Long-term Treatment With Nicotinamide Induces Glucose Intolerance And Skeletal Muscle Lipotoxicity

[lollipop]

Advice worth a second read!

@Regina @haidut +1

Actually, it was this post that led me to design an IDEAL (for me) weekly movement/fitness/yoga schedule.

 

[sladerunner69]

Hmm what about combining 500mg b3 with 200mg caffiene and 325mg aspirin? And repeating that dose 2-3 times during the day? Good strategy?

 

[sladerunner69]

Well, he ruined his teeth on his 30s by eating tons of wheat germ oil. I don't think that is any better than a little derailed metabolism. Also he took 1kg of pregnenolone for a year (and had luck nothing bad happened as consequence). He said he used to drink up to 10 strong coffees a day.

What I mean, I doubt moderate is the best word that defines him.

Actually, in one interview he mentioned he could drink as many as 40 cups because he was using caffiene to replace thyroid.

 

[Amazoniac]

@gbolduev
@Travis
Both of you might be interested in this discussion in case you missed.

 

[Travis]

Qi, Zhengtang, et al. "Long-term treatment with nicotinamide induces glucose intolerance and skeletal muscle lipotoxicity in normal chow-fed mice: compared to diet-induced obesity." The Journal of nutritional biochemistry 36 (2016): 31-41.

There were a few previous estimates of the human equivalent dose for this study on previous pages. One apparently comes from the 20 gram mouse and one the 150 gram rat. [chart] But the mice used in this study were 36 grams.

From this I get 1.054 grams to be the human equivalent dose (for a 70kg human (me!)). This is quite a bit. Not many people take this much every day for eight weeks.

Notice that the nicotinic acid amide group did not weigh any more.

However, we found no changes in body weight, fat mass and fasting blood glucose and insulin.

. We found no pronounced increase in hepatic lipid storage. Instead, NAM increased lipid content and decreased glycogen content in skeletal muscle.

Together, it can be concluded that NAM-induced insulin resistance in nonobese mice was associated with skeletal muscle lipid accumulation. In this work, the possible explanation for skeletal muscle lipid accumulation is that NAM reduced the capacity of exogenous FA oxidation and increased TAG esterification.

Additionally, we found that NAM selectively increased the mRNA levels of myosin II (IIa, IIb and IIx, fast-twitch fiber) and made a nonsignificant reduction in myosin I (slow-twitch fiber).

Fast twitch muscle can be good. How much can be explained by just this switch from slow-twitch to fast-twitch?

A possible explanation for NAM to induce insulin resistance and lipid accumulation could be that muscle fiber-type switching reduced lipid utilization and mitochondrial mass.

He admits that fast-twitch muscle fibers have lower mitochondrial mass, but he makes it sound like a bad thing. This can probably explain the differences in mitochondrial DNA found in the muscles of high-niacin-fed rats.

As type II myofiber has lower mitochondrial mass than type I myofiber (oxidative muscle fibers), our results are quite consistent with the skeletal muscle data in that NAM impairs mitochondrial function and reduces mtDNA content.

But total weight was identical and the liver was normal:

. This study did not explain why lipid accumulation occurs only in skeletal muscle but not in liver.

Most metabolic genes implicated in glucose and lipid utilization, including CPT-2, TIGAR, TBC1D1 and PRDM16, were reduced in the NAM-treated mice, while expression of PDK4, LKB1, AMPKα2, Cidea and UCP3, was increased (Fig. 2H–K).

In the muscle, some genes associated with reduced metabolism were decreased but some were increased. Adenosone monophoshate kinase α₂ was increased, but he does not talk much about this:

The net effect of AMPK activation is stimulation of hepatic fatty acid oxidation, ketogenesis, stimulation of skeletal muscle fatty acid oxidation and glucose uptake, inhibition of cholesterol synthesis, lipogenesis, and triglyceride synthesis, inhibition of adipocyte lipolysis and lipogenesis, and modulation of insulin secretion by pancreatic beta-cells. –Wikipedia

You can make this high-dose niacin sound either good or bad depending on your biases. The slight decrease in total insulin sensitivity could simply be the result of decreased mitochondrial capacity of type II fibers.

But are diacylglycerides a bad thing in the muscle, compared to glycogen? It is a more dense way to store energy than glycogen, and the increased fast-type II muscles could actually be a feather in the hat for niacin. Would this be good for tennis players and runners?

He spends some time talking about a deacetylase, an enzyme that deaceylates mitochondria post-translationally. These modifications are thought control metabolism or tag proteins for destruction. For example, protein kinase A increases metabolism, ultimately by carboxylating mitochondria. This is partly how CO₂ is thought to increase metabolism.

NAM inhibits SIRT1 deacetylase activity by binding to a conserved pocket adjacent to NAD⁺ and blocking NAD⁺ hydrolysis, rather than by increasing the NAD⁺ level or [NAD⁺]/[NADH] ratio.

So this happens directly, without niacinamide even becoming NAD⁺.

Contrarily, SIRT1 activity in the absence of NAM is enhanced by an increase in the NAD⁺ level or [NAD⁺]/[NADH] ratio. Interestingly, 5 mM NAM but not higher concentrations causes SIRT1 activation in fibroblasts, as demonstrated by decreased acetylation level of histone H3 and p53.

But somehow, a certain dose of niacinamide works in the opposite way on SIRT1. Maybe lower doses do this by increasing NAD⁺ (substrate)? He draws on two citations which show opposite effects on SIRT1. Perhaps there are differences in the study protocols that might explain this. He did measure the acetylation level on one mitochondrial protein (p53). But notice the increase in actin:

Maybe there is so much NADH inside of the cell that energy flow is increased and mitochondria is slightly downregulated (aecetylated) to compensate? There was no measure of any athletic parameters. It would have been nice to see how they would have done on a wheel test or a mouse swimming test (or chasing a piece of cheese around a track or something.)

The niacinamide also shifts methyl groups from methionine. This is probably a necessary result of taking niacin without folate. In natural foods, these are found in balanced proportions. This is a good thing to keep in mind. Effectors of methyl balance now officially include B₁₂, folate, methionine, and niacin.

 

[Amazoniac]

The niacinamide also shifts methyl groups from methionine. This is probably a necessary result of taking niacin without folate. In natural foods, these are found in balanced proportions. This is a good thing to keep in mind. Effectors of methyl balance now officially include B₁₂, folate, methionine, and niacin.

Very interesting. I didn't know that.

@haidut - his posts might interest you. You guys have so much in common, both can solve a 11*11*11 Rubik's cube in 5 min, on congested days.

 

[haidut]

Very interesting. I didn't know that.

@haidut - his posts might interest you. You guys have so much in common, both can solve a 11*11*11 Rubik's cube in 5 min, on congested days.

Thanks. Yes, niacinamide is a methyl sink, so in higher doses it acts similar to methionine restriction (known to prolong maximum lifespan more than restricting any other nutrient, including tryptophan). But in depleting methyl groups too much may create a problem with adrenaline deactivation, which depends on methyl groups. So, there is a sweet spot for niacin and niacinamide dosing and Hoffer thought that 1,500mg niacinamide daily is that sweet spot for lifespan extension. Same with methionine restriction - lower is better but no less than 2mg/kg methionine daily as less than that creates issues.

 

[Mito]

Thanks. Yes, niacinamide is a methyl sink,

But it seems to raise homocysteine. Niacinamide Increases Homocysteine

 

[Travis]

But it seems to raise homocysteine. Niacinamide Increases Homocysteine

Wow. This makes perfect sense. But I would think with a low-methionine diet, general niacin-induced demethylation wouldn't create a pathological level of homocysteine. The Japanese have lower homocysteine levels, on average.

I think a good approach is always to limit methionine. Although it's necessary, the aforementioned long-lived mice apparently were able to live this way—and longer—at lower intakes.

But perhaps the homocysteine effect can be counteracted by just adding a methyl donor?

Besides the brain-, artery-, and lipid-damaging homocysteine: methionine and arginine are the two precursors for polyamines. These are powerful growth-promoters thought to act somehow by stabilizing DNA. I need to read more about polyamines. Perhaps they permeate the nucleus to uncoil DNA? inducing replication in this manner?

I vote methionine to be amino acid public enemy #1, with tryptophan a close second.

 

[haidut]

I vote methionine to be amino acid public enemy #1, with tryptophan a close second

Cysteine is right up there with methionine but tryptophan is the only one that is directly carcinogenic. There is a reason it is the amino acid with the lowest levels in any protein containing food in nature.

 

[Texon]

Thanks. Yes, niacinamide is a methyl sink, so in higher doses it acts similar to methionine restriction (known to prolong maximum lifespan more than restricting any other nutrient, including tryptophan). But in depleting methyl groups too much may create a problem with adrenaline deactivation, which depends on methyl groups. So, there is a sweet spot for niacin and niacinamide dosing and Hoffer thought that 1,500mg niacinamide daily is that sweet spot for lifespan extension. Same with methionine restriction - lower is better but no less than 2mg/kg methionine daily as less than that creates issues.

@tca1000 @haidut
Haidut thank you! For mentioning Dr. Hoffer. I will take his clinical experience any day over a single animal study. IIRC, he mentioned that people with frank ptsd (wwII prisoners of war, etc.) developed a chronic need for much higher than typical doses for niacin/niacinamide to remain well.

 

[Highserotonin90]

Bump

 

[Texon]

Thanks. Yes, niacinamide is a methyl sink, so in higher doses it acts similar to methionine restriction (known to prolong maximum lifespan more than restricting any other nutrient, including tryptophan). But in depleting methyl groups too much may create a problem with adrenaline deactivation, which depends on methyl groups. So, there is a sweet spot for niacin and niacinamide dosing and Hoffer thought that 1,500mg niacinamide daily is that sweet spot for lifespan extension. Same with methionine restriction - lower is better but no less than 2mg/kg methionine daily as less than that creates issues.

@nathan10000

Just got an email dropped today about this thread, so I had forgotten I even made the comment above about Dr. Hoffer, etc. I guess it's worth saying again that I'd rather depend on a guy with decades of clinical experience vs. one or a few mouse studies. I personally deal with snp's (MTHFr/COMT, etc.) that impair processing of catecholamines, and NMD will reliably cause me some grief if I'm not careful to include corresponding doses of TMG and some other methyl donors. It's all very manageable, blood work is just fine, I also find that a combination of 500 mg of NMD, a 5 mg DHEA pill, sublingual methyl B12 and some TMG make for very interesting libido enhancement. I'm also just started supplementing 3 capsules/day of Moducare (tm) for a low level CLL condition.

 

[Highserotonin90]

@Texon Do you use MAO inhibitors A and B intermittently?

 

[Texon]

@Texon Do you use MAO inhibitors A and B intermittently?

No not unless some food or herb/spice happened to have that chemistry by chance.