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

[nathan10000]

As I asked above, I'm not sure how much oxidation really happens in muscle compared to the rest of the body's metabolism. It stands to reason that fast twitch fibres should work in a reduced energy state, because they are not endurance muscles, they have brief but high rates of contractile output.

If your muscles needed sugar constantly, all strength would be lost as soon as glycogen was depleted. This evidently is not the case.

Niacinamide seems to be aiding the effect of getting more from less, by keeping the muscle in a reduced state where it starts to actually store fat for fast twitch contractions. I did not realise this was even possible. I thought the common explanation was that you had to train the fibres to become bigger in order to hold more glycogen and thereby become stronger. Perhaps this is actually inefficient.

I have witnessed first hand a friend resolve their advanced NAFL disease with 500mg niacinamide/day. I do not think it creates liver problems, research indicates the complete opposite.

It doesnt create problem for the liver as you can see from the study, it saves the liver at the expense of muscle. Sooner or later liver wont be able to compensate.

 

[nathan10000]

What makes you say high blood glucose would be a normal consequence of shifting metabolism towards glucose oxidation rather than fat (even in muscles)?
How reducing fatty acids oxidation and increasing fat content in muscles would result in an "anti obesity" agent?

Again, at low doses niacinamide caused lipid accumulation and potently reduced FAO , so unless someone is lean and switches to a no fat diet I don't see why it would be beneficial to supplement with it.

To me it looks like a powerful tool that shouldn't be messed with unless someone has a very specific condition.



Ok but if it shifts the metabolism towards more glucose oxidation, your liver works well to store glycogen , and overall your body uses glucose efficiently I don't see why would you put on fat. It also sounds like FFA acids would increase if one consumes fat while supplementing with NAM

Niacinamide causes increase lipolysis even compared to control not specifically need to be on fat diet.

 

[chispas]

It doesnt create problem for the liver as you can see from the study, it saves the liver at the expense of muscle. Sooner or later liver wont be able to compensate.

At the expense? What expense? The muscle seems quite willing and able to function in glycolyic conditions. In fact, it seems preferable for some circumstances.

Never heard of hepatoxicity acquired from self administration of B3 long term in humans. Provide the evidence. This is a six week long study on rats eating crap food.

 

[nathan10000]

At the expense? What expense? The muscle seems quite willing and able to function in glycolyic conditions. In fact, it seems preferable for some circumstances.

Never heard of hepatoxicity acquired from self administration of B3 long term in humans. Provide the evidence. This is a six week long study on rats eating crap food.

Ya, i am sure that the increase lipolysis with high FFA,TG is good for liver.

 

[chispas]

Ya, i am sure that the increase lipolysis with high FFA,TG is good for liver.

Maybe things are less simplistic than you imagine. You seem to be correlating several seperate factors together. On what evidence do these factors constitute a field? How do you know that the body isn't more sophisticated in its handing of these different factors?

For a long time, people said ribose was a sugar like any other. They said the body had no way of identifying it as different from any other carbohydrate. This turned out to be patently false. Ribose is a special substance and the body knows what's good for it.

Just because your work out states one conclusion, does not prove anything across the board.

I think Ray proves the coherence of his philosophy by demonstrating the relevance of various protective substances to a range of circumstances. He writes from a general perspective that leads to a specific one. You are taking a specific case and constructing a generalisation. You need to show more evidence.

 

[nathan10000]

Maybe things are less simplistic than you imagine. You seem to be correlating several seperate factors together. On what evidence do these factors constitute a field? How do you know that the body isn't more sophisticated in its handing of these different factors?

For a long time, people said ribose was a sugar like any other. They said the body had no way of identifying it as different from any other carbohydrate. This turned out to be patently false. Ribose is a special substance and the body knows what's good for it.

For the evidence refer the paper. Ya, this is the same case like ribose. For a long time, some people said niacinamide inhibit lipolysis which turned out not to be true. "

Just because your work out states one conclusion, does not prove anything across the board.

I think Ray proves the coherence of his philosophy by demonstrating the relevance of various protective substances to a range of circumstances. He writes from a general perspective that leads to a specific one. You are taking a specific case and constructing a generalisation. You need to show more evidence.

Thanks to the researcher for finally clarifying about niacinamide. Ray advise to inhibit FFA , in the case of niacinamide its not useful for that purpose.

 

[haidut]

I was under the impression that type II fast twitch fibres are actually "fast" while the body is in a glycolitic state. Once muscles get hold of too much glucose as metabolism upregulates to an oxidative state, the slower type I fibres take precedence in doing the work. Over time, as the fascia structure of the muscle changes, type II fibres can even change to become slow as well. I can find you the research on this if you're interested.

If B3 is putting fat into the muscle and giving precedence to type II fast twitch fibres, is it sensible to infer that it is undesirable to try to make the body's muscles use glycogen? To my mind, this can only result in big, slow-twitch, powerlifter-style muscles.

Type I fiber is what you find predominantly in endurance athletes, at least that's my information.

 

[Agent207]

Nope, you are ruining the benefit of exercise as there is reduction in oxidation. You want a preworkout stack that increase lipolysis and increase oxidation.

Niacinamide causes increase lipolysis even compared to control not specifically need to be on fat diet.

So what then?

Btw, for strength anaerobic training I'm looking towards glycolysis over lipolysis.

 

[haidut]

I thought the main purpose to take niacinamide is to reduce lipolysis but the truth is it actually increase lipolysis and at the same time reduce oxidation in the muscle which is a dangerous combination. It is shifting your TG from adipose tissue to the muscle but not to the liver. So you are just buying more time, the liver will compensate for the increased lipolysis but eventually it lead to fatty liver.

Niacinamide is worse than high fat diet, at least in high fat diet muscle try to adapt by increasing fatty acid oxidation whereas niacinamide you have lower oxidation in the musle.
"HFD significantly enhanced FA oxidation (Fig. 5D), suggesting an active response to diets in skeletal muscle."

Look at the 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."

Is it fine to take a supplement which ruins your glucose control and increase lipid in your muscle?

Where did you get this idea that NAM was worse than HFD? I agree that the study shows niacinamide decreased insulin sensitivity, but HFD did a lot of other bad things while NAM had largely opposite effects on those biomarkers.
"...HFD significantly enhances FA oxidation (Fig. 5D), suggesting an active response to diets in skeletal muscle. HFD significantly reduced the expression of myosin I, IIa, IIb and IIx, whereas the decrease of myosin I and IIx was rescued by RSV (Fig. 5E). Gidea expression was depressed by HFD, but this reduction was strongly attenuated by RSV 9Fig. 5F). In white adipose tissue, Gidea expression correlates positively with lipid deposition and insulin sensitivity [47]. Strikingly, in the current study, skeletal muscle TAG concent correlates negativelt with mRNA levels of type I myosin and Cidea. Transcript levels of genes involved in mitophagy and autophagy were reduced by HFD, with an 80% reduction in PINK1 and 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."

NAM simply reduces FAO and the excess fat goes to the muscle as subcutaneous fat. HFD not only deposits fat everywhere, including the liver and abdominal area, but also reduced mitophagy and autophagy, and expression of all myosin types. NAM promoted the type II fibers and inhibited the type I.
I suppose if you believe that promoting FAO is a good thing then NAM is looking bad to you in that study. But advising people to increase lipolysis and FAO before exercise is dangerous IMO. Endurance athletes have the highest incidence of NAFLD, and there is a good reason for that - increased lipolysis.

 

[Agent207]

What is the mechanism by why niacinamide decreases insulin sensivity? And is there any other factors or circumstances to take into account for this effect?

 

[haidut]

For the evidence refer the paper. Ya, this is the same case like ribose. For a long time, some people said niacinamide inhibit lipolysis which turned out not to be true. "


Thanks to the researcher for finally clarifying about niacinamide. Ray advise to inhibit FFA , in the case of niacinamide its not useful for that purpose.

Niacinamide itself may not have a direct inhibitory effect on lipolysis but its metabolite NAD does. It is in fact one of the most potent inhibitors of lipolysis known, inhibiting lipolysis by 96% at 100uM concentration, which is achievable with a few grams of niacinamide (see attached screenshot). Interestingly, adenosine (and thus inosine) was just as potent as NAD, which could explain the performance benefits of inosine and its (ab)use by athletes. Niacinamide is much more effective than niacin in raising NAD, so while I am not discounting the findings of this study above, one study is not enough to counter the beneficial effects of niacinamide.
The effect of Nicotinamide Adenine Dinucleotide on lipolysis in adipose tissue in vitro
"...Under the conditions of the study, NAD was shown to be a potent inhibitor of the norepinephrine-induced fatty acid release from adipose tissue (Table I). This inhibition was proportional to concentration overa range of 10 4 to 10 7M. NAD is composed of nicotinamide mononucleotide (NMN) and Y-AMP joined through a pyrophosphate bridge. NMN itself was a comparatively weak inhibitor of fatty acid release as was nicotinamide. Nicotinic acid, on the other hand, was a very potent inhibitor."

"...KAPLAN et al. 12 have demonstrated that both nicotinic acid and nicotinamide can be incorporated into mouse liver NAD. However, nicotinamide appears to be approximately five times as effective as nicotinic acid in elevating liver NAD."


What is more important, NAM inhibits/prevent the wasteful conversion of glucose into fat, which suggests inhibition of the enzyme fatty acid synthase (FAS), which Ray has written about and is likely a curative target for cancer and diabetes.
[Effects of nicotinamide and oxythiamine on the lipogenic parameters of the adipose tissue of mice with non-insulin-dependent type of experimental ... - PubMed - NCBI
"...The influence of nicotinamide and oxythiamine on the activity of NADPH-producing dehydrogenases of glucoso-6-phosphate, 6-phosphogluconate, malate, isocitrate, as well as concentration and synthesis rate of fatty acids in fatty tissue were studied in experiments on mice with genetically conditioned non-insulin-dependent diabetes and hyperinsulinemia. It has been established that in these diseases the synthesis of fatty acids and their inclusion into lipids are activated without increasing the above enzymes activity. It is shown that nicotinamide and oxythiamine inhibit inclusion of C from glucose into free fatty acids, antivitamin intensifies lipolysis in the fatty tissue of the diseased animals."

 

[nathan10000]

Where did you get this idea that NAM was worse than HFD? I agree that the study shows niacinamide decreased insulin sensitivity, but HFD did a lot of other bad things while NAM had largely opposite effects on those biomarkers.
"...HFD significantly enhances FA oxidation (Fig. 5D), suggesting an active response to diets in skeletal muscle. HFD significantly reduced the expression of myosin I, IIa, IIb and IIx, whereas the decrease of myosin I and IIx was rescued by RSV (Fig. 5E). Gidea expression was depressed by HFD, but this reduction was strongly attenuated by RSV 9Fig. 5F). In white adipose tissue, Gidea expression correlates positively with lipid deposition and insulin sensitivity [47]. Strikingly, in the current study, skeletal muscle TAG concent correlates negativelt with mRNA levels of type I myosin and Cidea. Transcript levels of genes involved in mitophagy and autophagy were reduced by HFD, with an 80% reduction in PINK1 and 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."

NAM simply reduces FAO and the excess fat goes to the muscle as subcutaneous fat. HFD not only deposits fat everywhere, including the liver and abdominal area, but also reduced mitophagy and autophagy, and expression of all myosin types. NAM promoted the type II fibers and inhibited the type I.
I suppose if you believe that promoting FAO is a good thing then NAM is looking bad to you in that study. But advising people to increase lipolysis and FAO before exercise is dangerous IMO. Endurance athletes have the highest incidence of NAFLD, and there is a good reason for that - increased lipolysis.

I totally agree HFD is way worse than NAM is you compare all the side effects. I was only referring to FAO and lipolysis in my statement. Yes, endurance athletes are causing too much stress to the metabolism which is not advised. The person is asking about prework stack which is usually referred to strength training/bodybuilder. My point is dont overdo lipolysis or oxidation.

 

[nathan10000]

Niacinamide itself may not have a direct inhibitory effect on lipolysis but its metabolite NAD does. It is in fact one of the most potent inhibitors of lipolysis known, inhibiting lipolysis by 96% at 100uM concentration, which is achievable with a few grams of niacinamide (see attached screenshot). Interestingly, adenosine (and thus inosine) was just as potent as NAD, which could explain the performance benefits of inosine and its (ab)use by athletes. Niacinamide is much more effective than niacin in raising NAD, so while I am not discounting the findings of this study above, one study is not enough to counter the beneficial effects of niacinamide.
The effect of Nicotinamide Adenine Dinucleotide on lipolysis in adipose tissue in vitro
"...Under the conditions of the study, NAD was shown to be a potent inhibitor of the norepinephrine-induced fatty acid release from adipose tissue (Table I). This inhibition was proportional to concentration overa range of 10 4 to 10 7M. NAD is composed of nicotinamide mononucleotide (NMN) and Y-AMP joined through a pyrophosphate bridge. NMN itself was a comparatively weak inhibitor of fatty acid release as was nicotinamide. Nicotinic acid, on the other hand, was a very potent inhibitor."

What is more important, NAM inhibits/prevent the wasteful conversion of glucose into fat, which suggests inhibition of the enzyme fatty acid synthase (FAS), which Ray has written about and is likely a curative target for cancer and diabetes.
[Effects of nicotinamide and oxythiamine on the lipogenic parameters of the adipose tissue of mice with non-insulin-dependent type of experimental ... - PubMed - NCBI
"...The influence of nicotinamide and oxythiamine on the activity of NADPH-producing dehydrogenases of glucoso-6-phosphate, 6-phosphogluconate, malate, isocitrate, as well as concentration and synthesis rate of fatty acids in fatty tissue were studied in experiments on mice with genetically conditioned non-insulin-dependent diabetes and hyperinsulinemia. It has been established that in these diseases the synthesis of fatty acids and their inclusion into lipids are activated without increasing the above enzymes activity. It is shown that nicotinamide and oxythiamine inhibit inclusion of C from glucose into free fatty acids, antivitamin intensifies lipolysis in the fatty tissue of the diseased animals."

This is one of the latest study taking into account previous papers describing benefit of NAM. The whole study was done to better understanding the conflicting result of previous studies. The conclusion is it does increase FFA, TG, and lipolysis and it worsen insulin sensitivity. Now we need to find something better to inhibit lipolysis.

 

[haidut]

What is the mechanism by why niacinamide decreases insulin sensivity? And is there any other factors or circumstances to take into account for this effect?

Probably the increased lipolysis seen in this study. Increased lipolysis is well established to decrease insulin sensitivity, and they even mention fasting as another way to do it in healthy individuals.
"...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."

So, this could be due to some species difference in how niacinamide affects lipolysis as increase in NAD should lower lipolysis. At least it does in humans. There are studies using NAD injections directly in humans and it does lower lipolysis. It would be nice to see a direct study with niacinamide, but the human ones with diabetes already showed improvement in lipolysis and adipose tissue accumulation, so this is why this study is such a surprise.

 

[nathan10000]

NAM simply reduces FAO and the excess fat goes to the muscle as subcutaneous fat.

I wont be worried of subcutaneous fat. This is intracellular lipid which decrease insulin sensitivity.

"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"

 

[nathan10000]

Probably the increased lipolysis seen in this study. Increased lipolysis is well established to decrease insulin sensitivity, and they even mention fasting as another way to do it in healthy individuals.
"...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."

Ya but with glycogen accumulation.
but NAM causes decrease in liver and muscle glycogen.

 

[haidut]

Ya but with glycogen accumulation.
but NAM causes decrease in liver and muscle glycogen.

Yes, glycogen accumulation is not always a good thing. In the presence of increased lipolysis, which stimulates gluconeogenesis, it is a symptoms of diabetes.
Liver Disease and Diabetes Mellitus
"...Excess glycogen accumulation in the liver is seen in 80% of diabetic patients. Glycogen synthesis in the liver is impaired in diabetes due to defective activation of glycogen synthase. However, studies attesting to this were usually performed on animals with recently induced diabetes. In patients with chronic diabetes, glycogen accumulation is seen, and it is postulated that long-standing insulin deficiency may actually facilitate synthase activity. This and enhanced gluconeogenesis may account for the net accumulation of glycogen in diabetes."

Of course NAM will lead to lower glycogen if it inhibits FAO. What else are you supposed to oxidize to generate ATP? As the study says, NAM switches cell preference from fat to glucose, while increasing muscle accumulation of TG. HFD increases TG accumulation everywhere and makes the cells prefer fat for fuel with resulting increase in FAO. The latter one is what diabetes is - inability of cells to oxidize glucose due to excess fat making the cell prefer fat as a result of the Randle cycle. Elevated blood glucose levels in the blood are not necessarily indicative of pathology as long as that glucose is being oxidized. NAM promotes that activity. The only troubling thing is the increased lipolysis and on that point I would like to see more research. NAM has been shown to lower lipolysis in humans, so I am hoping that it is just a species difference effect.

 

[Agent207]

Probably the increased lipolysis seen in this study.

But could the increase in lipolysis be the consequence of greater glycogen usage under endurance or continuous stress, and faster depletion then?

"But be careful: Niacin can lower your level of athletic performance. It is interesting to note that, although niacin is essential for cell respiration process and the allocation of energy study the role of athletes has clearly shown that in some versions of niacin will reset the level of sporting achievements. If you take excessive doses of niacin before class, then your glycogen stores will be run out soon and you will soon feel the fatigue. During exercise, niacin, apparently prevents the release of fatty acids from fat deposits in the body and makes the energy source slozhnodostupnym. So way, the athletes whose sport special requests endurance, to avoid an overdose of niacin. But it is equally obvious that the highest dose of niacinamide taken before anaerobic exercise, can improve athletic performance, which is due to the fact that these athletes are an enormous part of the energy consuming its own muscle glycogen stores, and accelerated release of glycogen can lead to improved anaerobic energy release. Most researchers agree with these conclusions."

The Edge


For this kind of things it would be great to have a continuous glucose monitor.

 

[haidut]

But could the increase in lipolysis be the consequence of greater glycogen usage under endurance or continuous stress, and faster depletion then?

For this kind of things it would be great to have a continuous glucose monitor.

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

 

[nathan10000]

Yes, glycogen accumulation is not always a good thing. In the presence of increased lipolysis, which stimulates gluconeogenesis, it is a symptoms of diabetes.
Liver Disease and Diabetes Mellitus
"...Excess glycogen accumulation in the liver is seen in 80% of diabetic patients. Glycogen synthesis in the liver is impaired in diabetes due to defective activation of glycogen synthase. However, studies attesting to this were usually performed on animals with recently induced diabetes. In patients with chronic diabetes, glycogen accumulation is seen, and it is postulated that long-standing insulin deficiency may actually facilitate synthase activity. This and enhanced gluconeogenesis may account for the net accumulation of glycogen in diabetes."

Of course NAM will lead to lower glycogen if it inhibits FAO. What else are you supposed to oxidize to generate ATP? As the study says, NAM switches cell preference from fat to glucose, while increasing muscle accumulation of TG. HFD increases TG accumulation everywhere and makes the cells prefer fat for fuel with resulting increase in FAO. The latter one is what diabetes is - inability of cells to oxidize glucose due to excess fat making the cell prefer fat as a result of the Randle cycle. Elevated blood glucose levels in the blood are not necessarily indicative of pathology as long as that glucose is being oxidized. NAM promotes that activity. The only troubling thing is the increased lipolysis and on that point I would like to see more research. NAM has been shown to lower lipolysis in humans, so I am hoping that it is just a species difference effect.

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.....