Excess Nicotinamide Induces Reactive Oxygen Species Generation, Insulin Resistance, And Epig

[nathan10000]

Excess Nicotinamide Induces Reactive Oxygen Species Generation, Insulin Resistance, and Epigenetic Change in Rats and Humans
YIMING ZHOU, NANA CHEN, DA LI, WUPING SUN, SHI-SHENG ZHOU
Diabetes 67 (Supplement 1), 783-P, 2018
The implementation of grain fortification with niacin, commonly in the form of nicotinamide, has significantly increased niacin per capita consumption in U.S. from 1930s. Nicotinamide is the precursor of NAD and NADP, which participate in many biological reactions. Therefore, nicotinamide homeostasis is vitally important for the body. This study is to investigate the effects of excess nicotinamide on ROS generation, insulin resistance, and epigenetic change, which are hallmarks of type 2 diabetes.
We found acute nicotinamide overload increased ROS generation, insulin resistance, and reduced muscle glycogen level in adult rats. Besides these effects, long-term nicotinamide overload led to oxidative stress in kidney and liver, increased their DNA damage, and decreased their global DNA methylation profile. We further demonstrated that decreasing nicotinamide degradation and excretion level was crucial for the ROS generation- and insulin resistance-inducing effects using an impaired skin detoxification rat model.
Using oral glucose tolerance test (OGTT), we observed that in healthy volunteers, nicotinamide addition induced higher levels of ROS generation and insulin resistance in the early phase, followed by hypoglycemia in the late phase. Compared to controls, diabetic patients showed a disturbed nicotinamide degradation pattern, characterized by higher plasma N1-methylnicotinamide (NMN) levels and lower urinary degraded metabolite, N1-methyl-2-pyridone-5-carboxamide (2-Py).
Mechanistically nicotinamide degradation process was associated with ROS generation; excess nicotinamide led to higher ROS generation causing kidney and liver damage. We also found that excess nicotinamide disturbed the monoamine neurotransmitters degradation and DNA methylation by competing for the biological methyl-donor, betaine in the body.
In summary, our results indicate that excess nicotinamide may play an important role in type 2 diabetes.

 

[LeeLemonoil]

good find, warrants attention

 

[Kartoffel]

It would be interesting to know what they actually did in that study since there is no information regarding that in the abstract. In most of the rat studies they use crazy high doses that are directly injected into the blood stream. Still, I think any vitamin supplement should always be viewed with care since there is lots of data showing that supplementation with most products is useless at best, and might be harmful.

 

[Wolf]

Sick person requires less than a normal person and same can be said of a rat
I went from 4g daily to 500mg every now and then. Niacinamide.

 

[YourUniverse]

niacinamide != nicotinamide..? implications of nicotine?

 

[yerrag]

Interesting finding. I began taking 30mg/kg dosage per day, which amount to 2100mg/day of niacinamide. I needed to use this dosage for a developing chronic kidney disease condition. After 2 weeks, I upped the dosage to 3000mg/day. I immediately felt different, but I couldn't pin it down. I dialed down the dosage the next day, and I felt better. Usually not feeling well meant a disturbance in my blood sugar level, and maybe in this instance it was.

 

[Kartoffel]

The official daily requirement for b3 is 15-20mg per day. Not saying that this is sufficient but all the doses you mentioned sound rather very large in the context of normal intake via food.

 

[yerrag]

The official daily requirement for b3 is 15-20mg per day. Not saying that this is sufficient but all the doses you mentioned sound rather very large in the context of normal intake via food.

But you seem to have overlooked what necessitated my large dosage levels:

Niacinamide Can Treat Kidney Failure

 

[Kartoffel]

But you seem to have overlooked what necessitated my large dosage levels:

Niacinamide Can Treat Kidney Failure

I am not saying that it can't be therapeutic, or that large doses are neccessarily bad. I am just saying that large, "unphysiological" doses of any synthetic substance can have unforseen consequences depending on the situation in which the body is in.

 

[Kartoffel]

I am not saying that it can't be therapeutic, or that large doses are neccessarily bad. I am just saying that large, "unphysiological" doses of any synthetic vitamine can have unforseen consequences depending on the situation in which the body is in.

 

[yerrag]

I am not saying that it can't be therapeutic, or that large doses are neccessarily bad. I am just saying that large, "unphysiological" doses of any synthetic substance can have unforseen consequences depending on the situation in which the body is in.

I went above therapeutic dosage levels, felt the disturbance, and then dialed down the dosage. There are reasonable ways to be safe, but without going into therapeutic dosage levels, by staying on maintenance levels, one can hardly expect to benefit in terms of correcting a condition.

 

[Amazoniac]

The doses that Abram Hoffer used were insane:
Niacin Therapy Details

Most people don't realize that supplementing 10 mg with every meal is already enough to provide an unusually high amount when you consider what diet already provides.

But this is far from the ranges of internal cycling:
Niacinamide Or Just Plain Niacin?

6-9 g of NAD+ involves about 1.2-1.8 g of nicotinamide.​

In the majority of cases the physiological doses suffice, Abram's therapeutic uses weren't meant to compensate for an impairment in recycling as far as I know.

 

[haidut]

It is hard to comment on a study that is inaccessible. That being said, there have been studies with VERY high doses of niacinamide reversing or significantly delaying diabetes I onset in children, and even in adults. For diabetes II, lower doses in the 300mg-500mg daily are probably sufficient. So, unless I see the protocol they claim they used on their human subjects not much can be discussed.
The increased ROS, decreased muscle glycogen, and decreased methylation are not bad things. We have hundreds of studies on the forum showing the anti-cancer effects of many chemicals like aspirin, MB, progesterone, red light, B2, etc depends heavily on increased ROS generation. In general, increased ROS = increased metabolism, so without seeing the study I cannot say why they thought it was bad.
The decreased muscle glycogen is quite natural effect for a substance that lowers FFA and increases glucose oxidation. What else do you expect muscles to oxidize if you deprive them of fat?? Either glucose or amino acids. Amino acid oxidation was not increased (thank God) so glucose was the only thing remaining. The FAO inhibitor Mildronate has the same effects and I have not seen anybody label those effects as bad.
https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/JP274755
"...Food intake, physical activity and weight gain were not different between meldonium-treated and control rats. However, rats treated with meldonium showed a shift from fatty acids to carbohydrates as the main source for energy production under fed conditions and during starvation. This shift resulted in lower skeletal muscle glycogen stores."

The decreased DNA methylation probably needs no explanation as a good thing. Peat has multiple articles on the topic of overmethylation in cancer and the general aging process. In addition, we have multiple studies on the forum about methionine restriction increasing lifespan and treating obesity/diabetes. Niacinamide is a methyl sink and, similarly to glycine, will deplete the methyl group pool. Extreme depletion is probably not desirable but that would depend on the niainamide dose given, so again, I can't say if their results were legit.
In general, keep in mind that most studies adhere fanatically to the dogma that fat oxidation = good as it "prevents obesity, diabetes, etc". They also view ANY increase in blood glucose as bad since glucose and not fat is seen as the villain in metabolic diseases. But none of these are true, and all the recent drugs that powerfully lower HbA1c have lethal side effects like cancer, ketoacidosis, and increase all cause mortality. Lowering blood glucose kills, sometimes through ketoacidosis, which is the result of diabetes exacerbation these very drugs are designed to treat/prevent.
Study claims low HbA1c increases mortality risk

So, while the mainstream theory on fat = good, glucose = bad is very nice and theoretically consistent in reality it leads to more deaths and disease.
Just my 2c.

 

[Kartoffel]

It is hard to comment on a study that is inaccessible. That being said, there have been studies with VERY high doses of niacinamide reversing or significantly delaying diabetes I onset in children, and even in adults. For diabetes II, lower doses in the 300mg-500mg daily are probably sufficient. So, unless I see the protocol they claim they used on their human subjects not much can be discussed.
The increased ROS, decreased muscle glycogen, and decreased methylation are not bad things. We have hundreds of studies on the forum showing the anti-cancer effects of many chemicals like aspirin, MB, progesterone, red light, B2, etc depends heavily on increased ROS generation. In general, increased ROS = increased metabolism, so without seeing the study I cannot say why they thought it was bad.
The decreased muscle glycogen is quite natural effect for a substance that lowers FFA and increases glucose oxidation. What else do you expect muscles to oxidize if you deprive them of fat?? Either glucose or amino acids. Amino acid oxidation was not increased (thank God) so glucose was the only thing remaining. The FAO inhibitor Mildronate has the same effects and I have not seen anybody label those effects as bad.
https://physoc.onlinelibrary.wiley.com/doi/pdf/10.1113/JP274755
"...Food intake, physical activity and weight gain were not different between meldonium-treated and control rats. However, rats treated with meldonium showed a shift from fatty acids to carbohydrates as the main source for energy production under fed conditions and during starvation. This shift resulted in lower skeletal muscle glycogen stores."

The decreased DNA methylation probably needs no explanation as a good thing. Peat has multiple articles on the topic of overmethylation in cancer and the general aging process. In addition, we have multiple studies on the forum about methionine restriction increasing lifespan and treating obesity/diabetes. Niacinamide is a methyl sink and, similarly to glycine, will deplete the methyl group pool. Extreme depletion is probably not desirable but that would depend on the niainamide dose given, so again, I can't say if their results were legit.
In general, keep in mind that most studies adhere fanatically to the dogma that fat oxidation = good as it "prevents obesity, diabetes, etc". They also view ANY increase in blood glucose as bad since glucose and not fat is seen as the villain in metabolic diseases. But none of these are true, and all the recent drugs that powerfully lower HbA1c have lethal side effects like cancer, ketoacidosis, and increase all cause mortality. Lowering blood glucose kills, sometimes through ketoacidosis, which is the result of diabetes exacerbation these very drugs are designed to treat/prevent.
Study claims low HbA1c increases mortality risk

So, while the mainstream theory on fat = good, glucose = bad is very nice and theoretically consistent in reality it leads to more deaths and disease.
Just my 2c.

How exactely does glycine deplete the methyl group pool? I assume that upregulation of Glycine N-methyltransferase will reduce the methyl pool, and it has been shown that the enzymes is pretty much silenced in various cancers. But is there a clear relationship between glycine intake and the concentration of GNMT? Sorry, if you already discussed this elsewhere.

 

[Terma]

The GNMT increases especially from retinoic acid (lowered by T3 and folate derivatives); honestly I'm not sure to what limit it increases from glycine intake (there is also creatine synthesis) but there must be a limit.

Glycine is really not that comparable to niacinamide for methylation because GNMT is liver-specific enzyme (well some in kidney/pancreas - actually I'm not sure about kidney), so it can't negatively affect the adipose tissue metabolism as directly. Glycine can help FFA levels at those cells by increasing PPARgamma, this way it can help diabetes but without necessarily improving and in some cases even worsening obesity (this is common in the RP forum recommendations).

I really do not believe applying logic for cancer treatments holds for diabetes, sorry. There were new studies and posts from Travis suggesting DNA methylation and the methylation cycles in cells do not necessarily couple. Glycine is probably much safer in all these respects whereas NAD precursors although important I will not consume on the long-term in the Niacinamide form.

 

[Kartoffel]

and in some cases even worsening obesity (this is common in the RP forum recommendations).

Why/how would glycine worsen obesity?

 

[Terma]

Problems with the methylation cycle in the liver may also have to do with short-route BHMT (TMG) vs long-route (folate & B12) recycling, you can tell this because cortisol shifts methylation toward BHMT as does diabetes: Sci-Hub | Effects of diabetes and insulin on betaine-homocysteine S-methyltransferase expression in rat liver. American Journal of Physiology-Endocrinology and Metabolism, 290(5), E933–E939 | 10.1152/ajpendo.00498.2005 (there is a better one somewhere)

I tend to think dysfunctions in the liver methylation cycle are not best addressed with niacinamide - in the best case - while glycine is simply essential to it and further (consider other factors such as the body-wide 10g collagen synthesis shortfall study, and the fact the body evolved exposed to high glycine from time to time, and you see a better sense of safety or at least buffers).

 

[haidut]

How exactely does glycine deplete the methyl group pool? I assume that upregulation of Glycine N-methyltransferase will reduce the methyl pool, and it has been shown that the enzymes is pretty much silenced in various cancers. But is there a clear relationship between glycine intake and the concentration of GNMT? Sorry, if you already discussed this elsewhere.

Yes, glycine stimulates methionine excretion via GNMT.
https://www.fasebj.org/doi/abs/10.1096/fasebj.25.1_supplement.528.2

I think glycine also inhibits methionine absorption from diet but I can't find that study right now.

 

[Terma]

Why/how would glycine worsen obesity?

It's a feature of PPARgamma agonists. It's actually the mainstay mainstream treatment for diabetes, same as several things on this forum but more toxic. PPARgamma increases differentiation of fat cells. So it works partly by repartitioning the calorie load so individual fat cells are less hypertrophic and inflammatory, healthier, and can suck up more FFAs (though iirc it also does this in another way).

My memory is sketchy on this part, but PPARgamma increases some hormones (was it adiponectin?) to compensate for the fat storage in healthy people. In obese people some of that hormonal signaling is damaged, so they miss the compensation. (Furthermore in some cases it possibly appears worse due to the toxicity of the drugs, but it will happen anyway)

[Irrc chronic high baseline insulin was possibly one of the issues, can't look it up right now; in non-storage conditions PPARgamma actually facilitates FFA release]

 

[Kartoffel]

It's a feature of PPARgamma agonists. It's actually the mainstay mainstream treatment for diabetes, same as several things on this forum but more toxic. PPARgamma increases differentiation of fat cells. So it works partly by repartitioning the calorie load so individual fat cells are less hypertrophic and inflammatory, healthier, and can suck up more FFAs (though iirc it also does this in another way).

My memory is sketchy on this part, but PPARgamma increases some hormones (was it adiponectin?) to compensate for the fat storage in healthy people. In obese people some of that hormonal signaling is damaged, so they miss the compensation. (Furthermore in some cases it possibly appears worse due to the toxicity of the drugs, but it will happen anyway)

Thanks, I'll look into that.

Yes, glycine stimulates methionine excretion via GNMT.
https://www.fasebj.org/doi/abs/10.1096/fasebj.25.1_supplement.528.2

I think glycine also inhibits methionine absorption from diet but I can't find that study right now.

Thanks. Do you think there are any good reasons not to use rather high doses of glycine to prevent/reverse degenerative conditions such as colitis or liver damage? Several studies have used doses with human equivalents ranging from 20-50g to successfully treat these things.