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

[Agent207]

Yes, but niacinamide should have blunted that. It would be interesting to see a study with different doses of niacinamide. Maybe high or lower doses would have had different effects on lipolysis.
Another option for increase FFA is the so-called re-partitioning of the fat from liver to peripheral tissues. Caffeine is known to do the same in lower doses - i.e. raise FFA due to getting fat out of the liver and into the peripheral tissues. In lower doses, caffeine also inhibits FAO, reduces glycogen, and leans out the liver. Both caffeine and niacinamide (in this study) dramatically increase UCP3 expression, which means niacinamide is thermogenic

I remember you replied to me at an old thread about sirt inhibition, that niacinamide inhibited just above certain level, but not under (nmol/l). So maybe you're right an the net effect depends on dose. Also, @tyw suggested at another thread that sirt is good on fat burning metabolism, while inhibition was preferred on glucose metabolism (If I understood right).

 

[haidut]

If you are fine with niacinamide which
- decrease liver and muscle glycogen
- increase lipolysis
- decrease FAO
- increase intralipid accumulation in muscle
- decrease insulin sensitivity

I have nothing more to say.....

If you are fine with placing all of your eggs into one basket (this study) in the face of multiple human clinical trials showing benefit of niacinamide for type II diabetes, insulin resistance, and obesity then I also have nothing more to say...
Most of the findings of this study are positive, and the increased lipolysis is the only thing that bothers me. Again, the increased lipolysis probably deserves another study to clarify why it happens. However, the drug Mildronate, with proven benefits over 5 decades of clinical use, has very similar effects on metabolism (and caffeine does too) so I am not too worried.
Mildronate mediated muscle carnitine depletion increases carbohydrate oxidation in insulin resistant rats
"...Compared with CON, MIL reduced muscle carnitine (5.2±0.2 vs 0.5±0.1 mmol.kg−1 dm, [mean±SEM], P<0.001). MIL reduced lipid oxidation (400±22 vs 245±27 μmol.kg−1.hr−1, P<0.001) while increasing CHO oxidation (370±24 vs 623±117 μmol.kg−1.hr−1, P<0.05). Blood glucose was lower in MIL (6.0±0.2 vs 5.1±0.2 mmol.l−1, P<0.01), as was muscle glycogen (309±16 vs 241±21 mmol.kg−1 dm, P<0.05)."

Effects of long-term mildronate treatment on cardiac and liver functions in rats. - PubMed - NCBI
"...In the rats treated with a 400 mg ⁄ kg dose of mildronate, several significant changes in the plasma lipid profile were observed (table 5). After 4 weeks of treatment with the highest dose of mildronate, significantly lower plasma FFA concentration and significantly increased HDL-C level were observed in fed rats. In fasted rats, the plasma triglyceride concentration was significantly increased, LDL-C level was decreased, while other parameters remained unchanged (table 5). After 8 weeks of treatment with the highest dose of mildronate, significantly increased HDL-C level was observed in fed rats. In fasted rat plasma, LDL-C level was significantly decreased, while FFA and triglyceride concentrations were increased (table 5). After 12 weeks, mildronate treatment induced a dose-dependent and significant (400 mg ⁄ kg) decrease in the plasma b-hydroxybutyrate concentration (table 5). This effect was observed in both fed and fasted rats and the plasma b-hydroxybutyrate concentration decreased approximately twofold in the rats treated with a 400 mg ⁄ kg dose of mildronate compared to the control rats."


If you really want to test this - go on an exercise binge while ingesting stuff that increases lipolysis and FAO as you suggested to another forum user. See if you have any brain, liver or muscle function left to come back and report on the results.

 

[haidut]

I remember you replied to me at an old thread about sirt inhibition, that niacinamide inhibited just above certain level, but not under (nmol/l). So maybe you're right an the net effect depends on dose. Also, @tyw suggested at another thread that sirt is good on fat burning metabolism, while inhibition was preferred on glucose metabolism (If I understood right).

Yes, and SIRT1 is now known to be involved in cancer appearance and growth.
Sirt1 is a tumor promoter in lung adenocarcinoma
Overexpression of SIRT1 promotes metastasis through epithelial-mesenchymal transition in hepatocellular carcinoma

The HDAC inhbition properties of niacinamide, which are known to be good for cancer treatment, depend on its ability to silence the SIRT family.

 

[Agent207]

If you are fine with niacinamide which
- decrease liver and muscle glycogen
- increase lipolysis
- decrease FAO
- increase intralipid accumulation in muscle
- decrease insulin sensitivity

I have nothing more to say.....

My take:

Energy demand --> NAM --> FAO inhibition --> skyrocketed glycolysis rate / faster shortage --> cortisol --> lipolysis (paired with fao inhibition) -------> increased intramuscular fat, RI... etc.

That's a possible context.

 

[haidut]

My take:

NAM --> energy demand --> FAO inhibition --> increased glycolysis rate / faster shortage --> lipolysis --------> increased intramuscular fat, RI... etc.

That's a possible context.

See my response to Nathan and the studies on Mildronate. What you propose is consistent with what Mildronate is known to do, and niacinamide as well. The effects of Mildronate and niacinamide are remarkably similar to the point that now I will start referring to niacinamide as the "OTC Meldonium" when people ask me for alternatives.

 

[Evgenius]

The effects of Mildronate and niacinamide are remarkably similar to the point that now I will start referring to niacinamide as the "OTC Meldonium" when people ask me for alternatives.

lol, I think this is what Maria Sharapova was caught with last year and banned for one year from tennis.

 

[haidut]

lol, I think this is what Maria Sharapova was caught with last year and banned for one year from tennis.

Yes, Mildronate is well known on this forum. Peat has even recommended it to a few people before and now it is being studied as cancer treatment precisely because of its role in inhibiting FAO.
And to your point about athletes - there is probably a good reason for athletes to take it. If inhibiting FAO was a bad thing I wonder why all of these athletes would be taking such drugs instead of stuff that increase lipolysis and FAO as user Nathan suggested above...
Maybe because Sharapova and a few record breaking Chinese swimmers are stupid. I am sure that's the reason :)

 

[Agent207]

I agree Haidut, but let's not forget either that anything that leads to higher performance doesn't imply to be healthy for daily general use, specially on the elite sport business.

Btw, which one would you say is a worse scenario regarding niacinamide use for an exercise event? not taking it and leaving with normal lipolysis rate, or taking NAM and exposing to earlier and higher cortisol release?

I would argue this would be high circumstancial and individual dependent, like the type of exercise and the onset liver and metabolic function, but I'd like to know your take.

 

[Wagner83]

I have nothing more to say.....

The discussion is healthy imo.

 

[Peater Piper]

If PUFA is limited I think fat oxidation is not that bad, but for somebody with a degenerative conditions, and especially cancer, limiting fat oxidation is key to stopping the process. Sick people have persistent lipolysis, which eventually leads to rapid wasting so for them niacinamide is probably a Godsend. For more healthy folks, lower doses niacinamide like Peat suggested probably won't impair insulin sensitivity while still raising NAD levels and keeping the liver lean. Most endurance athletes have some form of fatty liver and I have seen this confirmed time and time again - i.e. if you burn mostly fat, and especially if it is PUFA, you will get "lean" (actually catabolic-looking) peripheral tissue but fatty liver. With niacinamide and aspirin it seems to be the opposite - i.e. keeps liver lean and stores the excess fat in muscles (but not in adipose tissue). Subcutaneous fat is probably the most benign form of storage and it has not been shown to increase risk of disease. Babies are like that. It is the vissceral fat and especially central obesity that leads to most of the health problems we associate with obesity and metabolic syndrome.
Also, inhibiting FAO is pretty well established target for protecting from CVD, strokes, seizures, etc. It's just that the drugs currently approved are very toxic. Here is one of them.
Etomoxir - Wikipedia

Note that it is approved for treating type II diabetes, so drugs that act like that (including niacinamide) must be beneficial for overall insulin resistance pathology, or at least protect from its worst effects.

I'm just trying to figure out how to disparate approaches seem to work. I know Peat doesn't like resveratrol, but if you look at the resveratrol treated group, it was highly protective of NAFLD on the high fat diet, and as opposed to the NAM group, reduced fat accumulation in the muscle while preserving insulin sensitivity.

Regarding the bolded, I couldn't find any studies even discussing it except for an isolated case, but I don't doubt it can happen, though is it really from mainly fat oxidation? Given how catabolic excessive endurance training can be, I would expect insufficient protein and excessive cortisol could be just as likely to cause it. We know protein deficiency is a major risk factor for NAFLD.

On other hand, moderate exercise, whether it be aerobic or anaerobic, has been shown to reduce NAFLD with few exceptions, even in the absence of weight loss. The majority of studies summarized here showed reduction in NAFLD:

Effects of exercise training on intrahepatic lipid content in humans

Resistance training, which we think of as being mainly anaerobic and relying on glucose, increases fat oxidation and lowers RER following exercise.

Fat metabolism and acute resistance exercise in trained men. - PubMed - NCBI

Obviously NAM is protective against and NAFLD, and Mildronate can be extremely beneficial as well by lowering carnitine and beta oxidation, but then we have increased beta oxidation through exercise being beneficial. carnitine being beneficial in a number of studies, resveratrol in this study, even coffee and caffeine seem to increase beta oxidation in many situations yet they've been shown to be beneficial overall. It appears incomplete beta oxidation is the primary issue, and either dramatically reducing beta oxidation, or improving beta oxidation to prevent lipid accumulation can be effective?

 

[haidut]

I agree Haidut, but let's not forget either that anything that leads to higher performance doesn't imply to be healthy for daily general use, specially on the elite sport business.

Btw, which one would you say is a worse scenario regarding niacinamide use for an exercise event? not taking it and leaving with normal lipolysis rate, or taking NAM and exposing to earlier and higher cortisol release?

I would argue this would be high circumstancial and individual dependent, like the type of exercise and the onset liver and metabolic function, but I'd like to know your take.

Mildronate was developed as a drug to treat heart disease and diabetes. Its performance enhancing effects were discovered much later. So, its safety and effectiveness for metabolic conditions like that has extensively studied and pretty much beyond dispute at this point. I am not advocating that everybody should start popping Mildronate or niacinamide. Younger, healthier people probably do not need any of these. But in older people FAO is upregulated and glucose oxidation is downregulated. It is the one metabolic hallmark of aging. The studies with glycine reversing aging in cells focused exactly on that aspect - i.e. reversing the inability of "old" cells to oxidize glucose. So, if you are over 35 and feeling like you can use a pick-me-up, then niacinamide, caffeine, inosine, etc could be things to try.
I think the rise of cortisol during strenuous exercise is unavoidable. I would much rather have cortisol rise first compared to adrenaline/FAO. The cortisol rises to provide emergency sugar to the brain and also to control inflammation triggered by the exertion.

 

[haidut]

I'm just trying to figure out how to disparate approaches seem to work. I know Peat doesn't like resveratrol, but if you look at the resveratrol treated group, it was highly protective of NAFLD on the high fat diet, and as opposed to the NAM group, reduced fat accumulation in the muscle while preserving insulin sensitivity.

Regarding the bolded, I couldn't find any studies even discussing it except for an isolated case, but I don't doubt it can happen, though is it really from mainly fat oxidation? Given how catabolic excessive endurance training can be, I would expect insufficient protein and excessive cortisol could be just as likely to cause it. We know protein deficiency is a major risk factor for NAFLD.

On other hand, moderate exercise, whether it be aerobic or anaerobic, has been shown to reduce NAFLD with few exceptions, even in the absence of weight loss. The majority of studies summarized here showed reduction in NAFLD:

Effects of exercise training on intrahepatic lipid content in humans

Resistance training, which we think of as being mainly anaerobic and relying on glucose, increases fat oxidation and lowers RER following exercise.

Fat metabolism and acute resistance exercise in trained men. - PubMed - NCBI

Obviously NAM is protective against and NAFLD, and Mildronate can be extremely beneficial as well by lowering carnitine and beta oxidation, but then we have increased beta oxidation through exercise being beneficial. carnitine being beneficial in a number of studies, resveratrol in this study, even coffee and caffeine seem to increase beta oxidation in many situations yet they've been shown to be beneficial overall. It appears incomplete beta oxidation is the primary issue, and either dramatically reducing beta oxidation, or improving beta oxidation to prevent lipid accumulation can be effective?

All good points. I think the main reason of increased FAO from endurance exercise causing NAFLD is that the fat that goes to the liver for excretion has estrogenic effect due to being mostly PUFA. On the other hand, fully saturated fat was shown to reverse even terminal cirrhosis. So, if you can somehow provide SFA to the liver while exercising then it should not be that bad. The beneficial effects of exercise are mostly due to increased thermogenesis, but it is done in a bad way - i.e. through increased adrenaline and conversion of the white into brown fat. The so-called "cold thermogenesis" has pretty much the same effect as "exercise". As soon as exercise starts to break down muscle it is no longer beneficial due to the increase of cysteine, methionine and tryptophan in the blood. And once it leads to increased adrenaline, that leads to increased availability of tryptophan in the brain and thus increased serotonin synthesis. The increase in serotonin in the brain is what makes you tired during (and after) exercise and is called the "central fatigue hypothesis". It has been shown to occur even in people with plentiful energy reserves or ones being fed by an IV while exercising. So, the point with any activity (at least to me) is this - while it is glycogen-bound and mentally stimulating/fun it is likely beneficial. Once it gets into the stage of adrenaline/lipolysis/tryptophan/serotonin/etc it is no longer good. For most people this means 10min - 30min of activity. Only very young and healthy people have glycogen reserves to depend on for hours.
Finally, the desire to regularly exercise that many people report and use to argue with Peat is actually a type of "addiction". Exercise has some dopaminergic effects initially and a ton of opioid activity due to the endorphins being released. So, quite a few of people that fanatically exercise are probably self-medicating for some type of physical pain or mental trauma. It is not a coincidence that so many people with depression like to run. Aside from the publicized effects of running on BDNF (which are mostly due to the "fun" factor in exercise and stop sharply when you overdo it), those endorphins can really blunt pain for many people. The same is true of drinking and once again, it is not a coincidence that people in pain of conditions like depression like to run or drink a lot, and most like both (often to an excess).

 

[Drareg]

If you are fine with niacinamide which
- decrease liver and muscle glycogen
- increase lipolysis
- decrease FAO
- increase intralipid accumulation in muscle
- decrease insulin sensitivity

I have nothing more to say.....

WSAG Alert!

Forum member posts study contradicting some of Peats views,puts burden of proof on forum members to disprove said study while ignoring studies that show positive outcomes from niacinamide.

PEAT IS WRONG AGAIN EVERYBODY now follow my blog and dedicate to me.

 

[Drareg]

Was there a 16 hour fast after last niacinamide injection?

 

[A.R]

. As soon as exercise starts to break down muscle it is no longer beneficial due to the increase of cysteine, methionine and tryptophan in the blood. And once it leads to increased adrenaline, that leads to increased availability of tryptophan in the brain and thus increased serotonin synthesis. The increase in serotonin in the brain is what makes you tired during (and after) exercise and is called the "central fatigue hypothesis".

So if someone is trying to build muscle, it would very important to keep serotonin levels in check to avoid a build up?

Nutrition | Mobile

Now I know why BCAA are so highly recommend on this forum

 

[haidut]

Was there a 16 hour fast after last niacinamide injection?

Oh, shoot, you are 100% right! I completely missed that. There was also a 3-day washout period before the insulin tests. So, I guess the statement of niacinamide raising lipolysis is incorrect. It's more like there is a rebound lipolysis 3 days after niacinamide discontinuation, but the NAD/NADH ratio is still elevated and FAO is still inhibited.
"...Three days after the last drug injection, the mice were derpived of food for 16h and then subjected to glucose tolerance tests (GTT) and insulin tolerance tests (ITT)."

 

[haidut]

So if someone is trying to build muscle, it would very important to keep serotonin levels in check to avoid a build up?

Nutrition | Mobile

Now I know why BCAA are so highly recommend on this forum

Absolutely. Serotonin is one of the most catabolic agents both for muscle and bone. Ray wrote about serotonin antagonists being anabolic for bone, and the same can be said about muscle. Serotonin stimulates CRH, ACTH, and cortisol synthesis independently of each other and obviously these in combination would be much more detrimental. One of the reasons serotonin antagonists lead to weight gain is just that - opposition of 5-HT2A "receptor" seems to abate the entire stress cascade (CRH, ACTH, cortisol, prolactin, adrenaline) and thus allow for lost weight to be regained. Cypro and ketotifen are common anti-cachexia drugs in the clinic for that reason.
The anabolic effects of BCAA are probably due at least partly to them lowering serotonin in the brain, but they would be more effective when used with other essential aminos and a bit of extra phenylalanine. Not only will that lead to increased MPS, but also decrease catabolism due to serotonin. BCAA on their own may lower dopamine as well, I would not take them on their own.

 

[A.R]

Absolutely. Serotonin is one of the most catabolic agents both for muscle and bone. Ray wrote about serotonin antagonists being anabolic for bone, and the same can be said about muscle. Serotonin stimulates CRH, ACTH, and cortisol synthesis independently of each other and obviously these in combination would be much more detrimental. One of the reasons serotonin antagonists lead to weight gain is just that - opposition of 5-HT2A "receptor" seems to abate the entire stress cascade (CRH, ACTH, cortisol, prolactin, adrenaline) and thus allow for lost weight to be regained. Cypro and ketotifen are common anti-cachexia drugs in the clinic for that reason.
The anabolic effects of BCAA are probably due at least partly to them lowering serotonin in the brain, but they would be more effective when used with other essential aminos and a bit of extra phenylalanine. Not only will that lead to increased MPS, but also decrease catabolism due to serotonin. BCAA on their own may lower dopamine as well, I would not take them on their own.

Now I know how I lost nearly 50kg body weight in about 6 months, from doing excessive exercise along with caloric restriction. The weight was just falling off. My serotonin levels must have been through the roof back then, and I can relate to your statement about exercise being an 'addiction', because it was for me when all this was happening.

It didn't take long for my body to crash though, and since then I've put all the weight back on with some extra. Again, like how suddenly all the weight went off, same way I've just suddenly ballooned up again.

 

[Drareg]

Oh, shoot, you are 100% right! I completely missed that. There was also a 3-day washout period before the insulin tests. So, I guess the statement of niacinamide raising lipolysis is incorrect. It's more like there is a rebound lipolysis 3 days after niacinamide discontinuation, but the NAD/NADH ratio is still elevated and FAO is still inhibited.
"...Three days after the last drug injection, the mice were derpived of food for 16h and then subjected to glucose tolerance tests (GTT) and insulin tolerance tests (ITT)."

Is fasting for 16 hours in mice the same for humans or do you have to extrapolate?
I thought mice will only last 3 days without food?
I'm sure they had water? Not sure of the methods.

 

[haidut]

Is fasting for 16 hours in mice the same for humans or do you have to extrapolate?
I thought mice will only last 3 days without food?
I'm sure they had water? Not sure of the methods.

I don't think it needs to be extrapolated as other rodent studies that lasted for a certain amount of time and then tried to replicate this in humans used the same timeframes. Mice can usually live for 2-4 days without food and then go into a comatose state similar to very deep hibernation in order to conserve fuel. Their fast metabolism is what does them in when there is no food around. In a lab environment, in that timeframe they will probably lose about 20%-30% of their weight and it is considered unethical to keep them alive after that so they get euthanized. So, yes, you are right, by the 3rd day of fasting that this study subjected them to the mice were not likely in a good state. Mice do not really need water, if the food provides enough moisture, and the study does not say if they kept drinking while fasting. Drinking water while fasting will also affect lipolysis and other parameters as water on a empty stomach raises GH and prolactin.