What Does Insulin Regulate Anyway?

I'm not a fan of arguments over semantics, but at the same time I can be a stickler for the notion that "words count" at times.  When I hear the word regulate, as in A regulates B, I substitute the word control.  So A controls B.  And this ultimately means that A determines what B is.  

Part of TWICHOO* is that insulin "fundamentally regulates" fat accumulation.  What Taubes is saying is that insulin regulates fat tissue mass.  Insulin controls fat tissue mass, and ultimately that means that insulin levels determine how fat you are.    *Taubes Wrong Insulin Carbohydrate Hypothesis Of Obesity

The TAG/FA Cycle

To state his case, Taubes zeros in on the TAG/FA cycle that occurs continually in the fat cell, and the known fact that insulin plays a role in  this cycle.  This is not in dispute, although the relative weight of insulin's actions on the outcome may be somewhat argued in these circles.

The full TAG/FA cycle is pictured at right (from Reshef et.al. 2003) -- the version Taubes discusses in GCBC.  We see that triglycerides and free fatty acids are constantly cycling both within the fat cells, and between the fat tissue and the liver and muscle tissues.  Some of the released fatty acids are re-esterified without leaving the fat cell, others are sent out in circulation and later returned to sender by the liver (VLDL).

Insulin stimulates the esterification of fatty acids into triglycerides on the "IN" side of the fat tissue, and suppresses the lipolysis of stored triglycerides by HSL on the "OUT" side.  It's a no-brainer then, that insulin works to put fat into and keep fat in your fat cells.  Game-set-match insulin, cased closed, QED, insert cliche here.

Let's assume insulin is the only hormone ...

Even though it is known that other hormones are involved in regulating this cycle, let's stipulate, for the sake of simplicity in this post, that insulin is the sole regulator of the TAG/FA cycle.  Let's also stipulate that uptake of dietary fat is regulated solely by insulin.  Repeat:  These are stipulations for the sake of a simplified argument, not statements of fact.

The question is, why is insulin doing this?  Is it to control how much fat you accumulate ... in other words to regulate the size of your fat stores?  It would appear not.

Where's the feedback?

The pancreas produces insulin.  If it produces too much and you get too fat, does the fat tissue signal back to the pancreas to stop producing so much?  Apparently not, or the obese would have a lower insulin response to stimuli, right?  Does the fat tissue produce anything that directly feeds back to the pancreas (e.g. in the form of direct pancreatic sensor) to tell it to shut down production a bit?  Again, apparently not.  I've not come across any mention in the literature of specific adipokine receptors on beta cells.  (Adipokines like TNF seem to mediate beta-cell death, but not via a specific receptor, and this pathological action is not the sort of physiological feedback we're looking for.)

What does the pancreas sense?  Well, for one, glucose levels ... we'll get back to that.  But what else?  Free fatty acids!!  We've discussed here many times before how fats, per se, do not elicit an insulin response but how NEFA do.  Remember, NEFA (non-esterified fatty acids, or free fatty acids, FFA) being the form of circulating fats that are taken up by cells and used for energy.   The point of control of NEFA levels is mostly at the release point from fat tissue.  Aside from the liver, which secretes fats largely as triglycerides in VLDL particles, adipose tissue is the only other tissue from which fatty acids flow out.  When NEFA levels are too high, excessive fatty acids are delivered to the cells and metabolic mahem within the cells ensues.  

So what does insulin actually regulate?  

Insulin regulates circulating levels of free fatty acids.  And how does it do this?  By acting on fat cells to control the rate of release and uptake of fatty acids.  How is this intended to be self-regulating?  By a feedback loop.  
Low circulating NEFA → reduced insulin → increased circulating NEFA (↓uptake/esterification, ↑HSL/release) → High circulating NEFA → insulin secretion → decreased circulating NEFA  (↑uptake/esterification & ↓HSL/release ) → low circulating NEFA ... rinse, repeat, etc.
Frankly, my dears, your pancreas doesn't give a damn about your fat tissue mass.  It's trying to regulate your NEFA levels.   Insulin ultimately has virtually no control over your fat mass.

What else does insulin regulate?  Insulin regulates circulating (blood) glucose levels.  Hmmm ... and in an exquisitely reciprocal fashion, I might add, to how it regulates NEFA when all things are running smoothly.  It does this by acting mostly on the liver and muscle cells to stimulate glucose uptake, inhibit glucose supplied by the liver (suppresses both gluconeogenesis and glycogen breakdown) and glucose disposal (increases glycogen synthesis and glycolysis or glucose burning).  Is there a feedback loop?  Certainly!  Insulin is secreted in response to high levels, and dialed back when levels drop.  When insulin levels drop the liver now delivers glucose (glycogen breakdown and gluconeogenesis) to circulation.  

And again, frankly, my dears, your pancreas doesn't give a damn about your liver either.  If too much glucose builds up to force de novo lipogenesis, or excessive NEFA lead to triglyceride build up in the liver -- aka fatty liver -- that's not your pancreas' concern.  It is only trying to regulate your circulating blood glucose and fatty acid levels.

So what regulates fat tissue mass?

The regulation of fat accumulation, fat tissue, requires a feedback from the fat tissue itself.  We know of one.  It's called leptin.  Too much fat accumulates when we take in more energy than we expend.  As fat accumulates, the fat cells secrete more leptin.  Leptin signals you to eat less and for the body to burn fuel at a faster rate (increases basal metabolism, boosts fatty acid oxidation).  That, folks, is regulating fat mass.   There may be other adipokines involved, and the leptin story turns out to be more complicated than early animal models would have predicted, but if we're looking for a feedback system that would appear to control fat mass, it is one involving leptin.

So ... to sum up:  

What does insulin regulate?  Nothing really.  It is the signalling molecule by which the pancreas regulates things, but let's not quibble too much over those semantics, shall we?

Insulin regulates circulating levels of glucose and 
NEFA to ensure a ready supply of energy at all times.  

Part II


TCO348 said…
What do you think of this explanation of glucose, insulin and diabetes? :


Is it accurate?
TCO348 said…
Insulin ultimately has virtually control over your fat mass

I think you meant 'virtually NO control'. Feel free to delete this comment. Do you have e-mail? Or do you just not want to deal with people e-mailng you? I would understand that.
TCO348 said…
BTW great post. This really clears things up for me.
Sanjeev said…
t1 diabetics have high blood glucose largely because the liver makes too much glucose. Insulin is an anti-catabolic hormone, meaning the body dismantles itself if there's no insulin present. (an over-generalization, but good 'nuf fer gubmint work)

With respect to t1 diabetes, insulin forces the liver to STOP making glucose. Many cells take up glucose just fine without insulin as long as the concentration within the cell is less than the concentration outside - glucose flows "down the gradient".

That's just a quick summary from memory, probably incorrect in places.

for a nuanced review of insulin read James Krieger's series on insulin here

That link's work safe but copy & paste the link below if you're paranoid
Wow - great post. So interesting. Thanks!
CarbSane said…
Thanks Taylor and FTD! I fixed the typo (or is that a miss-o?) and another little one I caught on second read. You can email me through my profile here. I try to return them, but don't always have time, especially lately what with the day job and all ;)

@Sanjeev: Yes, this misconception is rampant, but one thing about glucose uptake w/o insulin being greater that's a bit misleading is that that's because they also have more extreme hyperglycemia to drive it in.

Taylor I would say that vid is mostly accurate. I would just add that the glucose transporters do not need insulin to transport glucose, insulin enhances their number/migration to the surface to accept glucose. But the simplification is a "working model".
Thomas said…
@carbsane-maybe this is a little off topic but I'm wondering what you think. Over at another site I made the argument that the primary NAD in modern times is consistent over consumption (not wheat or PUFAs or dairy, etc. although these can be considered secondary). I say this because people seem to do much better when calories are mildly or moderately restricted even when diet quality is questionable (ex. the Twinkie diet or the potato diet or even Tom Naughton's Fat Head diet). When calories are over consumed, regardless or diet quality, things tend to go bad eventually. To me this makes over consumption the primary NAD (due to its more modern prevalence). But this never seems to be considered by the paleo crowd (and I generally like the paleo diet as a healthy diet, by the way). In fact, I was accused by another commenter on the other site for not considering internal hormonal mechanisms as being the problem and not over consumption. Apparently, according to this person, if our bodies don't regulate better through increased NEAT and/or decreased hunger, we are dysfunctional-it has nothing to do with a persons will, desire or psychology or routine. We are essentially slaves to our physiology. I think he's missing the forest for the trees, big time. But, I may be wrong (it's happened before-like when I thought carbs were a dietary evil). Am I off base considering over consumption as THE primary NAD?
Tsimblist said…
This comment has been removed by the author.
Tsimblist said…
@Thomas I would submit that the primary NAD is not even dietary. I nominate sedentary behavior as the primary NAD. The study in this post points me in that direction:

Here is a quote from the abstract:

"There are associated metabolic changes including a fuel shift toward glycolysis, decreased capacity for fat oxidation, and energy substrate accumulation in the atrophied muscles."

And this is the quote that really got my attention:

"Fat accumulation in disused muscle does not occur because
overall energy availability is in excess. With humans, fat
accretion occurred while subjects were in positive energy balance
[bed rest, (31), energy balance bed rest (23,32), or negative
energy balance (spaceflight; V. S. Oganov and A. D.
LeBlanc, Baylor College of Medicine, Houston, TX, personal

Even in negative energy balance, the muscles were losing the capacity for fat burning and accumulating fat droplets.
Tsimblist said…
Oops, that was a literature review and not a study.

Here is another quote from it that is most appropriate for the paleo crowd:

"In the wild state, disuse atrophy is a consequence of immobility, and an immobile animal cannot forage for food and so would not survive for long. The combination of chronic muscle unloading and adequate access to food is an “unnatural” state."
Anonymous said…

"When calories are over consumed, regardless or diet quality, things tend to go bad eventually. To me this makes over consumption the primary NAD (due to its more modern prevalence). But this never seems to be considered by the paleo crowd (and I generally like the paleo diet as a healthy diet, by the way)."

I think it is considered, but perhaps just not using your taxonomy.

An alternative way of looking at this is just to conceptualize a NAD as something - any factor, really - that leads to diseases in excess of some theoretical or actual wild or ancestral state.

Some of these NADs lead to overconsumption and energy excess, and so their effects are mediated VIA overconsumption, but overconsumption per se is not the NAD.

So rather than label excess intake a NAD, it might make more sense to say NADs cause negative effects on health by stimulating overconsumption, which could be effected via mechanisms ranging from the hormonal to the cultural (not mutually exclusive)

And there must be a reason for the overconsumption, right?

So we might have wheat, excess fructose linoeic acid, micronutrient deficiencies, a variety of things that affect food reward, all leading to overconsumption - energy imbalance - fat gain -IR - met syn,, etc.

"people seem to do much better when calories are mildly or moderately restricted even when diet quality is questionable"

I agree. There is evidence in other primates that one can eat a garbage diet but be much healthier on low calorie garbage than ad libitum garbage.


I think FR as a NAD is highly supported by this monkey study. Hyperpalatable monkey chow leads to premature aging unless counteracted by artificially constrained caloric intake.
Duffy Pratt said…

It doesn't make even Carbsane's hefty list of acronyms.

To me, NAD is a middle brow producer of stereo equipment. However, a quick search also shows The National Association for the Deaf, the National Advertising Division, "No abnormality detected", "No apparent stress", Nicotinamide adenine dinucleotide. It's bad enough that Carbsane overindulges in acronyms. Is it too much to ask that others commenting will at least give some explanation when they first introduce a new acronym that's not on the list here?
Duffy Pratt said…
I meant to write "no apparent distress" instead of "no apparent stress."
Thomas said…
@Tsimblist-thanks for the reference to the great lit review. I think over consumption and sedentary behavior are blood brothers.

@Dr. Harris-thanks for the comments. I enjoy your blog and hope you write more soon. I especially enjoy watching the evolution of your diet framework. The fact that you have changed your ideas a bit over time makes you one of the most respected diet bloggers out there IMO (as does your lack of financial interest in the whole thing).

I understand your point, and don't necessarily disagree. I'm just not totally convinced that humans don't have inborn impulses (not hard wired though) to eat as much as possible in order to "store up for the upcoming famine", which never comes in the modern first world (vs. a modern agent (NAD) that causes a dysfunction in the normal program-making us eat uncontrollably-although I believe this may a factor too). In essence, over consumption in the short term is a good thing, increasing chances of survival (this is assuming it's only short term). As famine is not physiological, the drive to over consume might be a default physiologic drive. If the lack never comes (a relatively new evolutionary experience), this drive has to be controlled in some way-via diet or whatever. It's difficult but doable, as the drive is plastic and can be manipulated and changed with persistence. This is just an idea based in personal experience and observation, and I'm not sold on it, by the way. And I realize that my explanation is extremely simplistic as well. But I do think that many, if not most people, have to "try" and reduce/control intake in order to maintain leanness over the long haul.

@Duffy-sorry. NAD stands for neolithic agents of disease and contextually refers to wheat (or gluten grains), linoleic acid, fructose, etc. Check out Dr. Harris's blog for more info.
CarbSane said…
@Kurt: "Some of these NADs lead to overconsumption and energy excess, and so their effects are mediated VIA overconsumption, but overconsumption per se is not the NAD."

Here is where you and I probably have the greatest disagreement. I see little evidence, for example, that linoleic acid leads to increased intake, and anecdotally I would say that it might even lead to decreased consumption based on palatability. Foods fried in butter or lard/tallow generally taste infinitely better than foods fried in veggie oil, for example. Wheat addictive? When I hear reports of people Jonesing on flour in a pinch I'll believe that one. ;)

What made the CAF rats actually overeat? It wasn't sugar or fat per se, it was human junk food. Even when folks consume "normal" quantities of these foods they "overeat" calories.

@Thomas: I agree. Our metabolisms seem far better adapted to dealing with temporary (or even extended) shortages, but not chronic overages.

@Tsimblist: I also agree! Activity cleans out the works and would prevent those ROS that cause damage.

Obesity used to be a disease of predominantly the rich. Those who could afford to eat very well and have others do the work of it (growing, harvesting, cooking, cleaning) for them. The flipside is that diseases associated with certain foods as staples may be less due to something inherently bad in that food, but more to deficiencies from lack of some other food in the diet.
Thomas said…
By the way, in my last post I did something that I think is done way too often and has gotten a little out of hand (shame on me). That is using an "evolutionary" explanation to make sense of a theory. Evolutionary explanations are too often taken as valid evidence, which it simply isn't.

Here's an example: I recently read about how an individual on a weight training program and a calorie deficit diet decided to temporarily stop the weight training to train for a walk-a thon (which was, for her, an increase in activity but at lower intensity). In the end, that individual, while claiming to maintain a calorie deficit diet, gained over 5 lbs of fat for her efforts. The "hunter gatherer" explanation given in the book for her weight gain was that her body, unable to find food with increased activity, went into starvation mode-store more energy by reducing lean tissue and increasing body fat. This explanation seems to make sense, except that people just do not gain fat when in a true calorie deficit (as far as I know anyway). After all of that complicated evolutionary explanation, I think the likely culprit was that she was eating more food and under-reporting, which has been validated by research time and again (I don't know of any research that validates starvation mode and fat gain while in a true calorie deficit). It could be that she became more hungry or that she walked with friends and started to socially eat out more or whatever-but a crashing metabolism from increased activity, I highly doubt it.

Evolutionary explanations have also been used time and again to validate carb's and insulin's role in fat gain, while the research (as far as I can tell) does not. Sometimes it seems evolutionary science and reasoning-speculative stuff-supersedes valid research in order to support incorrect theories. While evolutionary reasoning may turn out to be true in some or many cases, we cannot assume it to be validating. We just end up building our ideas on a house of cards.
Anonymous said…
'Hyperpalatable monkey chow leads to premature aging unless counteracted by artificially constrained caloric intake.'

Calorie Restriction and ageing is a whole area of research. I haven't seen much at all about what makes up the calories.
Lerner said…
Has anybody got an authoritative reference on how permeable the membrane phospholipid bilayers are to glucose? It's not easy to find.

Also, it bears mentioning that Taylor's youtube video is by the famous Khan Academy. The guy Khan started out with his graphics tablet and microphone, explaining something school-related to his niece. Since he has a good explanatory style, he received more and more views, then kept branching out until... he was ultimately given a few million dollars by some foundations to expand even more, including hiring translators.

His background IIRC is in math, not biological sciences.
Lerner said…
quoting eulerandothers: "Calorie Restriction and ageing is a whole area of research. I haven't seen much at all about what makes up the calories."

About 5 years ago I was reading a CRON group, to see what they said about the ON (Optimal Nutrition) part. It was generally a low fat approach -- also concerned about methionine->homocysteine -- also low on arachadonic acid - low Omega6/3 ratio - lots of vegetables - big on anti-oxidants.

That was also where I'd first heard of the typical Intermittent Fasting as well as every-other-day fasting.

Most believed in not-overeating or slightly under-eating, rather than the emaciation that you see in extreme examples - who were regarded as being psychologically rather than nutritionally motivated.
CarbSane said…
Hi Lerner: Glucose requires a transporter, but GLUT's are present at all times. Insulin just assists their migration to the surface as I understand it.

As to Khan, I am not familiar with this. I would only state that everything doesn't always need to be 100% technically accurate to be helpful, so long as it is not misleading on a critical issue (if that makes any sense).
Anonymous said…

The lipid bilayer is not very permeable to anything hydrophilic like glucose and not to most macromolecules, even with a gradient.

No transporters, no glucose uptake

Anonymous said…

"I'm just not totally convinced that humans don't have inborn impulses (not hard wired though) to eat as much as possible in order to "store up for the upcoming famine""

This is the thrifty gene hypothesis and I think it is pretty thoroughly refuted by extensive ethnographic studies and the observation of substantial fractions of western populations who stray slim in a food abundant environment with zero difficulty.

Extant hunter gatherers and primitive horticulturists have no problem spontaneously staying slim even when food is in abundance. Most anthropologists don't take this idea seriously, even if you see the idea touted on the web a lot. It simply fails as any kind of explanation for overeating or obesity.


"Calorie Restriction and ageing is a whole area of research. I haven't seen much at all about what makes up the calories."

Read the reference I posted - I am pretty sure they refer to the Teklad diet the monkeys are on and it's basically manufactured monkey junk food. You can read the ingredients if you do a little digging.
Anonymous said…
Hi Evelyn

"I see little evidence, for example, that linoleic acid leads to increased intake"

The evidence is not direct, but linoleic acid intake does correlate temporally with the obesity epidemic, more than sugar, HFCS or just about anything else that is novel on an evolutionary basis. Stephan agrees with you that the n-6 content of industrial oils may not directly contribute but feels that temperate industrial (high n-6) plant oils may contribute to enhanced FR as they are used to create junk food - whether that is specific to the n-6 content or not I am not sure.

I agree the case for n-6 specifically causing disease via overconsumption is circumstantial and not proven.

More importantly, excess n-6 disturbs eicosanoid production and contributes to oxidative stress. Even if these effects don't lead to obesity, their possible effects on cancer and inflammation are worrisome enough that I consider n-6 heavy industrial oils a putative NAD. The obesity bit would be icing on the cake.

I find it restricting to view all health through the lens of obesity. I suppose it is possible that energy imbalance is the final common pathway that mediates all diseases of civilization. That is, as long as you are not metabolically fat, you have little risk of heart disease or cancer as well as low risk of diabetes.

But cancer and heart disease went from rare to endemic long before the obesity epidemic that started in the mid 20th century.

We just don't know yet how much of western disease is due directly and solely to energy imbalance and how much cancer and autoimmune disease is due to noxious dietary agents (or deficiencies) unrelated to energy balance.

I am open to the idea that one could eat a hypocaloric diet loaded with white flour sucrose and soy oil and take micronutrient supplements and be as healthy as say, the Kitavans, but it seems pretty implausible to me.

" and anecdotally I would say that it might even lead to decreased consumption based on palatability. Foods fried in butter or lard/tallow generally taste infinitely better than foods fried in veggie oil, for example."

I agree that seems intuitive. But if you buy that the most palatable foods do not necessarily have the highest food reward - these concepts are related but not the same - then it makes sense that foods that taste kind of shitty can be some of the most highly rewarding foods.

It is not just tastiness; it is density, texture, maybe LACK of micronutrients, combinations of fat and carbohydrate, etc. I hypothesize that palatbility actually lives on an inverse u curve relative to FR.

I call this "the pringles effect".

Who thinks pringles taste better than maguro or a ribeye? No one I've ever met.

"Wheat addictive? When I hear reports of people Jonesing on flour in a pinch I'll believe that one. ;)"

Personally, I've seen cravings for bread and baked goods far more intense and intractable than for sugar or anything else. Gliadomorphins may account for this. I have no doubt wheat containing products can be addictive just based on anecdotal observation.

And bread, pasta, cookies, brownies, etc, - none of these exist without white flour - they would all be just liquid goop without gluten containing wheat to make them fluffy and delightful.

Of course white flour is inedible if not baked. Just as potatoes are inedible raw.

I'd like to emphasize that although I coined the term "neolithic agent of disease" (NAD) and originally used it to refer to 3 specific putative agents, I now use the term more expansively to mean basically any substance, factor or condition that might account for diseases that become more prevalent with the transition to a western diet.
bentleyj74 said…
I agree with KGH regarding white flour. It might need a FR category all to itself. I don't know of much that can be more enticing than plain white traditional french bread which consists of flour, water, and a miniscule amount of salt [and some starter from previous batch]. No added fat/sugar/enhancers. Just the SMELL .....[drifts away]....

Gluten free baked goods on the other hand... gourmet quality loaded with equal amounts fat and sugar don't compare. Not even close.
bentleyj74 said…
Regarding NAD, it's useful but still an unfortunate choice imo. It's already in common usage in the plural and usually preceded by "kicked in the".
Anonymous said…
What I read in the article cited by Kurt Harris was this: (regarding the diet of the monkeys in the study)

'The animals were evenly matched and randomized to control or CR diets, taking into consideration baseline food intake, body weight, and age. Individualized food
allotments were calculated based on daily food intake data that were collected for each animal over a 3- to 6-month period. Once animals were assigned to either control or CR groups, each CR animal’s individually determined baseline intake was reduced by 10% per month over a 3-month period to reach the desired 30% restriction.'

This seems to be saying that there weren't different diets. The diets were the same for the control and the test group. The test group (CR animals) had the same food, but it was reduced to a low level of intake (30% calorie restriction). Which is how a calorie restriction study would go!

In other words, both groups were eating monkey junk food - the difference is that the test group were just eating a lot less of the same stuff, junky though it may be, in measured amounts. The control group ate the same stuff, but they ate freely. That was not mentioned in the article, but mentioned here, in a Guardian article: http://www.guardian.co.uk/science/2009/jul/09/calories-diet-long-life?INTCMP=SRCH

@Lerner wrote:

'It was generally a low fat approach -- also concerned about methionine->homocysteine -- also low on arachadonic acid - low Omega6/3 ratio - lots of vegetables - big on anti-oxidants.'

I've only looked at one calorie restriction website for people who really limit calories in order to live longer and be healthier. I don't see specific nutrients mentioned. It's just low-fat (and lots of vegetables - I'm guessing because they give more volume for fewer calories because they have less fat.)


What I see in studies is just what this group says: reduction of calories, pure and simple. I don't see much (can't remember any, actually) about what makes up those calories.

I'm sure there are lots of calorie restriction groups and I don't know them. I got this calorie restriction organization from the Guardian, which had an article about calorie restriction years ago: http://www.guardian.co.uk/lifeandstyle/2004/sep/11/fitness?INTCMP=SRCH
CarbSane said…
When folks are physically addicted to a chemical they will take it in any form. This is why I don't buy into food addictions because you never hear of folks binging on plain foods. If folks are addicted to wheat, plain pasta would do in a pinch, and since there's more of the bad stuff in whole wheat, whole wheat pasta would be preferred. But WW pasta tastes horrible, and regular pasta plain w/o any sauce or butter is pretty disgusting. I notice bentley mentioned the aroma of fresh bread. I think if all baked goods were made from some other flour, those who overeat wheat-based foods would still overeat the same amount.

BTW, I'm not one who believes that it is what makes us fat is also what makes us sick. I believe there are things that make us fat but not sick, sick but not fat, and everywhere in between. :)

Inactivity is a big contributor in my opinion to illness.
Tsimblist said…
@eulerandothers & @Lerner

I recently ran across this study abstract when looking for ways to improve my lipid metabolism:

I did some digging and learned that protein restriction seemed to be giving similar benefits to calorie restriction. And methionine restriction seems to be why protein restriction works so well.
Lerner said…
wrt CR & vegetables: yes, non-starchy vegetables were big in CRON theory because of providing low-cal food volume, but as much or more so because of phytochemicals - especially antioxidants. Most everything was based on the Free Radical Theory of Aging (FRTA). The more calories you burn for fuel, the more ROS are made inside mitochondria. So FRTA says eat low-cal and high-antioxidant.

One thing that stood out to me was the dogmatic nature. Plus, people would actually get angry over Atkins. However, from what I've seen in more recent times, LCers surpass that 'us versus them' attitude by a mile.

FRTA said that you should reduce ROS, etc to a minimum. But lookee here, if you take some nematodes and give them a drug which forces their mitochondria to produce *more* of ROS, then they actually live longer. But if you also give an antioxidant, then they don't live longer.

Lonidamine Extends Lifespan of Adult Caenorhabditis elegans by Increasing the Formation of Mitochondrial Reactive Oxygen Species.

PMID: 21932172 http://www.ncbi.nlm.nih.gov/pubmed/21932172

That centers around the concept of hormesis - that small amounts of stressors can be healthy for you. Since exercise increases mitochondrial ROS, then again I'd repeat my personal mantra that exercise makes the body run right, as long as you don't overdo it.
bentleyj74 said…

You make a good point about taking it in any form and by any means even very inconvenient ones but I still gotta think there is SOMETHING not accounted for with regard to refined wheat products. If it's simple FR [and I'm not ruling that out] it's still unique in that you have to render it basically inedible [uncooked] to lower it's reward adequately.

Can you absorb/digest the elements that KGH thinks might be involved from eating raw flour? If they aren't availble from uncooked wheat it would make sense that uncooked wheat is the drop off point regarding seeking behavior. Just speculating out loud.

You don't have to wade very far into celiac territory to discover that, no, alternative flours will not do the trick no matter how skillful and expensive the blend. No matter how much frosting you put on it or how much chocolate you put in it. That theory can be leveled like sauron just walked into the room with a few mouse clicks.

People experience anger, longing, and even clinical depression just like an addict when they have to change from wheat flour to alt flour even if they can still have all the sugar and fat they want.

Wheat is sort of the gremlin in the gears for me gumming up the works of FR theory which I otherwise like very much.
Lerner said…
@Tsimblist: yep, the last that I was there, the CRONers #2 concern after calories was the methionine from red meat etc. One strategy was to take supplemental B6, B12, folic acid to try and insure that methionine was fully converted to cysteine rather than to homocysteine. (That relates to Dr McCully and his "Homocysteine Revolution" where he'd noticed on autopsy that some rare 1-2 yrs old died of atherosclerosis.) The other strategy was just to minimize consumption of methionine.

But yet actual trials on the homocysteine theory of atherosclerosis have failed.

Thanks for pounting out that study, Dietary methionine restriction increases fat oxidation in obese adults with metabolic syndrome. It's news to me.
CarbSane said…
@bentley: Perhaps my personal experiences cloud my judgment on this one, but I have no problems giving up wheat other than I do enjoy the occasional pasta, and for meals on the go, a sandwich or wrap is hard to beat. I think that had wheat not become a staple flour for whatever reason, humans would have bred other grains for the properties.

I see the reason for drug and alcohol addiction being so difficult is that both alter judgment and thinking abilities. This is why with alcohol, total abstinence is required for some. Even there, with drugs, there are other factors. As in nobody ever just happens across a little cocaine. If it's served up at the parties you're attending you're hanging with the wrong crowd.

I've been addicted to caffeine many times in my life, but never craved it either. And the one time I went cold turkey for Lent, the last thing I wanted after my first cup was another one!

Wheat seems to be more habit and conditioning to me. Dunno ... :)

I know two folks who became celiac in their 30's. For both the transition was more of finding foods w/o gluten than anything, as well as the expense of it.

I hope I never develop a wheat intolerance because I would miss some of my favorite (occasional these days) indulgences. Don't give me any low carb, low fat, low whatever, wholegrain, nonsense pizza. I want my real thin crust NY style pizza when I'm going to eat it!!
Anonymous said…
Dietary methionine restriction increases fat oxidation in obese adults with metabolic syndrome.
'Sixteen weeks of dietary MR in subjects with metabolic syndrome produced a shift in fuel oxidation that was independent of the weight loss, decreased adiposity, and improved insulin sensitivity that was common to both diets.'

Was this the study that explains: 'protein restriction seemed to be giving similar benefits to calorie restriction. And methionine restriction seems to be why protein restriction works so well.' or was that found elsewhere? The calorie restriction - lifespan connection isn't so apparent to me.
Anonymous said…
Lonidamine Extends Lifespan of Adult Caenorhabditis elegans by Increasing the Formation of Mitochondrial Reactive Oxygen Species.

'Extension of lifespan requires activation of pmk-1, an orthologue of p38 MAP kinase, and is abolished by co-application of an antioxidant, indicating that increased ROS formation is required for the extension of lifespan by lonidamine. Consistent with the concept of mitohormesis, lonidamine is capable of promoting longevity in a pmk-1 sensitive manner by increasing formation of ROS.'

You say:
That centers around the concept of hormesis - that small amounts of stressors can be healthy for you.

This might interest you, then:
Hormesis, cell death and aging.

'Many molecules that cause cell death also elicit autophagy, a cytoprotective mechanism relying on the digestion of potentially harmful intracellular structures, notably mitochondria. When high doses of these agents are employed, cells undergo mitochondrial outer membrane permeabilization and die. In contrast, low doses of such cytotoxic agents can activate hormesis in several paradigms, and this may explain the lifespan-prolonging potential of autophagy inducers including resveratrol and caloric restriction.'


Beneficial effects of mild stress (hormetic effects): dietary restriction and health.

' The effects of DR are considered to result from hormetic mechanisms. These effects were reported by means of various DR regimens, such as caloric restriction, total-nutrient restriction, alternate-day fasting, and short-term fasting. Mild dietary stress, including restriction of amount or frequency of intake, is the essence of DR. '

There is also this:
Discriminating between energetic content and dietary composition as an explanation for dietary restriction effects.

'A constant quantity of the sugar solution was consumed in all dietary dilution treatments, hence caloric intake was proportional to sucrose concentrations. Although the present study does not disqualify the relevance of nutrient composition in other species, our data unequivocally demonstrate that caloric
restriction alone is sufficient to extend life span and invalidate alternative explanations.'

This last did not involve primates. However, a lot of the caloric-restriction research (relating to longevity) was done, and still is done on yeasts, other species, and then eventually on primates.
Lerner said…
@Euler (pronounced ‘oiler’, after a math guy): yes indeed, that is of interest. Thanks. My current thinking is that fasting is very good for 'waste disposal' via proteasomes and lysosomes (and it sure makes me feel good). Yet in typical Intermittent Fasting, the usual binge eating is possibly very dangerous because of high postprandial BG and TAG (Homburg Cream and Sugar study, e.g.). So I devised a pattern of not eating until around noon, then frequent small meals with low GI afterward. Any observations on that?

I didn't know that resveratrol was an autophagy inducer. The last I knew it was all Sirt-1 related. Any other molecules? Your cite at impactaging.com didn't have a list.

Also, your cite on macro comp being less important than CR is a good pointer. I believe there's controversy on that but for now I'll continue to go on the assumption that macro composition is in general largely irrelevant if one avoids extremes.

Btw, here's a free full review:
http://www2.uni-jena.de/biologie/ieu/he/own_pub/Ristow_ExpGerontol2010.pdf 2010

How increased oxidative stress promotes longevity and metabolic health:
The concept of mitochondrial hormesis (mitohormesis)
Tsimblist said…

"or was that found elsewhere?"

Yes, elsewhere in places like this:
(Methionine-deficient diet extends mouse lifespan, slows immune and lens aging, alters glucose, T4, IGF-I and insulin levels, and increases hepatocyte MIF levels and stress resistance)
Anonymous said…

About resveratrol:
Recent anti-aging studies on caloric restriction and resveratrol

'Moreover, resveratrol (RSV), a plant derived polyphenol, was shown to increase SIRT1 catalytic activity and mimics many aspects of CR in all eukaryotes tested. Therefore, RSV displays great promise in the prevention of illness and delay the aging process.'
Anonymous said…

Caloric restriction.

'There are profound tissue level changes in metabolism with a generalized shift from carbohydrate to fat metabolism. Four pathways have been implicated in mediating the CR effect. These are the insulin like growth factor (IGF-1)/insulin signaling pathway, the sirtuin pathway, the adenosine monophosphate (AMP)
activated protein kinase (AMPK) pathway and the target of rapamycin (TOR) pathway. These different pathways may interact and may all play important roles mediating different aspects of the response. Exactly how they generate the health benefits remains open for debate, however CR results in reduced oxidative stress and enhanced autophagy, both of which could be essential components of the beneficial effects. Most data about the effects of CR in mammals comes from work on rodents. There is limited work on non-human primates that shows promising effects and one randomized controlled trial in humans where physiological markers of the CR response are consistent with the responses in mice and rats.'

I think the randomized controlled trial is CALERIE. In pubmed, search with 'CALERIE' for the design and results. There are some results relating to glycemic load.

This was a much different kind of study, using human subjects, because the participants who
calorie-restricted were from the Calorie Restriction Society. Great reading!:
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