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Michael R

Mechanisms of CR-Associated Impaired Glucose Tolerance

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Hi Michael,

 

I hope you are well. Sorry about those GIFs. My crow munching image above was meant to be a bit of a mea culpa in your direction as well, showing I can make fun of myself too. Nobody seems to be nearly as amused by that image as I was making it ☺.

 

Er ... no, it isn't. As you quoted,...

 

I'm not sure how you interpreted my quote, but you did check the same box as Saul for your level of CR severity (both "fairly severe') - I can show you the SurveyMonkey screen capture if you want proof. I recognize you protested the way I characterized the different levels, and I respect and understand that. In fact I think you are right - no humans practice "severe" CR, if that is equated with anything like what the rodents are subjected too.

 

All I was trying to point out was that it seems at least possible that Saul is practicing CR a little less severely than you are, despite you both characterizing your CR as "fairly severe", and that different might at least in part be reflected in your very different BMIs (20-22.5 vs. < 16). Given that Saul seems quite reticent to share any details about his diet, and I haven't heard an update from you on that front in several years, its really hard to know calorie-wise how you compare.

 

And do you think your and Saul's degree of CR could be meaningfully compared if we actually did know both your daily calorie counts? Even if we accurately accounted for calories you both expend in exercise, and corrected for any over/under estimations of calorie intake on either of your parts (mostly Saul's part I would expect. Sorry Saul - but I think even you'd agree Michael is much more meticulous than you about tracking calories and nutrition). I still think no meaningful comparison could be made between the two of you based on an accurate estimate of calories in vs. calories out. In short, it seems to me absolute calorie intake (even minus expenditures) doesn't seem like a good way to gauge degree of CR. 

 

You are of course correct, that weight or BMI isn't a good metric either. BMI and calorie intake are very loosely connected at best, and neither is probably a very good way to estimate CR benefits (whatever they may be). Saul clearly exercises which would increase his calorie needs, but he may have a very slow metabolism and therefore be able to maintain a healthy BMI for a man his age (might even stand to be a little higher...) while still eating like a bird ☺. In that case, perhaps he has the best of both worlds - he's able to eat very few calories, while preserving enough fat and muscle mass to avoid issues with glucose intolerance, compromised immunity, sarcopenia, and bone loss (oops, scratch that one off) that some other very thin, seriously CRed folks (particularly older ones) seem to suffer from (including me in the past).

 

As I said, Saul appears to be doing something right, and be a very lucky man. We could learn a lot from him if he'd agree to share more about his diet and lifestyle. Unfortunately he doesn't appear anxious to do so, which is certainly his prerogative. Perhaps I'll try to pry it out of him during the Costa Rica trip, between or during our adventures together. If I learn anything useful, I'll try my best to share them for old-time's sake, with Saul's permission of course.

 

It's funny, in the old days (i.e. a week ago), some of your comment above would have raised my hackles. I'd have accused you of chanting the same old calorie-related mantra again, and it would have been off to the races. Heck, I might even have re-posted one of your GIFs. ☺

 

Now, your comments are like water running off a duck's back. I think I really have turned over a new leaf, or turned a page, or something...

 

I think you enabled me to burn up my strident, self-righteous attitude in one final conflagration of passive-aggressive expression. Thanks for bearing the brunt of it with such dignity and aplomb. You're a good man. Like Saul in fact, who has also received his own sizeable dollop of my wup-ass in the past in the spirit in which it was always intended - in good fun, but sometimes going too far, as I see now.

 

Michael, I hope one day you'll forgive me and we can be friends again. Until that time, know that I'm working to try to make the world a better place, having learned much from you. Thank you for that.

 

May you live long and prosper.

 

--Dean

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This topic is a little bit old, but I want to contribute it with a speculation of mine apart from other most likely reasons. Too much stretching of stomach&intestine due to eating too much calorically dilute foods in high quantities may also contribute to this. As a result of increased absorption surface and absorption rate due to increased pressure, you ingest faster than normal glucose your body can handle.

 

Another thing CR practitioners can do is to have 1 or 2 feast days in a month and eat more protein (and food in general) than necessary (preferably animal protein if you are not vegan) to increase growth hormones for pancreatic cell growth. According to V. Longo, CR doesn't have this occasional re-feeding periods, there might be some merit to this.

Edited by Burak

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This topic is a little bit old, but I want to contribute it with a speculation of mine apart from other most likely reasons. Too much stretching of stomach&intestine due to eating too much calorically dilute foods in high quantities may also contribute to this. As a result of increased absorption surface and absorption rate due to increased pressure, you ingest faster than normal glucose your body can handle.

Your intestinal tract is not made of cheesecloth ;) .

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Michael, why do you think our intestinal track is not inherently loose? There should be an evolutionary advantage to this. Yes, it prevents chewed foods to directly go to the rectum but it also squeezes and juices the foods to increase touching surface and thus the absorption. By the way, your ability to dismiss ideas that do not serve your purpose is extraordinary :)

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Michael, why do you think our intestinal track is not inherently loose? There should be an evolutionary advantage to this. Yes, it prevents chewed foods to directly go to the rectum but it also squeezes and juices the foods to increase touching surface and thus the absorption.

 

I do think the intestinal tract is inherently loose: I just know that this has nothing to do with the rate of absorption of most nutrients, including glucose. The gut is quite intentionally not a highly permeable membrane, and the rate of nutrient absorption is not determined by the size of the "holes" in it, nor can these "holes" be stretched: your gut needs to protect you from taking in bacteria, allergens, etc, and is therefore a very tightly-formed and selective barrier. Aside from very small molecules, like water and electrolytes, most nutrients can't even cross the intestinal wall unless actively absorbed — including glucose absorption. Even the gaps that do exist between cells (tight junctions) don't simply "stretch wider," even if your intestinal walls stretch out (as of course they do every time you eat): they are formed to very precise dimensions by genetically-programmed machinery.

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Thank you Michael. After your explanations and a careful thought, I agree that some kind of unintended glucose leakage does not seem to be possible in normal conditions. But how about the other side: Doesn't our intestinal track produce more enzymes to overcome this massive load which leads to increased absorption?

 

Nevertheless, I still agree that impaired glucose tolerance in CR should mostly depend on the volume of adipose tissue (especially BAT), muscle and liver where glucose should go and be processed rather than flow around aimlessly in the bloodstream.

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First, I'm going to quote a chunk relevant to this thread that I originally posted elsewhere:
 

 

 

In the LC circle, it is well-know that you need to "carb" up 2-3days before doing a OGTT to avoid IGT result. Their usual explanation is that LC increase insulin resistance in the muscle, an utterly normal physiological response to carbohydrate restriction.


In my book, when CR folks start to exhibit the metabolic profile of low carbers and start to use their same excuses for what is clearly impaired metabolic health (i.e. "benign starvation diabetes"), I say that's the time to start worrying.

in this case I think there's strong biological plausibility to what they're saying about the OGTT. Acutely, in response to a meal with a non-trivial amount of carb, the body releases insulin and the peripheral tissues respond to suck the glucose up. But during normal daily overnight fasting — and more dramatically in extended fasting (so-called "starvation diabetes"(3,4) which Blagoskonny thinks is informative on the effects of rapamycin), counterregulatory hormones are up to facilitate release of stored glucagon, enable ketosis and gluconeogenesis, and the liver and muscles are in a state of metabolic insulin resistance as part of normal mitochondrial fuel-switching; all of this helps shield the brain's glucose supply. This situation is completely reversible after break-fast on a daily basis, and after a short period of refeeding in "starvation diabetes".

It would be surprising if a similar situation did not reign (on both fronts) for nutritional ketosis on a very-low-carb diet, and such a phenomenon is anecdotally reported (concerning OGTTs that can be normalized by a few days' return to a non-ketogenic carb intake — which is what's recommended anyway). However, I'm not aware of a formal study to document this.

Cf. the notion of type II diabetes secondary to chronic energy excess being the result of chronically overloading both systems at once, leading to loss of mitochondrial and metabolic capacity for fuel-switching,(1) and Denise Minger's similar notion of the "macronutrient swampland."

Finally, much of the metabolic profile of low carbers is really quite favorable, and resembles people on CR (super-low TG, high HDL, generally good fasting glycemia and HbA1c), etc. Of course, much of this is itself likely the result of energy restriction ...

Next, from my opening post in this thread:
 

(As a reminder, when I was originally tested by Luigi on a relatively high-protein diet and with very high IGF-1 in 2006, my OGTT was the best he had ever seen (and I was tested after Saul, whose OGTT was the best out of the rest of the cohort by a significant margin). I haven't been in for an OGTT since my protein reduction, but my HbA1c has gone from ≤5 (normal) in all tests prior to lowering my protein intake to ~5.6 (high-normal to at-risk) afterward in a series of tests. Since it's not fasting glucose that's the problem, it's evidently postprandial).

 
I also underwent a GlycoMark test, which seemed to reinforce a finding of IGT. Quoting myself again,
 

in an earlier post I'd suggested using Glycomark, which measures the sugar alcohol 1,5-anhydroglucitol (1,5-AG) and is apparently a pretty good marker of chronic postprandial glucose excursions (tho' this would get at one's day-to-day level of such excursions which might not represent  the underlying functional capacity of the organism as well as an OGTT if one is doing things to proactively manage such excursions). Unfortunately (tho' somewhat to my relief, after getting an alarming-looking result), it turns out that Glycomark has a few problems for many people like us: first, teh sugar in question is generally thought to be pretty widely distributed in plant foods, but is known to be esp. high in soybeans, so tofu-munchers might get false reassurance from the test which they might be especially inclined to believe if their critical thinking were impaired from all that soy. (And, actually, even if you don't eat soy, I wonder if (and I've yet to find any data on) whether it might also be high in other legumes).
 
Second, two trials have reported that weight loss on a Zonish diet artificially lowers Glycomark (1,2), which could give you a false positive for IGT. [see references at original post.

 
And not only is GlycoMark a problematic surrogate for IGT: as Dean and others have noted, HbA1c is a Poor Measure of Glucose Control in Healthy Folks, or at any rate with slow RBC turnover (indicated by low bilirubin, which many CR people have) and/or low iron levels (ditto).
 
Happily, I can now report that I recently went in for a new OGTT — and came out handling that big chug o' sugar just fine.
 
Because they had used a somewhat frequently-measured 2 h OGTT at WUSTL, I arranged to have a close approximationi done with LEF: I got ahold of the blood lab and "special ordered" their Glucose Tolerance Test (4 specimens) (which normally measures glucose at baseline, 1 hour, 2 hours and 3 hours after the drink has been administered), and asked them to instead set it up to sample at baseline, 30 mins, 1 h, and 2 h.  Without getting into the numbers, my results were highly satisfactory.
 
Now, does that mean all of my concern between my first highish HbA1c in 2011 and this last test was a total artifact, and my glucose tolerance has been excellent all along? I can't say for sure, because several important things have changed, bringing me back to where I was back in 2006 at WUSTL.
 
First, for several of those intervening tests, my weight and level of CR was at its most severe, whereas I intentionally gained back 10 lb between a test in early 2016 and this last test,returning the weight I was at in 2006 at WUSTL. As Dean notes above, the CR-IGT group at WUSTL had significantly lower BMIs than the CR-NGT, and this could plausibly explain IGT as simply being a function of not having enough of muscle (and other metabolically-active tissue) to suck up a 75 g bolus of glucose. To the extent that this explains an individual's poor OGTT, his might actually be benign: it would neither mean that one's beta-cells were dysfunctional, nor that one had some kind of "hidden" insulin resistance not caught up by HOMA-IR (which mostly measures hepatic insulin resistance): one just didn't have anywhere to put 75 g of glucose, which is fine if you never expose yourself to that kind of shock except for testing purposes.
 
I'm not convinced that this is the explanation, however, for several reasons. First, even with all that "extra" weight, I am still extremely goddamned skinny (as I was in 2006), and slimmer by a substantial margin than my pre-CR setpoint. Second, I continued to have HbA1c nudging into borderline-prediabetic even during a previous period of being up at my current peak between June 2012 and early 2014— but that previous weight gain was due to an injury that kept me from running for an extended period of time, to which I did not compensate with reduced energy intake, so it's confounded by lack of energy burning, likely sluggish metabolism, and likely lower % muscle in my lower body as compared to 2006 or today. And those high HbA1cs were coming in on a low-GI, Zonish diet: it's hard to believe that even my skinniest frame couldn't suck up the carb in those mixed meals, and you would expect in general that metabolically-active tissue would track energy (including carb) intake.
 
On the other hand, throughout that previous, involuntarily higher-weight period, my protein intake continued to be on the lower end of my historical range, albeit not at its lowest, and IGF-1 continued to be extremely low at almost every testing. After having gotten back to running, my weight gradually came down to its nadir, and unsurprisingly my IGF-1 remained low and HbA1c highish. Growing concerned about the very low IGF-1 both for its own sake and because of its possible link to what I at least thought to be CR-associated IGT, I initially increased my protein intake without increasing my energy intake, and to my surprise (and concern) my IGF-1 did not respond in my subsequent test, nor in a followup one.
 
It was at that point that I decided I had to take in some more energy, not just more protein. And after having raised my energy intake and "bulked up" (ha!) to the same weight as 2006 — but now with that extra protein and being physically active again, unlike in the involuntary weight-loss period — my IGF-1 and IGF-1:IGFBP3 climbed up to (finally!) just about exactly where I'd want them to be: similar to the vegans in Fontana's protein-CR-IGF-1 study, which is both substantially lower than those values had been in 2006, but also significantly higher than they had been in nearly every test from 2011 until this last test.
 
And, my HbA1c also looks normal again, despite my bilirubin still being very low, my very-low-normal ferritin, normal iron, and normal non-ferritin iron functional status markers.
 
So, was my glucose tolerance fine all along? Or have I regained my very tight control thanks to more muscle mass? Or because of higher IGF-1? Dunno.
 
But I'm certainly glad to have all these numbers finally where I want them to be — and I'd' strongly encourage people not to speculate, nor (like me) to procrastinate about getting an OGTT if you have any reason to suspect you might be a CR-IGT candidate, but to get yourself tested if you can.

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Michael, if one had undesirable OGTT result wouldn't it make sense to get further testing, maybe an insulin assay or glucose clamp tests to identify if there is a weak insulin response or reduced sensitivity to normal or elevated insulin?

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