physical activity.
However researchers are so utterly deluded that they think it is possible to ignore millions of years of evolution and solve all our problems with pills.
Sulphur deficiency - eat more protein.
Copper deficiency - eat some liver.
Is there any evidence gut biota can remote control mitochondrial expression through chemical or DNA means? This would explain their apparent role in modulating insulin resistance and be a possible way to channel dietary effects.
@Bolabli
Current Diabetes Reports (2011)
Volume: 11, Issue: 3, Pages: 154-9
ISSN: 15390829
DOI: 10.1007/s11892-011-0191-1
PubMed: 21431853
Abstract:
Several reviews recently explored how the gut microbiota was able to control host energy metabolism, and thereby the development of adiposity. In this review, we focused on the state of the art that supports a link between the gut microbiota composition and activity, and the management of glycemia associated with overweight and diabetes. Several microbial-derived compounds are related to disturbances of glucose homeostasis including the gram-negative-derived lipopolysaccharides. Some nutrients with prebiotic properties, which escape the digestion in the upper part of the gut, modify the composition of the gut microbiota in favor of bacteria that could play a beneficial role on glucose homeostasis, namely by modulating the endocrine function of the gut, and by reinforcing the gut barrier. Adequate intervention studies in diabetic patients are required to assess the relevance of those experimental data for human health.
Hi John,
'Do you think the Cu added to the antioxidant cocktail would have made a difference--I would guess still no significant benefit?...'
I think you're right, it wouldn't have worked. A recent trial of copper in Alzheimer patients did not work, despite much evidence of copper deficiency.
But possibly, the antioxidant cocktails would have worked if they'd had both copper and manganese. In fact it's pretty extraordinary that they didn't, considering that the most important antioxidant enzymes (superoxide dismutases) depend on these metals.
Perhaps the Alzheimer patients would have been helped by manganese too. Copper gets stuck in lysosomes unless intracellular trafficking systems are working well, and trafficking depends on an enzyme called Vps34, which in vitro has an absolute dependence on manganese. This enzyme also controls autophagy, which fails in Alzheimer's.
Would supplements and/or lifestyle changes that enhance mitochondrial bio-genesis be beneficial?
I'm thinking supplements like PQQ or Pterostilbene and exercise with calorie restriction.
Jane,
But then after Mn, we'd need ___, then ___, etc...Why not simply just a multivitamin/mineral?...Of course I'd doubt that'd work, though there's that weird relatively recent trial with weight loss and multivitamin.
Interesting article on making oyur mitochondria more efficient:
http://biketechreview.com/performance/supply/48-mitochondria-the-aerobic-engines
What is the connection/relationship between untreated hypothyroidism and mitochondrial dysfunction?
Is mitochondrial dysfunction a result of genetic misfortune or are there environmental causes (e.g., chemical exposures and endocrine disrupters in the workplace, home, personal care products, air etc.)?
blogblog:
I am on the same page with you regarding the benefit of whole foods versus supplements. Some have suggested that vitamins and minerals in whole foods operate synergistically to promote health. I don't know about the research on this idea?
You mention the benefits of eating organ meats, such as liver. I know I should but I have not eaten liver in 30 years. How can I prepare it to make it tasty?
@STG,
try some chicken livers fried with bacon.
The easier option is to eat some pate or liverwurst. About 100g per week should be enough.
The way to achieve healthy mitochondria is extremely simple. It is called aerobic exercise. eg Most of the extra bulk in a cyclists legs is due to far more mitochondria and more capillaries than a sedentary person.
HGs burn 3-5x as many calories during physical activity as typical modern Westerners.
STG,
I have had negative experiences with K2, alpha-tocopherol, and gamma-tocopherol (cold, back pain). I have tried vitamin D3, Mg, butter oil, cod liver oil, and skate liver oil all at different times with a similar diet. I noticed that the skate liver oil and butter oil maybe made my skin smoother. Of course, those two are more "food" than the others, which didn't do anything noticeable. My diet is pretty good, and I never eat "junk."
Just some math, based on stats on wikipedia and bayes theorem.
P(O) is the probability that someone is obese = 35%
P(D) is the probability that someone has type II diabetes = 7.8%
P(O|D) is the probability that someone is obese, given that they have type II diabetes = 55%
And P(D|O) is the probability that someone has type II diabetes, given that they are obese.
By Bayes Theorem, P(D|O) = 12%. If overeating is an effect of Obesity (not a cause), I'm hard-pressed to say that overeating is a cause OR an effect of T2DM. The link between the two is relatively silly.
Even in the case where P(O|D) = 100%, that is, everyone with diabetes turns out to be obese, P(D|O) is only 22%.
There are too many confounding variables in the A => Obesity, T2DM, and overeating theory.
Hi John, I entirely agree.
But the point about copper and manganese is this. If you eat a lot of meat, your requirement for copper and manganese goes up. Meat has a lot of highly available iron, and iron is very difficult to excrete. It accumulates, and causes oxidative stress, which is implicated as a major cause of disease. In practically every disease you can think of, excess iron is found in the damaged tissue.
All aspects of iron metabolism and transport require copper. In copper deficiency, iron cannot get out of the liver, so you have malfunctioning liver (look up 'copper fatty liver') AND anaemia, because the iron can't get to the bone marrow to make haemoglobin.
Manganese is if anything even more important. A recent paper has shown that excess iron prevents entry of manganese into mitochondria, and this can cause diabetes. The diabetes could be prevented by extra manganese.
The paper is from 2008, and its title is 'Iron-mediated inhibition of mitochondrial manganese uptake mediates mitochondrial dysfunction in a mouse model of hemochromatosis'.
Macadamias have a significant amount of manganese and copper in case anyone was wondering.
Justin
the low insulin levels accompanying caloric restriction probably account for some of the lifespan extension seen in fruit flies and monkeys and every creature in between. In rats, caloric restriction increased mitochondrial numbers in the liver, and these mitochondria generated fewer free radicals while making the same amount of the cell-fuel ATP as mitochondria from normally-fed rats. Crucially, adding insulin prevented these changes (López-Lluch G, 2006), suggesting that it was the low insulin conditions accompanying caloric restriction which caused there to a larger population of younger and more efficient mitochondria. The macronutrient which is lowered the most in caloric restriction is carbohydrate.
@Jane,
the problem is actually due to a not eating any organ meats rather than eating too much red meat.
A (human) carnivore needs to eat the whole animal not just the muscle tissue.
Without knowledge in biochemistry may I be so bold as to speculate that it is the insulin resistance/diminished insulin action, i.e. intracellular insulin deficiency that causes mitochondrial dysfunction/damage and altered metabolism?
"Insulin signaling meets mitochondria in metabolism"
http://www.ncbi.nlm.nih.gov/pubmed/20638297 (abstract only)
"Insulin Signaling Regulates Mitochondrial Function in Pancreatic β-Cells"
http://www.plosone.org/article/info:doi%2F10.1371%2Fjournal.pone.0007983
"Contribution of impaired myocardial insulin signaling to mitochondrial dysfunction and oxidative stress in the heart"
http://circ.ahajournals.org/content/119/9/1272.long
"Effect of Insulin Deprivation on Muscle Mitochondrial
ATP Production and Gene Transcript Levels in Type 1
Diabetic Subjects"
http://diabetes.diabetesjournals.org/content/56/11/2683.full.pdf
"Intracellular site of insulin action: Mitochondrial Krebs cycle"
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC323891/pdf/pnas00318-0102.pdf
I didn't read these, just browsed at the concluding parts but they seem interesting.
Defective mitochondria are not unique to insulin resistant muscle, they are also present in cancer cells (Warburg effect). There is a theory that upregulation of glycolysis leads to genomic instability which may lead to cancer. The link between cancer and metabolic syndrome may be mitochondrial dysfunction??
"Cancer as a metabolic disease"
http://www.nutritionandmetabolism.com/content/7/1/7
Just some thoughts...
Hi blogblog, this is an interesting question. Eating the whole animal would obviously help, but I'm not sure it would solve the problem. Even the Inuit and Maasai ate quite a lot of plant food (see Chris Masterjohn on this) which would have provided both manganese/copper and compounds that prevent iron absorption such as tannins and phytate.
But nowadays you can't just eat a whole cow. Is it enough to eat liver now and then? Well, liver does have a lot of copper, but it has a terrible iron-manganese ratio. Not as bad as muscle meat - even grass-fed beef has an iron-manganese ratio of about 100, see this paper -
http://www.ncbi.nlm.nih.gov/pubmed/20374819
- but beef liver has a ratio of 20 when ideally it would be closer to 1. Manganese is very easy to excrete, unlike iron, so it's difficult to get too much unless you work in a manganese smelter.
@Jane,
the problem is determining cause and effect. It likely that iron accumulation is a symptom of underlying disease (eg diabetes) rather than a cause. A healthy human is able to control absorption of iron from the gut.
All mammals have evolved from insectivores/carnivores so we have had about 120 million years to adapt to eating meat.
Everything I have read suggests that plant foods were minor component of both Inuit and Masai diets. In the case of the Masai plants seemed to be used mainly for medicinal use rather than as foods.
@blogblog,
'It likely that iron accumulation is a symptom of underlying disease (eg diabetes) rather than a cause.'
Can you give me arguments and/or evidence for this? If the iron is not causing the damage, what is?
It's true that iron absorption is regulated. A high-iron diet will result in down-regulation of iron transporters. The problem is that these are also manganese transporters.
Jonty,
What is the name of the paper [López-Lluch G, 2006] you cited? I tried to look at all 2006 papers and didn't see the claim about insulin.
Olga & blogblog: Motley, my two-yo neutered male cat, is apparently as carb sensitive as I am. On any cat food with grains in it he develops a nasty oily coat and heavy dandruff. I changed his diet to mainly fish and chicken, a bit of cod liver oil, with a small amount of gluten free, high protein kibble, and he's sleek and handsome. We both are eating essentially the same vlc diet--and we are glad we do!
@John
"Calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency"
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1413655/
Another interesting datum "Hepatic Autophagy Is Suppressed in the Presence of Insulin Resistance and Hyperinsulinemia" - autophagy would otherwise recycle those elderly mitochondria and make way for new ones. http://www.jbc.org/content/284/45/31484.full
Maybe hyperinsulinemia is the kiss of death here
@Jane,
The fact is that the scientific community currently have no detailed understanding of iron regulation in mammals. It will be decades before this changes.
The 120 million year evolutionary history of humans as primates suggests that we are extremely well adapted to the amounts of iron encountered in a meat based diet.
The presence of iron deposits in diseased tissue doesn't prove that iron causes the disease. It simply shows that iron accumulates in certain disease states.
@nancan,
cereal based diets cause absolute havoc with the health of cats and dogs. It totally disrupts their gut flora causing a multitude of health problems.
A acquaintance of mine cured her labrador retriever of severe atopic eczema in a month simply by switching from dried food to canned food.
@Jane
High insulin leads to excessive storage of iron; high levels of iron go on to contribute to disease and further worsen insulin sensitivity, but ultimately high iron levels are not causative of the problem, they are merely symptomatic yet another symptom of having too much insulin too much of the time.
http://www.nejm.org/doi/full/10.1056/NEJM200009213431215
"High body iron stores are associated with abnormally altered glucose homeostasis in patients with type 2 diabetes,3 and serum ferritin concentrations are higher in patients with diabetes than in the general population.4 The development of hemochromatosis in some patients with type 2 diabetes may be the consequence of an anomalous trend toward iron accumulation mediated by mechanisms other than mutations in the HFE gene."
http://www.medical-hypotheses.com/article/S0306-9877%2803%2900231-7/abstract
"There is growing evidence that increases in both hematocrit and body iron stores are components of the insulin resistance syndrome. The ability of insulin and of IGF-I – whose effective activity is increased in the context of insulin resistance – to boost activity of the transcription factor hypoxia-inducible factor-1α (HIF-1α), may be at least partially responsible for this association. HIF-1α, which functions physiologically as a detector of both hypoxia and iron-deficiency, promotes synthesis of erythropoietin, and may also mediate the up-regulatory impact of hypoxia on intestinal iron absorption. Insulin/IGF-I may also influence erythropoiesis more directly, as they are growth factors for developing reticulocytes. "
I think it is very naive to assume all metabolic diseases are nothing more than attributed to mineral status. It is clear at this point in time that mineral status does affect metabolic status (e.g. magnesium is very important for normal glucose tolerance), however the abnormal mineral status of glucose intolerant people is mostly attributed to abnormal levels of insulin. Just as glucose intolerant hyperinsulinemic people clearly are storing food energy as body fat, it is also true they are storing - ushering in cells - excessive sodium, magnesium, iron, just to name a few.
The abnormal mineral status did not cause the hyperinsulinemia, it is symptomatic of it, however once in place it does worsen the trend.
When we observe that people with high insulin have high levels of intracellular magnesium/low mag levels, do we assume lack of magnesium caused their high insulin, or is it more likely that a multifactored environmental/genetic reaction resulted in hyperinsulinemia, which then skewed their magnesium status?
If the magnesium was primary, why are we not curing diabetes and obesity with magnesium yet?
To assume a simple mineral supplement or eating bone broths or whatever can resolve or cause these issues, most of the time, reduces the complexity of glucose intolerance and subsequent diseases to uselessness.
I more than anyone wished it was true, but I have seen only slight benefits from addressing my mineral status - slight benefits are still significant to well being, but in no way is it true that my severe endocrine and weight problems are as simple as high or low mag and iron.
**Note, when I was obese, my H&H levels were abnormally elevated, which I attribute, in hindisight, to hyperinsulinemia + uncontrolled PCOS (as elevated testosterone further increases H&H, in addition to insulin + IGF).
After weight loss and control of PCOS my H&H levels are low normal, and when I was very food restricted/thin/not on leptin I was mildly anemic.
The reason people become anemic after weight loss, even if they take minerals and eat red meat, is because you can NOT store iron and make hgb without insulin and IGF.
@blogblog,
'The fact is that the scientific community currently have no detailed understanding of iron regulation in mammals. It will be decades before this changes.'
It's true that iron regulation is very complex, so much so that it's probably correct to say the scientific community as a whole has no detailed understanding of it. But it's quite different among scientists who work on it. There is in the literature, if you read it diligently for a long time as I have done, a very good understanding.
Hi Wooo, good to see you.
'High insulin leads to excessive storage of iron.' Not sure what you mean by this. Insulin is a member of the growth factor family, and all members of this family increase intracellular iron because it's needed for growth.
The iron we are talking about is free or loosely bound iron. Iron stored in ferritin isn't really a problem. But, it can be released from ferritin by reactive oxygen species. Oxidative stress means free iron, and damage.
'..The abnormal mineral status did not cause the hyperinsulinemia..'
So what did cause it? In glucose intolerance, the first phase of insulin secretion is lost and the second phase enhanced, meaning delayed hyperinsulinemia. See 'Metabolic abnormalities in impaired glucose tolerance'.
Obviously, beta cells are not doing their job. They are not sensitive enough to glucose, and they're making too much insulin when they shouldn't and too little when they should. They are damaged, and eventually their owners will be diagnosed with diabetes.
@blogblog
Thank you very much for your link on gut biota. But the concrete mechanism remains a mystery I understand and a subject of speculation.
On iron. You are certainly correct in line of principle but underestimate the prevalence of hidden (say heterozygotic) hemacromatosis in Northern Europe and alpha thalassemias in Southern Europe. Many more people than you think have become somehow adapted to cereals and mosquitos, although at a high metabolic cost. Generally speaking the weak point of the paleo position is that it hugely underestimates how fast evolution can run subject to external environmental pressure. My understanding so far is that that too much insulin causes tissue/liver iron loads by overstimulating ferritin and these cause in turn insulin resistance as a cellular safety net. Most of the benefits of going low carbs / mildly ketogenic is that you reverse the process and deplete your toxic iron stores from tissue and give your mitochondria some relief from peroxidation. Most of the benefits from vinegar, ginseng or curcumin (as far as liver is concerned) is that they help take iron out of tissue back into the blood circle. This obviously means that serum ferritin is a very poor and unreliable indicator of iron status in liver and muscle, especially when you are insulin resistant. To have an understanding of the process look at what happens in toddlers suffering from iron overload because B5 cannot form coenzyme a and wonder why turning them into ketosis is so effective. Insulin is an overall primordial storage signal: fat, iron, we are eating. Ketosis is simply the opposite. Get rid of the existing stocks including iron cellular toxicity
Bolalbi,
"...prevalence of hidden (say heterozygotic) hemacromatosis..."
...me!
"...more people than you think have become somehow adapted to cereals and mosquitos, although at a high metabolic cost."
Are you implying being a carrier for hemachromatosis is the "cost"? Can you explain that statement further?
@blogblog
I forgot to mention a key point applying to everybody, irrespective of hidden hemacromatosis or thalassemias.
Your iron absorption mechanism is certainly ok, but was not conceived to cope with milk and milk products chronically boosting insulin levels after age 3. So iron tissue storage slowly becomes upregulated especially in the liver until resistance fatally develops to shield mitochondria from disaster. Then the better the mitochondria the later disaster happens or does not happen at all. Get rid of milk and you'll get rid of iron overload, fatty liver and insulin resistance. Or if you want to eat milk, minimize red meat and stay anemic. After all those who have adapted to milk have better insulin resistance than the others but are not supposed to kill taboo cows. I wouldn't like to call "mitochondrial disfunctionality" the status of those who have not adapted to milk insulin overload in a lifetime. Let's call them paleo energy saving mitochondria. The good old ones needed to hunt without fainting. Now unfairly despised as dysfunctional because of lack of evolutionary gratitude.
Bolalbi, i do one liter of evil milk per day + lots of evil sucrose + evil chocolate, ( plus a shitload of meat and cheese) all this evil insulin @ iron is killing me. you guys are so funny.
http://img37.imagevenue.com/galshow.php?gal=gallery_1316767296840_148lo
btw i also do, minimal training, sleep a lot and eat tons of yolks. im telling you some day im going to get really fat and sick.
No gets an insulin overload (regardless of what they eat) if they only eat once or twice a day.
The entire three meals a day, plus regular snacks, concept only dates back about 200 years to the start of the industrial revolution. Before then people typically ate one or two large meals a day.
Hi All,
The concept of iron overload as a consequence vs a cause of metabolic syndrome is an important one that has been of interest to me for some time.
Back in the PUFA and cirrhosis series I found a table suggesting hepatic iron content was related to degree of fatty liver/NASH on a level playing field iron content of the diet, but the diet information was buried a layer of refs deep and, when I tracked it down, was indeterminate as to exactly how the animals had been fed. Must have been a nutrition paper...
I feel it matters as metabolic syndrome appears to be rare in humans on high meat diets until you bring in the Usual Suspects.
Peter
@Jane
Hi Jane. If insulin and IGF lead to excessive iron storage as ferritin it is probably likely these also lead to high free iron.
There are many, many factors involved in developing glucose intolerance; mineral status is a small one.
It would take days to describe every known genetic and environmental and developmental factor that leads to these conditions, and what we know is still really little (which is why there is so much debate, and so much room for people to stay stupid things like "insulin makes you thin" - we are so ignorant, blatantly false statements like this can clear unflagged because we are so uncertain no one is sure enough to say THAT IS FOOLISH AND WRONG). Who is going to argue someone if they themselves barely understand the premise? Who wants to adopt a position which isn't well understood? This is why we tolerate so much conflict in obesity discussions and research - none of us really know, anyway. The evidence isn't strong enough in any direction, it allows for a lot of craziness to break through.
Before humans understand things scientifically, it's amazing the level of craziness that can emerge to explain phenomena. Diseases were caused by humors, the treatment was leeching/blood letting. Germs were a hypothetical possibility. Right now, in obesity research, we are in the "germ theory vs blood letting" phase.
One major factor that is often ignored: sleep duration. People hardly sleep today, this is the first environment where people routinely, and for long periods of time, starve themselves of sleep, while in the presence of a sugar rich calorie rich diet. The negative effects of sleep deprivation on glucose metabolism and pro-obesigenic/diabetogenic nature of it is some of the most easily replicated research. People have known to become TEMPORARILY diabetic by not sleeping for 24 hrs.
For some reason, people think it is a good idea to sleep 5 hrs a night and wake up early in the morning to go to the gym to lose weight.
I think it is just a bit naive to assume that finding the optimal mineral balance will cause or cure us, the big picture suggests a WHOLE lot more than minerals are involved. It would be great if it were that simple, though.
Peter, have a look at this paper on iron in non-alcoholic fatty liver disease. NAFLD patients apparently have iron overload, which the paper links to copper deficiency.
http://www.ncbi.nlm.nih.gov/pubmed/18505688
RESULTS: NAFLD patients had lower hepatic copper concentrations than control subjects (21.9 +/- 9.8 vs 29.6 +/- 5.1 microg/g; P = .002). NAFLD patients with low serum and liver copper concentrations presented with higher serum ferritin levels (606.7 +/- 265.8 vs 224.2 +/- 176.0 mg/L; P < .001), increased prevalence of siderosis in liver biopsy specimens (36/46 vs 10/47 patients; P < .001), and with elevated hepatic iron concentrations (1184.4 +/- 842.7 vs 319.9 +/- 451.3 microg/g; P = .020).
Jane,
I have to say that copper keeps coming up in CVD, has done for decades. When I get the chance I'll stick up the thoughts on iron overload possibly being a result of met syn and you can have a pick over it for copper status. Not sure when it will happen though, I'll have to go through the cirrhosis series to dig stuff out.
Peter
"These folks have odd muscle tissue.
a) They don't have many mitochondria, b) many of their mitochondria look crap and c) many of their mitochondria are dying."
Is there practical suggestions as to what these folks could do improve the health and/or numbers of their mitochondria?
"Much of the "pathology" is actually adaptive but being pushed to the point where there are problems in other systems."
Yes that's what I'm coming to realise. Systems that are adaptive when used acutely in response to some environmental factor become seriously maladaptive when they are jammed on chronically.
Some of them can become unjammed again by changing the environment (mainly diet) but sometimes it's too late. You can avoid the end result without necessarily undoing the damage.
I have gnolls on my reading list, when I find time. So far I've been looking at stuff well upstream of the mitochondria, so there's more stuff to look at.
Welcome to Narflk by the way. I live just over the border in Suffolk and I guarantee you will never eat so well. Grass-fed beef, lamb, outdoor pigs, fish, local veggies like asparagus and purple sprouting . . . one factor in the local longevity and healthy elderly folks may be sufficient selenium in the soil thanks to the glaciers. OTOH a big negative factor is the James Padgett, aka The Abbatoir. See if you can get referred to the Narflk and Narch, or Ipswich, or consider stocking up on lethal quantities of Propofol, topping yourself will be quicker and less painful than having them do it for you should you have the misfortune to become ill.
LIVER:
Someone asked about liver:
All that is needed is to fry very LIGHTLY in a pan, of e.g. butter, grass-fed, ideally, optionally mixed with coconut oil.
Just enough to change the surface colour all-over from that deep purple colour to light red, all over.
Combine with whatever amount you like of whatever muscle meat you like, also gently fried, and, if you are like me, throw one or more free range eggs into the pan and fry them gently.
If all that is not enough, then season lightly with good quality pepper and best sea-salt.
Enjoy.
Kings would have fought battles for this stuff.
And rightly so.
Kidneys are almost as good.
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