62 replies to this topic

[Brett Black]

Numerous members of the Calorie Restriction Society mailing list, including some of the best-known practitioners of calorie restriction like Michael Rae and Paul McGlothin, are reporting that they have developed impaired glucose tolerance(sometimes termed "pre-diabetes.")

There is concern and debate about what this could mean for the long-term health and lifespan of calorie restriction practitioners.

Some members are suggesting that strict adherence to dietary and lifestyle modifications commonly used to manage diabetes could now be warranted, including very low carbohydrate diets, ultra-low low glycemic index diets and exercising immediately after every meal.

The past several years has seen a move amongst many CRS members toward favoring a lower protein diet, as this type of diet seems to reduce levels of insulin-like growth factor(IGF-1), which has been linked to longevity in animals and also some human populations. There is ongoing speculation that it may be the combination of calorie restriction with lower protein diet that has been the key factor in inducing impaired glucose tolerance, with some apparently only experiencing impaired glucose tolerance after also reducing their protein intake. Whether or not the impaired glucose tolerance is reversible with cessation of caloric restriction and/or increased protein intake is unknown.

From a statistical and scientific perspective the low number of cases(relatively speaking) and the lack of experimental controls means that making a formal and reliable causal connection between calorie restriction and impaired glucose tolerance may not be possible. However, the numerous and growing number of reports of impaired glucose tolerance do raise serious concerns for many, and highlight the potential risks and unexpected consequences associated with engaging in poorly-studied self-experimentation.

The recent upswing in reports of impaired glucose tolerance also follows earlier widespread reports from CRS members of reduced testosterone levels, diminished libidos and low bone density linked to calorie restriction diets.

More on this developing issue can be found at the following links:

http://arc.crsociety...ad.php?2,210428
http://arc.crsociety...ad.php?2,210291
http://arc.crsociety...ad.php?2,210403

[cheezeweezel]

Thank you for posting this.

[Saintor]

I have seen other studies to say the contrary (better glucose management), but assuming what you report, how is that bad and isn't this way to be the natural way to be?

We developed an higher tolerance because we over-abused all this sugar/glucose in the last 100 years. But it is not the what our biological system was used to for 50 000+ years.

http://www.consumerh...=19990303141416

In 1816, the average sugar consumption per person was 15 pounds per year. In 1955, the average sugar consumption was 120 pounds per year. Now in 1990 it is about 180 pounds per person per year.

No way this hypothetical "Impaired glucose tolerance" means that CR is bad.

[niner]

I have seen other studies to say the contrary (better glucose management), but assuming what you report, how is that bad and isn't this way to be the natural way to be?

We developed an higher tolerance because we over-abused all this sugar/glucose in the last 100 years. But it is not the what our biological system was used to for 50 000+ years.

In 1816, the average sugar consumption per person was 15 pounds per year. In 1955, the average sugar consumption was 120 pounds per year. Now in 1990 it is about 180 pounds per person per year.

We are certainly consuming too much sugar today, but we didn't adapt to it over 200 years. That simply isn't enough time for that sort of genetic evolution. Instead, a great many people are getting sick from all that sugar, and most people are getting fat from it.

No way this hypothetical "Impaired glucose tolerance" means that CR is bad.

What would it take to convince you that CR might have some downsides?

[cheezeweezel]

I have seen other studies to say the contrary (better glucose management), but assuming what you report, how is that bad and isn't this way to be the natural way to be?

I am unaware that there are any *long-term*, *human* studies of CRON with RDA-level protein consumption. If there are, I would very much like to know about it!

I only know about either short term (e.g. biosphere), high-protein, or non-optimal-nutrition studies (e.g. Keys).

While clearly Michael and Paul are not in and of themselves statistically significant, the fact that both of them have developed IGT under long-term RDA-protein CRON (with low IGF-1) should at least be a cause of concern to them, their loved ones, and anyone considering RDA-level protein CRON (e.g. me).

So, I very much appreciate being made aware of this, and would love to know if there is a study that demonstrates that Michael and Paul are genetically unlucky, rather than impacted by their dietary choices. And I don't see how IGT can be good, or natural, even if it is manageable. That is not to say, however, that the advantages of the low IGF-1 might not outweigh the disadvantages of IGT.

Furthermore, I wish both Michael and Paul best in managing this - they have both given much to the community.

-cw

Edited by cheezeweezel, 29 June 2012 - 05:43 PM.

[Saintor]

We are certainly consuming too much sugar today, but we didn't adapt to it over 200 years. That simply isn't enough time for that sort of genetic evolution.

We certainly adapted to extra sugar in 200 years and nobody said that it was related to genes. There are other parameters to stretch (hormones, biochemistry,...)

[niner]

We are certainly consuming too much sugar today, but we didn't adapt to it over 200 years. That simply isn't enough time for that sort of genetic evolution.

We certainly adapted to extra sugar in 200 years and nobody said that it was related to genes. There are other parameters to stretch (hormones, biochemistry,...)

Well, you obviously aren't an evolutionary biologist, or even a regular one. If we've adapted to sugar, how do you explain the epidemic of obesity, metabolic syndrome, and diabetes.

[TheFountain]

Um, most of the people I have spoken with who have done long term CR and had blood work done had their A1C numbers in the 4-5 range. That is exactly where you want to be with regard to glucose tolerance. This seems like it might be exception to the rule?

[cheezeweezel]

Um, most of the people I have spoken with who have done long term CR and had blood work done had their A1C numbers in the 4-5 range. That is exactly where you want to be with regard to glucose tolerance. This seems like it might be exception to the rule?

I don't think that A1C is a good indicator of the kind of pre-diabetes that Michael and Paul are exhibiting. Doesn't this just show the average blood glucose level? Michael and Paul, I believe, have excellent fasting blood glucose. The issue is the results of the "oral glucose tolerance test" - which tests reponse to the two-hour response to an impulse of glucose after a fasting period.

Do you know a large number of folks who have had oral glucose tolerance tests after long-term, RDA-ish protein level CRON?

Edited by cheezeweezel, 29 June 2012 - 08:38 PM.

[niner]

While IGT is something to be concerned about, how bad is it, exactly? CRONies don't tend to wolf down large amounts of anything, much less sugar megadoses on an empty stomach. For all we know, it goes away as soon as you return to a normal diet anyway. This might be a tempest in a teapot.

[platypus]

Adding more muscle would certainly help, but it might be impossible on their diets?

edit: I find it remarkable that they discuss minutiae of their diets but body-composition, i.e. the amount of muscle they are able to carry on their frame does not even enter the discussion (ok I didn't read all of the crsociety threads yet but this is my impression).

Edited by platypus, 29 June 2012 - 09:25 PM.

[cheezeweezel]

While IGT is something to be concerned about, how bad is it, exactly? CRONies don't tend to wolf down large amounts of anything, much less sugar megadoses on an empty stomach. For all we know, it goes away as soon as you return to a normal diet anyway. This might be a tempest in a teapot.

It might swirl in a teapot, indeed.

I would be *very* interested to know if Michael is raising his protein intake in response, igf-1 be darned. I believe that Paul is already on record that he is plowing bravely onward because, as you say, this can be managed.

However, it is not a good thing. This does imply, I would guess, at least somewhat higher blood glucose levels after meals, with the accompanying glycation, even if it is reversible, and does not lead to T2D.

For myself, I was at higher protein anyway (zoneish) to maintain muscle mass, as I am not yet in stasis. I think I'll just keep it there for a bit as I try to learn more. And I'll start to experiment with blood glucose.

cw

Edited by cheezeweezel, 29 June 2012 - 09:42 PM.

[TheFountain]

Um, most of the people I have spoken with who have done long term CR and had blood work done had their A1C numbers in the 4-5 range. That is exactly where you want to be with regard to glucose tolerance. This seems like it might be exception to the rule?

I don't think that A1C is a good indicator of the kind of pre-diabetes that Michael and Paul are exhibiting. Doesn't this just show the average blood glucose level? Michael and Paul, I believe, have excellent fasting blood glucose. The issue is the results of the "oral glucose tolerance test" - which tests reponse to the two-hour response to an impulse of glucose after a fasting period.

Do you know a large number of folks who have had oral glucose tolerance tests after long-term, RDA-ish protein level CRON?

A1C is an indicator of how your hemoglobin holds on to sugars over a long term period. The 4-5 range indicates your system is dispensing with all sugars, including glucose, in a healthy and timely order.

[cheezeweezel]

Um, most of the people I have spoken with who have done long term CR and had blood work done had their A1C numbers in the 4-5 range. That is exactly where you want to be with regard to glucose tolerance. This seems like it might be exception to the rule?

I don't think that A1C is a good indicator of the kind of pre-diabetes that Michael and Paul are exhibiting. Doesn't this just show the average blood glucose level? Michael and Paul, I believe, have excellent fasting blood glucose. The issue is the results of the "oral glucose tolerance test" - which tests reponse to the two-hour response to an impulse of glucose after a fasting period.

Do you know a large number of folks who have had oral glucose tolerance tests after long-term, RDA-ish protein level CRON?

A1C is an indicator of how your hemoglobin holds on to sugars over a long term period. The 4-5 range indicates your system is dispensing with all sugars, including glucose, in a healthy and timely order.

Then I'd love to see some analysis of what we know about *who* has done RDA-protein-level (not zone), for how long, and what the statistics look like. I'll try to find what I can about the study that Paul and Michael were tested in...

[TheFountain]

Um, most of the people I have spoken with who have done long term CR and had blood work done had their A1C numbers in the 4-5 range. That is exactly where you want to be with regard to glucose tolerance. This seems like it might be exception to the rule?

I don't think that A1C is a good indicator of the kind of pre-diabetes that Michael and Paul are exhibiting. Doesn't this just show the average blood glucose level? Michael and Paul, I believe, have excellent fasting blood glucose. The issue is the results of the "oral glucose tolerance test" - which tests reponse to the two-hour response to an impulse of glucose after a fasting period.

Do you know a large number of folks who have had oral glucose tolerance tests after long-term, RDA-ish protein level CRON?

A1C is an indicator of how your hemoglobin holds on to sugars over a long term period. The 4-5 range indicates your system is dispensing with all sugars, including glucose, in a healthy and timely order.

Then I'd love to see some analysis of what we know about *who* has done RDA-protein-level (not zone), for how long, and what the statistics look like. I'll try to find what I can about the study that Paul and Michael were tested in...

Good idea. It could indicate something for these individuals. But my hunch is the majority of CR practitioners are still doing fairly well as long as their diets are nutrient dense.

[maxwatt]

I suspect they may have overloaded on simple carbs at some point. If you restrict protein, and limit fats, what else is there? Glycemic index is key to controlling post-prandial sugar.

[niner]

I suspect they may have overloaded on simple carbs at some point. If you restrict protein, and limit fats, what else is there? Glycemic index is key to controlling post-prandial sugar.

I'm starting to think that GI is less important than what you mix it with. A supposedly high GI bread, if eaten with a lot of good olive oil will not have the same high GI. Getting a decent amount of protein and fat on board will keep the carbs from unloading their sugars too rapidly. So like you say, if you restrict protein and fat, you might be looking at a blood sugar problem. I presume that anyone hardcore enough to be a CRONie wouldn't have a problem checking post-prandial blood sugar on a fairly regular basis. If only we had the technology for a permanent indwelling glucose meter, or a non-invasive one...

[Brett Black]

Here's the first study that showed impaired glucose tolerance in some calorie restricting humans(including members of the CR Society mailing list):

1. Age (Dordr). 2010 Mar;32(1):97-108. Epub 2009 Nov 11.

Effects of long-term calorie restriction and endurance exercise on glucose
tolerance, insulin action, and adipokine production.

Fontana L, Klein S, Holloszy JO.

Washington University School of Medicine, St. Louis, MO 63110, USA.
lfontana@dom.wustl.edu

Calorie restriction (CR) slows aging and is thought to improve insulin
sensitivity in laboratory animals. In contrast, decreased insulin signaling
and/or mild insulin resistance paradoxically extends maximal lifespan in various
genetic animal models of longevity. Nothing is known regarding the long-term
effects of CR on glucose tolerance and insulin action in lean healthy humans. In
this study we evaluated body composition, glucose, and insulin responses to an
oral glucose tolerance test and serum adipokines levels in 28 volunteers, who had
been eating a CR diet for an average of 6.9 +/- 5.5 years, (mean age 53.0 +/- 11
years), in 28 age-, sex-, and body fat-matched endurance runners (EX), and 28
age- and sex-matched sedentary controls eating Western diets (WD). We found that
the CR and EX volunteers were significantly leaner than the WD volunteers.
Insulin sensitivity, determined according to the HOMA-IR and the Matsuda and
DeFronzo insulin sensitivity indexes, was significantly higher in the CR and EX
groups than in the WD group (P = 0.001). Nonetheless, despite high serum
adiponectin and low inflammation, approximately 40% of CR individuals exhibited
an exaggerated hyperglycemic response to a glucose load. This impaired glucose
tolerance is associated with lower circulating levels of IGF-1, total
testosterone, and triiodothyronine, which are typical adaptations to
life-extending CR in rodents.

PMCID: PMC2829643
PMID: 19904628 [PubMed - indexed for MEDLINE]

http://www.ncbi.nlm....pubmed/19904628
http://www.ncbi.nlm....les/PMC2829643/
http://www.ncbi.nlm....rticle_9118.pdf

[Brett Black]

The Fontana paper I posted above lays out several hypotheses for the cause(s) of impaired glucose tolerance, including the low muscle mass of calorie restrictors, but it doesn't mention any connection with a lower protein diet. The low protein connection was made on the CR Society mailing list. Another connection made on the CRS list is that calorie restrictors who do a lot of exercise may not be getting IGT. One possibility that springs to my mind is that muscle mass and function may be modulated by both dietary protein and exercise, and this could tie all these factors together.

[Chupo]

It sounds an awful lot like physiological insulin resistance. It's been known in low carb communities for decades. During starvation or carbohydrate restriction, muscle cells become insulin resistant in order to reserve glucose for the parts of the brain, red blood cells, and other cells that cannot run on FFA or ketones. Fasting blood glucose may increase but HbA1c remains low. Oral glucose tolerance tests will show you're diabetic if you haven't given your body enough time to re-adapt to a higher carb intake. If that's what this is, it's not pathogenic and is temporary.

Peter Dobromylskyj at Hyperlipid made a post about it a few years back. http://high-fat-nutr...resistance.html

Edited by Chupoman, 30 June 2012 - 06:45 AM.

[InquilineKea]

So basically CR reduces levels of insulin-like proteins, and the result of that is that if you suddenly binge on a really high sugar diet, then maybe your glucose levels will rise higher because of that?

That isn't intrinsically a bad thing. Insulin-like proteins do just as much damage as glucose does. If glucose levels never rise high enough due to a healthy CRON diet, then there's no need to upregulate the proteins associated with insulin production.

Maybe this just shows that there are flaws in the ways that we test for prediabetes.

[Chupo]

Maybe this just shows that there are flaws in the ways that we test for prediabetes.

I believe it is flawed. Low carbers are instructed to consume 150g carbs/day for three days prior to an oral glucose tolerance test in order to avoid a misdiagnosis of (pre)diabetes. They should also consider fasting insulin as it should be elevated in true prediabetes and diabetes except type 1 of course.

[Brett Black]

Numerous members of the Calorie Restriction Society mailing list, including some of the best-known practitioners of calorie restriction like Michael Rae and Paul McGlothin, are reporting that they have developed impaired glucose tolerance(sometimes termed "pre-diabetes.")

There may be an error in my initial post to this thread, specifically in the quote above. Paul McGlothin may never have reported developing impaired glucose tolerance(I don't know of any instance in which he reports having developed it.) In the following linked discussion Paul states "my glucose level was classified as high normal glucose after two hours":
http://arc.crsociety...0536#msg-210536

Edited by Brett Black, 01 July 2012 - 02:43 AM.

[pmcglothin]

Thank you for correcting this, Brett. I responded to this yesterday by stating that I most certainly do not have impaired glucose tolerance

My A1c always comes in under 5 so does Meredith's. We are monitored by a team of doctors including a superb endocrinologist who frequently congratulates us for our glucose control.

Frankly those with problems have IMHO have eaten very high fat CR diets and/or very high protein for years. I have never done that. Nor do I recommend it for anyone traveling the CR Way.


Dietary fat content alters insulin-mediated glucose metabolism in healthy men.

American Journal of Clinical Nutrition. 2001 Mar;73(3):554-9.
Bisschop PH, de Metz J, Ackermans MT, Endert E, Pijl H, Kuipers F, Meijer AJ, Sauerwein HP, Romijn JA.
Source

Departments of Endocrinology and Metabolism, Clinical Chemistry Laboratory of Endocrinology, and Biochemistry, Academic Medical Center, University of Amsterdam, The Netherlands. p.h.bisschop@amc.uva.nl
Abstract

BACKGROUND: A high dietary fat intake is involved in the pathogenesis of insulin resistance.

OBJECTIVE: The aim was to compare the effect of different amounts of dietary fat on hepatic and peripheral insulin sensitivity.

DESIGN: Six healthy men were studied on 3 occasions after consuming for 11 d diets with identical energy and protein contents but different percentages of energy as fat and carbohydrate as follows: 0% and 85% [low-fat, high-carbohydrate (LFHC) diet], 41% and 44% [intermediate-fat, intermediate-carbohydrate (IFIC) diet], and 83% and 2% [high-fat, low-carbohydrate (HFLC) diet]. Insulin sensitivity was quantified by using a hyperinsulinemic euglycemic clamp (plasma insulin concentration: approximately 190 pmol/L).

RESULTS: During hyperinsulinemia, endogenous glucose production was higher after the HFLC diet (2.5 +/- 0.3 micromol x kg(-1) x min(-1); P < 0.05) than after the IFIC and LFHC diets (1.7 +/- 0.3 and 1.2 +/- 0.4 micromol x kg(-1) x min(-1), respectively). The ratio of dietary fat to carbohydrate had no unequivocal effects on insulin-stimulated glucose uptake. In contrast, insulin-stimulated, nonoxidative glucose disposal tended to increase in relation to an increase in the ratio of fat to carbohydrate, from 14.8 +/- 5.1 to 20.6 +/- 1.9 to 26.2 +/- 2.9 micromol x kg(-1) x min(-1) (P < 0.074 between the 3 diets). Insulin-stimulated glucose oxidation was significantly lower after the HFLC diet than after the IFIC and LFHC diets: 1.7 +/- 0.8 compared with 13.4 +/- 2.1 and 19.0 +/- 2.1 micromol x kg(-1) x min(-1), respectively (P < 0.05). During the clamp study, plasma fatty acid concentrations were higher after the HFLC diet than after the IFIC and LFHC diets: 0.22 +/- 0.02 compared with 0.07 +/- 0.01 and 0.05 +/- 0.01 mmol/L, respectively (P < 0.05).

CONCLUSION: A high-fat, low-carbohydrate intake reduces the ability of insulin to suppress endogenous glucose production and alters the relation between oxidative and nonoxidative glucose disposal in a way that favors storage of glucose.


PMID: 1123793

[Chupo]

It's eating high fat AND high carb that's the problem. If you eat high fat, and low carb, there shouldn't be a problem. It's been used to treat diabetes forever.

[TheFountain]

It's eating high fat AND high carb that's the problem. If you eat high fat, and low carb, there shouldn't be a problem. It's been used to treat diabetes forever.

What about moderate fat and moderate carb? A lot of people on CR seem to do fine on that, with excellent A1C scores.

[TheFountain]

It's eating high fat AND high carb that's the problem. If you eat high fat, and low carb, there shouldn't be a problem. It's been used to treat diabetes forever.

Wait a minute, the study that pmcglothin posted was in a high fat, low carb context. So what are you talking about? Understand that high fat, low carb on normal calorie intake helps diabetes symptoms. We are talking about a CR setting.

Edited by TheFountain, 02 July 2012 - 09:32 PM.

[Chupo]

It's eating high fat AND high carb that's the problem. If you eat high fat, and low carb, there shouldn't be a problem. It's been used to treat diabetes forever.

Wait a minute, the study that pmcglothin posted was in a high fat, low carb context. So what are you talking about? Understand that high fat, low carb on normal calorie intake helps diabetes symptoms. We are talking about a CR setting.

The subjects were injected with glucose and insulin. That doesn't naturally happen on a low carb diet. The lesson should be, don't inject yourself with glucose and insulin if you're on a low carb diet.

As for the CR setting. CR has much in common with ketogenic diets as they are burning fat much of the time.

Edited by Chupoman, 02 July 2012 - 10:28 PM.

[TheFountain]

The subjects were injected with glucose and insulin. That doesn't naturally happen on a low carb diet.

But they were compared with other subjects on differing macronutrient ratios weren't they?

Oh I think I see what you mean now. But still, weren't the macronutrient ratios of the other participants more moderately designed?

Edited by TheFountain, 03 July 2012 - 05:22 PM.

[Chupo]

The subjects were injected with glucose and insulin. That doesn't naturally happen on a low carb diet.

But they were compared with other subjects on differing macronutrient ratios weren't they?

Oh I think I see what you mean now. But still, weren't the macronutrient ratios of the other participants more moderately designed?

Sorry it took so long. They were the same participants but it was a crossover design with different macronutrient ratios, yes. Here's the full text: http://www.ajcn.org/...t/73/3/554.full

The reason I posted that it might be physiological insulin resistance is because CR mice (I know we aren't mice but that's all we have for now) seem to create fat just to turn around and burn it. Wouldn't that be hard on the liver?

CR mice oxidized four times as much fat per day as ad libitum (AL)-fed controls (367 +/- 19 vs. 97 +/- 14 mg/day, P < 0.001) despite reduced energy intake from fat. This increase in FA oxidation was balanced by a threefold increase in adipose tissue FA synthesis compared with AL. Expression of FA synthase and acetyl-CoA carboxylase mRNA were increased in adipose and liver in a time-dependent manner. We conclude that CR induces a surprising metabolic pattern characterized by periods of elevated FA synthesis alternating with periods of FA oxidation disproportionate to dietary FA intake. This pattern may have implications for oxidative damage and disease risk.

http://www.ncbi.nlm....pubmed/19887594

When you're in fat burning mode, as many here may be, it takes longer to metabolize a high glucose load.

Edited by Chupoman, 14 July 2012 - 03:50 AM.