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

[Rad]

This should be it.

 

[DaveFoster]

I don't know of anybody who takes niacinamide without other supplements.

 

[haidut]

This should be it.

Great, thanks.
Well, couple of things. The study does discuss niacinamide being helpful in human studies with T2DM, as well as some T1DM cases. It also mentioned the few studies where niacinamide (NAM) was detrimental, so it tries to replicate both sets of findings. Long story short, the study has quite a few gems that are very good to know and data on them was lacking so far.

1. Niacinamide is a fatty acid oxidation inhibitor, much like the drug Mildronate, even though the mechanism of NAM is likely through SIRT1 inhbition (as I posted about in another thread: Niacinamide Lowers Fatty Acid Oxidation By Inhibiting SIRT1). The good news is that this in vivo study shows that even a relatively low-dose NAM is pretty good as an alternative to Mildronate. Since the study used mice, the HED of NAM was about 7.5mg/kg daily. More importantly, this same dose also inhibited SIRT1, which is the likely mechanism behind decreased fatty acid oxidation. Consequently, NAM shifts cell fuel preference to glucose and this is probably what led to the decreased glycogen stores as I conjectured earlier. I view this as a profoundly positive effect and rejoice that we finally have in vivo study confirming both the ability of NAM to inhibit FAO as well as profoundly inhibit SIRT1, and in quite reasonable doses at that. Finally, as expected, NAM doubled NAD/NADH ratio levels even at this relatively low dose.
"...NAM reduced exogenous FA oxidation and increased TAG esterification in skeletal muscle (Fig. 2C and D).We measured the concentration of the intracellular lipid metabolite DAG in skeletal muscle. We found that NAM led to a significant increase in skeletal muscle DAG content compared with controls (Fig. 2E) but no change in ceramide content (Fig. 2F). We also found that NAM caused a significant muscle loss in EDL (Fig. 2G). The present data demonstrate that NAM alters energy substrate preference in skeletal muscle and reduces the capacity of FA oxidation."

"...As expected, NAM treatment decreased SIRT1 mRNA and protein expression in skeletal muscle (Fig. 4C, E and F). The pronounced increase in acetylation level of p53 was observed in NAM-treated mice (Fig. 4D and F). These results suggest that SIRT1 deacetylase activity, including its expression, was inhibited by NAM in skeletal muscle. Meanwhile, NAM increased [NAD+]/[NADH] ratio (Fig. 4A), whereas the total NAD(H) levels in skeletal muscle were not altered."

2. Niacinamide has an effect on muscles similar to androgens. This is also not surprising as I posted about NAM ability to increase both expression and binding affinity of androgen receptor (AR) but the study was in vitro (Niacinamide Is Androgenic And Increases Dht Effects/signaling). Just as androgens do, NAM increased expression of type II muscle fibers (fast twitch) and caused a small decrease in type I muscle fibers (slow twitch). Once again, something very consistent with switching preference to glucose oxidation as opposed to fat oxidation. Ray also mentioned recently in one of his interviews that androgens strongly increase cell preference for sugar as opposed to fat. I also view this as a profoundly positive result, as NAM basically mimics the effects of strength training and/or androgen administration. Combining NAM with something like pregnenolone/DHEA, androsterone, or even progesterone will likely amplify this effect. We may have something close to a gym in a pill with such combinations but I still think strength training has its place in a healthy lifestyle.
"...Furthermore, we found that NAM selectively increased the expression of type II myosin, such as IIa, IIb and IIx, and resulted in a nonsignificant reduction in type I myosin (Fig. 3I). 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."

3. Insulin resistance or diabetes induced by high-fat diet (HFD) are quite different than the what NAM did even though both approaches are characterized by elevated glucose levels. NAM seems to increase blood glucose simply by shifting preference to glucose oxidation while the HFD induced by reducing mitophagy and autophagy (which were actually drastically increased by NAM). It also suggests that NAM could be an anti-obesity agent, potentially at the expense of reduced "insulin sensitivity" but the definition of such sensitivity is obviously problematic and can be quite broad and arbitrary. Finally, high fat diet and resveratrol induced fatty acid oxidation much like the recent studied with cancer and HFD found as well.
"...Strikingly, in the current study, skeletal muscle TAG content correlates negatively with mRNA levels of type I myosin and Cidea (Fig. 5H, R=−0.635; Fig. 5I, R=−0.565). Transcript levels of genes involved in mitophagy and autophagy were reduced by HFD, with an 80% reduction in PINK1 and a 40–50% reduction in NIX, FOXO3 and LC-3b (Fig. 5G). These findings suggest that diet-induced insulin resistance is also associated with the increase in skeletal muscle lipid accumulation, whereas chronic NAM treatment differs greatly from HFD in the associated underlying mechanisms."

"...Here, we investigated the effects of NAM on lipid content in liver and skeletal muscle. We found no pronounced increase in hepatic lipid storage. Instead, NAM increased lipid content and decreased glycogen content in skeletal muscle. Previous studies demonstrated that nonalcoholic fatty liver disease is tightly associated with insulin resistance in nonobese nondiabetic subjects [57]. Intramuscular triglycerides content was inversely related to insulin sensitivity in nonobese humans [58]. These findings suggest that ectopic lipid deposition in nonadipose tissue protects against obesity rather than insulin resistance. Lipotoxicity represents the elevation of lipids and/or lipid metabolites within blood or tissues with subsequent metabolic disorders and contributes to skeletal muscle insulin resistance [59]. In addition, previous studies reported that insulin resistance decreased activation of glycogen synthase in skeletal muscle in young nonobese patients with type 2 diabetes [60]. However, fast-induced insulin resistance in healthy individuals was associated with glycogen accumulation and increased intramuscular lipid content in skeletal muscle [61], suggesting a great difference from nonobese diabetics in glycogen metabolism. 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."

"...Our results indicated that HFD-induced insulin resistance was also related to skeletal muscle lipid accumulation. In contrast to NAM, HFD enhanced the capacity of exogenous FA oxidation, which could be an adaptive response to diet in skeletal muscle. Muscle transcript levels of genes for mitophagy and autophagy were largely repressed by HFD, whereas RSV did not rescue these effects."

"...In conclusion, the present results suggest that long-term treatment with NAM, although at lower dose, leads to glucose intolerance and skeletal muscle lipid accumulation in mice fed regular chow. The findings suggest that NAM-mediated metabolic disorders are related to mitochondrial dysfunction and adaptive responses of mitophagy and autophagy. Although HFD has a similar effect to NAM on glucose homeostasis and skeletal muscle lipid metabolism, HFD differs largely from NAM treatment in the effects on mitophagy, autophagy, Cidea and myosin expression."


TLDR: If there is sufficient amount of fat in your diet, taking the HED of 7.5mg/kg NAM may cause some lipid accumulation in muscle but NO such accumulation liver. High fat diets generally causes both muscle AND liver lipid accumulation and the effects on insulin resistance by HFD and NAM are quite different. Also, NAM inhibits SIRT1 pretty potently even at that low-ish dose and as a result dramatically inhibits fatty acid oxidation (FAO), which shifts the fuel preference over to sugar. The drug Mildronate, with many proven benefits and performance enhancing effects, has the same overall metabolic effects minus the SIRT inhibition. The inhibition by NAM of SIRT1, FAO, and raising of NAD/NADH levels is likely to be very beneficial for a number of degenerative conditions including CVD, neurological conditions, cancer, autoimmune conditions, wasting diseases, etc. NAM may be helpful even as a drug for obesity at the expense of mild lipid accumulation in muscle.

 

[HealthisWealth]

Your making too much sense,you will be labelled dogmatic Peat follower soon.

Keep in mind China is where a lot of niacinamide is produced,it's hugely profitable(billions)and the competition is heating up with producers.
It's a good thing the producers are based in China as its a fair and open society and the government would not try to Influence big business in any way whatsoever with threats of misinformation to hurt prices unless they pay more for example,the lysine and citric acid scandals were one off occurrences.

Do you have the link of those scandals?

 

[Evgenius]

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.

Do we want to impair mitochondrial function, I find this quite concerning about niacinamide.

 

[Wagner83]

So it makes sense that someone who needs to lose weight and a lot of fat would not want to supplement with niacinamide before he oxidized all his fat . Same for someone who has not switched to a low fat diet .

 

[A.R]

So it makes sense that someone who needs to lose weight and a lot of fat would not want to supplement with niacinamide before he oxidized all his fat . Same for someone who has not switched to a low fat diet .

Sorry if I missed it,

But what would be the most effective way to oxidise fat?

 

[haidut]

Do we want to impair mitochondrial function, I find this quite concerning about niacinamide.

They listed some markers of mitochondrial function that niacinamide downregulated but it upregulated others. I need to do more digging on both types before I can say that niacinamide impairs mitochondrial function. It did increase UCP3 levels, which is what drugs like DNP do. So, niacinamide may very well be raising metabolism but increasing heat production.

 

[haidut]

So it makes sense that someone who needs to lose weight and a lot of fat would not want to supplement with niacinamide before he oxidized all his fat . Same for someone who has not switched to a low fat diet .

Not really, no. The study found no change in weight between NAM group and controls. It also said that the accumulation of fat in the muscle is the tradeoff between staying lean and insulin sensitivity. So, the mice on NAM stayed lean at the expense of decreased insulin sensitivity. It's in one of the quotes from the study I provided.

 

[Peater Piper]

Not really, no. The study found no change in weight between NAM group and controls. It also said that the accumulation of fat in the muscle is the tradeoff between staying lean and insulin sensitivity. So, the mice on NAM stayed lean at the expense of decreased insulin sensitivity. It's in one of the quotes from the study I provided.

The controls actually had slightly less fat and more lean body mass, though. The NAM group had more subcutaneous fat. The differences weren't significant, but having slightly more fat, higher triglycerides, FFAs, more insulin, and lower insulin sensitivity doesn't seem like a very good deal, although we're talking about mice, and niacinamide's shown some specific benefits in humans. It seems like, since NAM is limiting not only lipolysis but beta oxidation as well, it would be best to keep dietary fat intake quite low to avoid intramuscular fat deposits, which would hopefully keep insulin sensitivity high.

I'm still not sure why beta oxidation is considered such a negative, assuming PUFA is limited. It seems like most problems are caused when excessive amounts of both FFAs and glucose are in the bloodstream (as in T2 diabetes). Increasing FFAs while lowering glucose tolerance does just that, and it seems like that's what happened here. What makes this favorable over appropriate beta oxidation and improved insulin sensitivity?

Here's a study comparing feeding isocaloric high fat or high carbohydrate diets to mice. The high carbohydrate diet lowered SIRT1, which we're looking at as a positive here, but also increased inflammation and led to hepatic steatosis. Clearly I'm missing something.

Isocaloric Pair-Fed High-Carbohydrate Diet Induced More Hepatic Steatosis and Inflammation than High-Fat Diet Mediated by miR-34a/SIRT1 Axis in Mice : Scientific Reports

 

[Queequeg]

I just started on Niacinamide and now am confused. Why again is it beneficial to lower fat oxidation? I can see that for athletes that this may be good for increased performance but for someone on a normal fat diet (limited PUFA) wouldn't niacinamide just increase fat deposits.

 

[Wagner83]

Not really, no. The study found no change in weight between NAM group and controls. It also said that the accumulation of fat in the muscle is the tradeoff between staying lean and insulin sensitivity. So, the mice on NAM stayed lean at the expense of decreased insulin sensitivity. It's in one of the quotes from the study I provided.

OK so on the "chow" diet (pretty low in fat and high in fiber/complex carbs from what I get) niacinamide did not lead to significant weight gain, just less glycogen in muscles and liver and more fat in muscles. So someone on a pretty low fat high carb diet may not put on weight if niacinamide is supplemented, but wouldn't someone overweight want to burn his fat first rather than keep it stored in muscles ? To me it sounds like niacinamide would slow down the process of burning stored fat quite potently.
Also I heard many times that muscles burn fat at rest, isn't its accumulation within muscles a result of impairing this process?

 

[jyb]

I just started on Niacinamide and now am confused. Why again is it beneficial to lower fat oxidation? I can see that for athletes that this may be good for increased performance but for someone on a normal fat diet (limited PUFA) wouldn't niacinamide just increase fat deposits.

I think the idea is that when taking such supplements you'd be on a very low fat diet so the fat wouldn't get stored. What would be the point of eating fat for energy when you completely kill fatty acid oxidation...

 

[haidut]

The controls actually had slightly less fat and more lean body mass, though. The NAM group had more subcutaneous fat. The differences weren't significant, but having slightly more fat, higher triglycerides, FFAs, more insulin, and lower insulin sensitivity doesn't seem like a very good deal, although we're talking about mice, and niacinamide's shown some specific benefits in humans. It seems like, since NAM is limiting not only lipolysis but beta oxidation as well, it would be best to keep dietary fat intake quite low to avoid intramuscular fat deposits, which would hopefully keep insulin sensitivity high.

I'm still not sure why beta oxidation is considered such a negative, assuming PUFA is limited. It seems like most problems are caused when excessive amounts of both FFAs and glucose are in the bloodstream (as in T2 diabetes). Increasing FFAs while lowering glucose tolerance does just that, and it seems like that's what happened here. What makes this favorable over appropriate beta oxidation and improved insulin sensitivity?

Here's a study comparing feeding isocaloric high fat or high carbohydrate diets to mice. The high carbohydrate diet lowered SIRT1, which we're looking at as a positive here, but also increased inflammation and led to hepatic steatosis. Clearly I'm missing something.

Isocaloric Pair-Fed High-Carbohydrate Diet Induced More Hepatic Steatosis and Inflammation than High-Fat Diet Mediated by miR-34a/SIRT1 Axis in Mice : Scientific Reports

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.

 

[haidut]

I just started on Niacinamide and now am confused. Why again is it beneficial to lower fat oxidation? I can see that for athletes that this may be good for increased performance but for someone on a normal fat diet (limited PUFA) wouldn't niacinamide just increase fat deposits.

Google for "Mildronate" and read up on the benefits of this drug. It is a fatty acid oxidation inhibitor. Also, the studies I posted lately on cancer all point to fat oxidation being both a cause of tumor appearance and accelerator of tumor growth and metastasis.

 

[haidut]

OK so on the "chow" diet (pretty low in fat and high in fiber/complex carbs from what I get) niacinamide did not lead to significant weight gain, just less glycogen in muscles and liver and more fat in muscles. So someone on a pretty low fat high carb diet may not put on weight if niacinamide is supplemented, but wouldn't someone overweight want to burn his fat first rather than keep it stored in muscles ? To me it sounds like niacinamide would slow down the process of burning stored fat quite potently.
Also I heard many times that muscles burn fat at rest, isn't its accumulation within muscles a result of impairing this process?

I think it means that some people may not even need niacinamide. If lipolysis is low (i.e. low-stress lifestyle, not exercising yourself to exhaustion) then you can probably skip the niacinamide. But if you have problems with liver or some other degenerative condition, which is usually characterized by excessive lipolysis then a lipolysis inhibitor and fatty acid oxidation inhibitor like niacinamide or Mildronate may be very beneficial.

 

[Queequeg]

I think the idea is that when taking such supplements you'd be on a very low fat diet so the fat wouldn't get stored. What would be the point of eating fat for energy when you completely kill fatty acid oxidation...

The RP approved food list still contains a lot of fat in it. I wouldn't call a diet that encourages coconut oil, ice cream, butter, fatty meats like oxtails and shanks, and milk as low fat. There has to be something else going on.
Im still reading through this but it is helpful understanding this
Ray Peat, PhD Quotes on Therapeutic Effects of Niacinamide – Functional Performance Systems (FPS)

 

[jyb]

The RP approved food list still contains a lot of fat in it. I wouldn't call a diet that encourages coconut oil, ice cream, butter, fatty meats like oxtails and shanks, and milk as low fat. There has to be something else going on.

I doubt that this list is for those who supplement niacinamide...

 

[Queequeg]

I doubt that this list is for those who supplement niacinamide...

Unless you have a quote or link that says this, then you are just guessing. Again I think that there is more to Niacinamide. I read through the functional alps link and it seems that the main benefit according to Ray is the reduction of PUFA release (lypolysis) and oxidation. He dosn't seem so concerned with SUFAs and says that they are healthful. Also no where does he say to reduce fat intake when taking niacinamide.

 

[Mito]

I'm still not sure why beta oxidation is considered such a negative, assuming PUFA is limited.

Why again is it beneficial to lower fat oxidation?

Ray Peat:

"When fats are oxidized instead of glucose, more oxygen is needed to produce the same amount of energy, and less carbon dioxide is produced. While lactic acid and a more reducing balance in cells activate the excitatory glutamatergic system, an increased concentration of carbon dioxide inhibits that system."

"The use of lactate or beta-hydroxybutyrate as metabolic fuel shifts the balance in the reductive direction, the way ethanol metabolism does."

"Oxidation of sugar is metabolically efficient in many ways, including sparing oxygen consumption. It produces more carbon dioxide than oxidizing fat does, and carbon dioxide has many protective functions, including increasing Krebs cycle activity and inhibiting toxic damage to proteins."