Too much of a good thing?

December 26, 2009 9:28 AM

Pellagra is an awful disease. Its symptoms are the four D's -- diarrhea, dermatitis, dementia, and death, unpleasant by anyone's standards. Caused by a deficiency in niacin, pellagra is uncommon in developed nations thanks to the fortification of bread products with niacin. But could excess niacin be causing the rapid rise in type II diabetes?

While type II diabetes (T2DM) is a multi-factorial disease, a likely combination of genetic susceptibility and environmental factors,, much emphasis has been placed on the concept of oxidative stress as a proximal cause for the insulin resistance seen in T2DM.

Building on prior work, a new study from China suggests that (a) niacin causes oxidative stress and insulin resistance, (b) people with T2DM can't get rid of niacin as easily as healthy people without a family history of T2DM, (c) medications that are known to cause insulin resistance also impair the body's ability to excrete niacin, (d) niacin can be excreted in sweat, and not sweating enough causes a niacin buildup and insulin resistance, and (e) lots more.

A smoking gun? Probably not, but for now it may affect the way niacin is used to treat high cholesterol, which so often comes along with T2DM.

posted by greatgefilte (31 comments total)

Aw, crap.
(big-ass bottle of Niacin supplements for sale, slightly used)

Damn, stupid pancreas. Insulin resistance in futile!
posted by mer2113 at 10:08 AM on December 26, 2009 [1 favorite]

FTA: Sweating eliminated excessive nicotinamide

So... exercise? Part of the regimen for Type II Diabetes?

Also, that lede might should maybe focus on excessive niacin, rather than the tangential topics of pellagra and niacin in food.
posted by squorch at 10:09 AM on December 26, 2009

also it makes you write in when you mean to write is... (the insulin resistance does)
posted by mer2113 at 10:10 AM on December 26, 2009

You know who uses massive doses of Niacin in one of their spiritual healing rituals, don't you?
posted by scalefree at 10:18 AM on December 26, 2009 [6 favorites]

Very interesting post GG, thanks.
posted by doctor_negative at 10:33 AM on December 26, 2009

Chemtrails could be the culprite, too.
posted by KokuRyu at 11:00 AM on December 26, 2009

I meant "culprit"... Snark derailed by poor proofreading...
posted by KokuRyu at 11:00 AM on December 26, 2009

Interesting, but assuming they can also get insulin and a reasonable amount of testing supplies, the diabetes is definitely the lesser of two evils.

I know untreated diabetes can be fatal, but what about undertreated diabetes? I'm assuming they'd try to stretch their medication as far as possible, taking half doses, putting off taking doses, etc.
posted by mccarty.tim at 11:05 AM on December 26, 2009

Er, I misread. I thought it said "developing nations," not "developed nations."

Still, it looks like we've stopped a truly awful disease but caused an unpleasant one in its wake. Sounds like typical medicine.

If all it takes is exercise to sweat out the toxin, this sounds pretty easy to treat and in line with existing prevention for diabetes. It's an interesting consequence, but thankfully means that we're not clueless to fight it.

Perhaps we'd be smart to try to get more whole wheat flour in food in place of niacin fortifications, though. It'd cost more, but the public health is worth it. And it'd likely taste better, too.
posted by mccarty.tim at 11:09 AM on December 26, 2009

No offense, but this is why metafilter is really, really, really bad when it comes to nutrition and medical science in general. We don't do that well (in addition to fat, circumcision, gun control etc.). Just look at the HFCS debates for a display of fundamental lack of understanding coupled with argumentativeness. Not a great combo. This post is another example.

The China study cites nicotinamide. Fortification of food is with nicotinamide. Meanwhile, high cholesterol is treated with niacin which is nicotinic acid and not the same thing at all, at all. Nicotinamide is the amide of nicotinic acid. The body reacts utterly differently to these two, as anyone who takes niacin can tell you - nicotinic acid often causes a flushing reaction, which nicotinamide does not. If you took a lot of nicotinamide it would do NOTHING for your high cholesterol - only nicotinic acid would. So it is stupid to say about the study "it may affect the way niacin is used to treat high cholesterol". It has NOTHING to do with it. These two have very different physiological effects. Such complete lack of understanding of the very basics, provides no value to the post.

Furthermore, I note this study is in rats. Anybody who has spent any time looking at such studies knows that it's a long, long, long way from applying results in rats to humans. As far as I know, nobody has characterized how to translate NAD/NADH metabolism from rats to humans. At best, this suggests avenues of research. It says nothing whatsoever about effects in humans. Ignore, and disregard.
posted by VikingSword at 11:10 AM on December 26, 2009 [29 favorites]

From the last link:
CONCLUSION: These findings suggest that nicotinamide overload, which induced an increase in plasma N1-methylnicotinamide, associated with oxidative stress and insulin resistance, plays a role in type 2 diabetes.

That's a pretty qualified statement. It may or may not have anything to do with Type II diabetes.
posted by Brandon Blatcher at 11:57 AM on December 26, 2009

Niacin has long been observed to raise plasma glucose levels in some people, but this effect appears to be reversible; stop niacin, and glucose should normalize as well. Your doctor should be aware of this. A cumulative damage hypothesis-- that niacin has some associated toxicity which is irreversible-- would be something quite different.

No meaningful clinical correlations can be drawn from the linked study, which really is kind of a poorly structured mish-mash of observations: first, that nicotinamide clearance is reduced in a small sample of insulin resistant individuals, fair enough, and second, that in rats overdoses of nicotinamide can lead to acute changes in glucose tolerance, possibly coupled through an oxidant mechanism, and finally that the skin is a prominent site of clearance of niacin. The first and third observations, fine, though I have no idea why they are included in this study-- whatever novelty is here is predominantly contained in the middle section, looking at rats.

The authors show that high doses of niacin can acutely affect plasma glucose tolerance. High, in this case, is 100 or 400 mg/kg given intraperitoneally, several times the dosage a human would be on orally-- and intraperioneal dosage almost always results in more rapid and complete absorption. In the early experiments, glucose tolerance is tested 2h following the last dose- definitely an 'acute' loading, and not supportive of a chronic injury hypothesis.

My big problem is with the experiments which the authors put in suggesting that niacin-metabolite (NMN) generated oxidative stress is coupled to glucose tolerance. Based off of changes in NAD/NADH ratios and plasma H2O2, again acutely, the authors suggest that niacin dosing increases oxidative stress, again acutely.

They then follow this up with an experiment based around giving tamoxifen or olanzipine, inhibitors of antioxidant activity, among many other things, prior to NMN. This should be the 'showcase' experiment of this study, though it's not a great approach: examining whether antioxidant inhibitors enhance NMN's effect on glucose tolerance. First, they show that these slow clearance of NMN, which suggest that they would confound any observation of antioxidant-related effects of these compounds, rendering this approach overall hard to interpret. Nontheless, they soldier on, but then completely screw up their critical experiment: they show glucose tolerance data for tamoxifen-loaded animals, with or without NMN dosing, without any presentation of control-loaded animals. Essentially, the data shown is completely inconclusive because the critical comparson, between tamoxifen-loaded and -unloaded animals, has been completely omitted. As a result, it's impossible to conclude anything meaningful about antioxidant-dependent effects from this segment of the study.

In short, this paper is completely incoherent. The evidence connceting NMN dosing to increased ROS in the blood is present but kind of weak, but the authors completely fail to show that this ROS generation is connected in any way to the loss of glucose tolerance. While I can see how the antioxidant-inhibition studies could possibly provide weak evidence for such a link, if properly designed, the way the data is presented is uninterpretable.

More importantly, all of the presented studies are designed in such a way that they test only acute effects of niacin, and not chronic ones, or test the effects in such a way that acute and chronic effects can't be distinguished from each other. Essentially, the data presented in this paper doesn't address this question at all. Given the clinical observations surrounding niacin, I'd hypothesize that given enough of a washout period the treated rats would resolve back to normal glucose tolerance.
posted by monocyte at 11:57 AM on December 26, 2009 [4 favorites]

Aargh, and VikingSword's comment about nicotinamide and nicotinic acid is completely correct, so substitute nicotinamide for niacin in my previous comment. Nicotinic acid is metabolized to nicotinamide, and both have similar effects on blood glucose, but this paper doesn't address niacin itself.
posted by monocyte at 12:02 PM on December 26, 2009

VikingSword: So it is stupid to say about the study "it may affect the way niacin is used to treat high cholesterol". It has NOTHING to do with it. These two have very different physiological effects. Such complete lack of understanding of the very basics, provides no value to the post.

Hang on, hang on, I wasn't totally asleep when I posted this. Nicotinic acid is converted to nicotinamide in the body in order to synthesize NAD and NADP. The suggestion of the paper is that screwing up the NAD+/NADH balance might lead to some nasty metabolic effects, and the inefficient metabolism of nicotinamide could be the driver behind it. Why is such a stretch to think that excess iatrogenic niacin could be a bad thing if this is the case?

monocyte: Nontheless, they soldier on, but then completely screw up their critical experiment: they show glucose tolerance data for tamoxifen-loaded animals, with or without NMN dosing, without any presentation of control-loaded animals. Essentially, the data shown is completely inconclusive because the critical comparson, between tamoxifen-loaded and -unloaded animals, has been completely omitted. As a result, it's impossible to conclude anything meaningful about antioxidant-dependent effects from this segment of the study.

I see your point, but two figures back they show the effect of NMN dosing on glucose tolerance with, obviously, a control. Are you suggesting that the tamoxifen vehicle or administration could cause the effects shown? Maybe so, but I don't think it's enough to disregard the whole experiment.

Niacin has long been observed to raise plasma glucose levels in some people, but this effect appears to be reversible; stop niacin, and glucose should normalize as well.

You could argue the same thing about T2DM and other kinds of insulin resistance, that it's an acute condition that resolves with weight loss, exercise, and a better diet.

I dunno, it's not the best paper in the world, but I think it's still interesting. If some people have genetically-determined impaired nicotinamide clearance, and they go and eat tonnes of niacin/nicotinamide-rich food chronically (baked goods and meat), it's not a huge leap to suggest that it might have something to do with their T2DM.
posted by greatgefilte at 1:11 PM on December 26, 2009 [1 favorite]

Agreed with Monocyte and Vikingsword. I wouldn't change anything based on the results of this study.

Can I just mention here how much I hate the use of "oxidative stress" without qualifiers? Exercise clearly causes a lot of "oxidative stress" yet it's abundantly clear that it doesn't cause T2D. The whole mania for oxidative stress in T2D won't lead to any useful therapies - systemic antioxidants have been proven not to work.
posted by benzenedream at 1:31 PM on December 26, 2009

That's a pretty qualified statement.

Virtually all conclusions in scientific studies are qualified. That's the nature of the beast.
posted by Justinian at 1:33 PM on December 26, 2009

pellagra is uncommon in developed nations thanks to the fortification of bread products with niacin
I think many European countries do not fortify bread products, but pellagra is uncommon here as well.
posted by davar at 1:42 PM on December 26, 2009

Hang on, hang on, I wasn't totally asleep when I posted this. Nicotinic acid is converted to nicotinamide in the body in order to synthesize NAD and NADP. The suggestion of the paper is that screwing up the NAD+/NADH balance might lead to some nasty metabolic effects, and the inefficient metabolism of nicotinamide could be the driver behind it. Why is such a stretch to think that excess iatrogenic niacin could be a bad thing if this is the case?

You know how they say a little knowledge is sometimes worse than none? This is a good example. Just because nicotinic acid is converted to nicotinamide in the body doesn't mean administration of nicotinic acid and nicontaminade will have the same physiological effect, even if the metabolic pathway were identical. It's enough that the rate of absorption, saturation and excretion is different for there to be different physiological effects (something that many missed in the HCFS threads - the same amount of fructose in the presence vs absence of fiber has a radically different physiological impact). And do the rates of f.ex. metabolite clearance differ for nicotinic acid vs nicotaminade? Why yes, they do.

I suggest, that unless you have characterized the entire pathway and all dependent effects - in humans - it is foolhardy in the extreme to treat nicotinic acid and nicotaminade as interchangeable for whatever impact you choose, including insulin resistance. We have seen repeatedly how seemingly tiny differences in compounds have dramatic differences in outcomes once they are introduced into the human body... the pharma industry for one is acutely aware of this, since they've made and lost billions on just such small nuances.
posted by VikingSword at 4:08 PM on December 26, 2009

VikingSword: I'm trying not to smile too much, but it's not a little ironic that the paper you linked to looked at the metabolism of nicotinic acid and nicotinamide in four animals, all of them non-human. :)

Anyway, I'm certainly not suggesting that this flawed-yet-interesting paper is going to shake things up right away, but given that different forms of niacin result in varied nicotinamide production (page 2), and niacin use has been linked to altered glucose levels (page 4), it might be something to think about.
posted by greatgefilte at 4:32 PM on December 26, 2009

For long time we are suggested to consume natural food ingredients. Follow the old way to be health.
posted by ldii at 4:44 PM on December 26, 2009

I'm trying not to smile too much, but it's not a little ironic that the paper you linked to looked at the metabolism of nicotinic acid and nicotinamide in four animals, all of them non-human. :)

Err, where's the irony? I did that precisely because the Chinese study used rats. The paper I linked to shows that even in rats (as well as other animals) the clearance rates varied between nicotinic acid and nicotaminade - so you can't treat these as equivalent even in rats. In other words, the argument for equivalence falls flat even in these lab settings, for this paper - and your completely unfounded equivalence for those two even in rats, and we haven't even begun to talk about translating this to humans.

Anyway, the entire thing is pretty stupid - I mean, if these two were the same physiologically, you wouldn't have as major a discrepancy as nicotinic acid being indicated for hyperlipidemia and nicotaminade not. If it's that big of a difference for lipid impact, why would any sane person assert that it's necessarily equivalent when it comes to impact on insulin resistance? That needs to be proven, and smiling isn't enough.
posted by VikingSword at 4:48 PM on December 26, 2009

Cheese and bloody crackers, no need to get snippy! No one suggested they were equivalent, only that if nicotinic acid is metabolized to nicotinamide, and nicotinamide may have untoward effects in certain people, perhaps the use of nicotinic acid in those people should be looked at further. Why is this an issue?
posted by greatgefilte at 5:04 PM on December 26, 2009

greatgefilte, you are being disingenuous when you say "no one suggested they were equivalent" - first you link to a study that uses nicotinamide specifically, and it is nicotaminade specifically that food is fortified with, and then you leap to link to niacin (nicotinic acid) which is used with hyperlipidemia. What justified that leap? Certainly not the paper you linked to. It is highly irresponsible without noting - prominently - that these two compounds have radically different physiological impact. You did no such thing - and there are plenty of people who take niacin to control cholesterol. Cheese and bloody crackers indeed. If you want to make the case that excess niacin leads to T2DM than make it - but the paper you linked to does not, and does not even talk about the same substance. This is a result in rats that has nothing to do with either niacin or niacin in humans. If your standards of what is noteworthy are this low, then I have a suggestion that we look into moon rocks and T2DM, because both humans and rocks are composed of atoms. It was incumbent upon you to at least indicate that niacin is not the same as nicotaminade before linking this study and niacin - spuriously - to T2DM in humans - you did no such thing, and that's why you were taken to task for it.
posted by VikingSword at 5:21 PM on December 26, 2009

VikingSword, you're right in that I should've pointed out the difference between the two compounds, but it doesn't take away from the fact that nicotinamide is a major metabolite of nicotinic acid, and that nicotinic acid has already been shown to cause higher glucose levels, enough so that nicotinic acid/niacin is relatively contraindicated in diabetics unless closely supervised. What part of that are you disputing?
posted by greatgefilte at 5:42 PM on December 26, 2009

Also, can you _please_ spell 'nicotinamide' correctly? It's not a fruit drink!
posted by greatgefilte at 5:44 PM on December 26, 2009

Speaking as a Type II diabetic, the lack of decent information here is really fucking annoying. The back and forth about the validity of the study is really great too.
posted by Brandon Blatcher at 5:58 PM on December 26, 2009

For long time we are suggested to consume natural food ingredients. Follow the old way to be health.

The old way was what led to fortification. Did your rush to shitpost prevent you from reading the poster's summary, never mind the articles linked?
posted by rodgerd at 6:04 PM on December 26, 2009

Speaking as a Type II diabetic, the lack of decent information here is really fucking annoying. The back and forth about the validity of the study is really great too.

I concur with you 100%. There is a really bad tendency for the popular press accounts to take random studies and draw absurd conclusions and make really bad recommendations. The effect on the lay public is highly deleterious. It confuses people and often leads them to make unsound health choices, or throw up their hands and give up trying to make a sensible dietary/lifestyle plan. This is a major reason for my irritation with the presentation of this post. I understand that sensationalizing findings gets more eyeballs, as do far reaching extrapolations and speculation, but when human health is at stake, it behooves us to at least be responsible in qualifying any speculation and specifying parameters. People take niacin to control often dangerous hyperlipidemia, and there is no evidence that niacin causes insulin resistance. Btw. elevated glucose levels do not translate directly into insulin resistance or DM - look at the controversy over coffee, the consumption of which raises blood sugar levels, and yet some studies indicate regular coffee drinkers have lower levels of DM. Again, focusing on a single data point (f.ex. glucose levels) misses the fact we are dealing with complex and dynamic systems, and unless you account for all the variables, you should not be making recommendations.
posted by VikingSword at 6:26 PM on December 26, 2009

VikingSword, you're right in that I should've pointed out the difference between the two compounds, but it doesn't take away from the fact that nicotinamide is a major metabolite of nicotinic acid, and that nicotinic acid has already been shown to cause higher glucose levels, enough so that nicotinic acid/niacin is relatively contraindicated in diabetics unless closely supervised. What part of that are you disputing?

I'm disputing your linking niacin with DM and this study in any way whatsoever. In direct answer to your question, the relationship between nicotinic acid in various formulations and diabetes and glucose levels is quite complex. And we should not conflate glucose levels that result from nicotinic acid action with diabetes. As a matter of fact the exact opposite might be the case:

"Niacin could be diabetes treatment

Niacin, the B vitamin which is known to raise blood glucose levels when consumed in large quantities - making it inappropriate for use as a diabetes treatment - could in fact be effective in treating the disease, provided the dosage is small enough.

This is the claim of researchers from the University of Texas Southwestern Medical Center, who carried out a trial of extended release niacin under the Niaspan brand, produced by Kos Pharmaceuticals. The findings of the trial are reported in this week's Archives of Internal Medicine.

The 148 participants in the trial showed a significant improvement in lipid levels and minimal changes in glycemic control following medication with Niaspan.

"Previous reports have shown that niacin in high doses raises blood glucose, but this trial shows that in doses of 1,000 milligrams per day and 1,500 mg/d, niacin therapy was well-tolerated and changes in glycemic control were minimal," said Dr Scott Grundy, the study's lead author. "Low doses of an extended form of niacin also had favourable effects on blood lipids and lipoproteins.""

Again, this shows the danger of a blanket statements here. There are profound effects dependent on form (and even formulation!), dosage and the overall treatment protocol, so again, if you have a speculation, please back it up with some reliable data - this study is emphatically not it when it comes to niacin and T2DM.
posted by VikingSword at 6:42 PM on December 26, 2009

No, this is a big misinterpretation. The amounts in foods and the amounts used to treat cholesterol - the amounts this study talks about - are not in like with our dietary exposures.

Sensationalist hype.
posted by verapamil at 2:42 PM on December 27, 2009

I was going to deconstruct the stats (which are remarkably clean for a sample group of 28) but then I found the bit where they stacked the deck with subjects who already have type II diabetes.
posted by kalessin at 4:25 AM on December 28, 2009