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

[Regina]

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.

Fabulous thread!! Haidut, I remember in one of your interviews with Danny Roddy, you referred to lipolysis as something like a wolf in sheep's clothing.
I think I did the same thing as A.R. above going back to aikido while on The Perfect Health Diet (which includes intermittent fasting and low fructose). At least, I think I catabolized whatever shred of PUFA that was left in me. I was probably like one of those fasted mice with high GH and prolactin and everything else. Thankfully, I wasn't euthanized and I crawled over to Peating. Re-inflated but in a good way. Thank you

 

[bdawg]

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.

How do you explain SSRI induced weight gain?

 

[A.R]

Fabulous thread!! Haidut, I remember in one of your interviews with Danny Roddy, you referred to lipolysis as something like a wolf in sheep's clothing.
I think I did the same thing as A.R. above going back to aikido while on The Perfect Health Diet (which includes intermittent fasting and low fructose). At least, I think I catabolized whatever shred of PUFA that was left in me. I was probably like one of those fasted mice with high GH and prolactin and everything else. Thankfully, I wasn't euthanized and I crawled over to Peating. Re-inflated but in a good way. Thank you

It's great for you that you was able to find peat in the catabolised state, and re inflated your body with goodness.

 

[Drareg]

This is a referenced study (61) from the original study posted.

Insulin resistance after a 72-h fast is associated with impaired AS160 phosphorylation and accumulation of lipid and glycogen in human skeletal muscle | Endocrinology and Metabolism


"During fasting, human skeletal muscle depends on lipid oxidation for its energy substrate metabolism. This is associated with the development of insulin resistance and a subsequent reduction of insulin-stimulated glucose uptake. The underlying mechanisms controlling insulin action on skeletal muscle under these conditions are unresolved. In a randomized design, we investigated eight healthy subjects after a 72-h fast compared with a 10-h overnight fast. Insulin action on skeletal muscle was assessed by a hyperinsulinemic euglycemic clamp and by determining insulin signaling to glucose transport. In addition, substrate oxidation, skeletal muscle lipid content, regulation of glycogen synthesis, and AMPK signaling were assessed. Skeletal muscle insulin sensitivity was reduced profoundly in response to a 72-h fast and substrate oxidation shifted to predominantly lipid oxidation. This was associated with accumulation of both lipid and glycogen in skeletal muscle. Intracellular insulin signaling to glucose transport was impaired by regulation of phosphorylation at specific sites on AS160 but not TBC1D1, both key regulators of glucose uptake. In contrast, fasting did not impact phosphorylation of AMPK or insulin regulation of Akt, both of which are established upstream kinases of AS160. These findings show that insulin resistance in muscles from healthy individuals is associated with suppression of site-specific phosphorylation of AS160, without Akt or AMPK being affected. This impairment of AS160 phosphorylation, in combination with glycogen accumulation and increased intramuscular lipid content, may provide the underlying mechanisms for resistance to insulin in skeletal muscle after a prolonged fast".

"prolonged fasting is associated with reduced sensitivity to insulin (30). This phenomenon was first described in 1859 by Claude Bernard (3) and was termed “starvation diabetes.” Insulin resistance in skeletal muscle plays a key role in this adaptive response (4). During fasting, skeletal muscle switches its energy substrate metabolism predominantly to oxidation of lipids (30), and insulin-stimulated glucose uptake in skeletal muscle is reduced"

 

[Agent207]

72h? Who the hell fasts 3 days in a row? I think occasional fasting, like 24h. no more than once in a month will have some benefits like purgating/detoxifying, with no negative impact on metabolism. On a healthy system, I see fasting as another hormetic tool -like exercise- which to ripe benefits from, when done right.

On the other side, for a daily basis I also see desirable to limit the "eating window" to around 12 hours, half of the day.

 

[haidut]

How do you explain SSRI induced weight gain?

It's not a good weight gain, it is mostly fat. Anti-dopaminergic drugs are notorious for causing weight gain due to lowered metabolism and if SSRI have systemic anti-dopamine effects then this weight gain is to be expected. The weight gain from serotonin antagonists is usually not just fat. Many bodybuilders use ketotifen and cypro to gain muscle.

 

[whodathunkit]

Ha this is like a description of every Peat Supplement I have tried, at least at first. Caffeine/B vitamins/ fat soluble vitamins/protein/calcium/raw carrot is great! I feel like crap on it!

I know, right? LOL

Worth noting is that many supps that have disagreed with me initially I can circle back around to after I get some metabolic things fixed and have success. Progesterone is one Peat thing that didn't used to work for me and now does, CoQ10 is a non-Peat thing, etc. Perhaps this has happened to you.

Niacin/niacinimide seems to be the lone holdout. I did a niacin experiement a couple years ago that did okay in the beginning but then it crashed my thyroid and it's been back to square one.

All the reading I've done on niacin and its derivatives makes me think like maybe it just isn't the best idea, at least not for people who need to lose weight. Maybe for lean people who want to get a little healthier. Peat seems like he's always been a pretty moderate person and never had or driven himself to the metabolic problems some of us have around here.

 

[Agent207]

Peat seems like he's always been a pretty moderate person and never had or driven himself to the metabolic problems some of us have around here.

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.

 

[A.R]

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 :)

You mention how niacinamide and mildronate have similar effects, would you know why athletes don't take niacinamide instead as a legal alternative?

 

[whodathunkit]

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

Good point. I didn't know that about the WGO! Peat's a reformed PUFA-holic.

Seriously..by moderate I mean he's never been overweight or had a problem with food or other addictive substances that drive many of us to metabolic hell. Coffee notwithstanding. And coffee is a pretty mild thing to overdo, on the whole. It conveys benefits even when overdone...both my parents were coffee hounds to that extent for a long time, and my 80 y/o mother's blood sugar regulation is still better than mine.

I often wonder what my body and life would be like today if I hadn't overeaten to the extent that I did, for so many years. When I quit drinking and drugging I turned to food, and that's when the problems really began.

Don't let most overweight people tell you they eat almost nothing. That may be true after a period of time when the metabolism is so screwed it can't work right, but most heavy people have done a big bunch of overeating, for a very long time, before they reach that point. Plus, people notoriously under-report what they eat.

Gluttony crashes everything, starting with the liver function and digestion. It's a downward spiral from there.

 

[Wagner83]

I think you are wrong about Peat. He got badly irradiated at 5, and had very strong migraine problems depending on when and what he ate. He was susceptible to many problems similar to women and I think this is partly what got him into researching this field. When you are prone to frequent migraine finding solutions is a holy grail of relief from what I see. He has had strong allergic reactions to various foods (e.g. an ice cream which formula was changed to include carraghenan) and supplements. This is probably one of the reasons (along with what he noticed in people he interacted with) why he is very careful with the foods and supplements he picks. He also had to eat thousands and thousands (was it 10 000?) of calories at some point in his youth .

 

[whodathunkit]

@Wagner83: women problems don't have much to do with it. Why on earth would you bring that up? I was referring to an individual's ability to be moderate or not in their behaviors. Immoderation isn't a trait peculiar to women, and moderation isn't a trait peculiar to men. Women may have more of a proclivity to gain a bit of weight because of body and hormone composition, but all truly overweight people have a problem with moderation that transcends a person's sex.

AFAIK Peat has never been overweight or had a problem with drug or alcohol abuse. Although maybe he dabbled in a little too much LSD back in the day. But even that's not really addicting. Too stimulating while at the same time being non-functional. You can't pass through everyday life while you're tripping. Me and my friends all used acid when we were younger and none of us got hooked on it the way we did weed, coke, or alcohol.

Point is, again, that moderation or lack of it isn't restricted to one sex or the other. Bringing up sex is irrelevant to that part of this discussion.

 

[haidut]

You mention how niacinamide and mildronate have similar effects, would you know why athletes don't take niacinamide instead as a legal alternative?

A number of reasons, the two big ones being that up until now there was really no study on niacinamide and how it affects all of these various biomarkers similarly to Mildronate. To most people, including sports doctors, niacinamide is a puny, ineffective vitamin
Second reason is that Mildronate has been in use for decades as performance enhancing drug so a top athlete would likely go with something that is known to work instead of experimenting with vitamins. However, given that Mildronate is now banned by WADA, is somebody in sports were to read this forum they may start spreading the words that niacinamide on its own or especially in combination with inosine may very well give Mildronate a run or its money, and it is also unbannable and probably undetectable even if abused.

 

[Regina]

A number of reasons, the two big ones being that up until now there was really no study on niacinamide and how it affects all of these various biomarkers similarly to Mildronate. To most people, including sports doctors, niacinamide is a puny, ineffective vitamin :)
Second reason is that Mildronate has been in use for decades as performance enhancing drug so a top athlete would likely go with something that is known to work instead of experimenting with vitamins. However, given that Mildronate is now banned by WADA, is somebody in sports were to read this forum they may start spreading the words that niacinamide on its own or especially in combination with inosine may very well give Mildronate a run or its money, and it is also unbannable and probably undetectable even if abused.

sssshhhhhh. Nothing to see here.

 

[Regina]

It's great for you that you was able to find peat in the catabolised state, and re inflated your body with goodness.

Thank you. I'm very grateful.
I switched to 0% milk and ramped up my fruit intake and that halted the chubbiness.

 

[A.R]

A number of reasons, the two big ones being that up until now there was really no study on niacinamide and how it affects all of these various biomarkers similarly to Mildronate. To most people, including sports doctors, niacinamide is a puny, ineffective vitamin :)
Second reason is that Mildronate has been in use for decades as performance enhancing drug so a top athlete would likely go with something that is known to work instead of experimenting with vitamins. However, given that Mildronate is now banned by WADA, is somebody in sports were to read this forum they may start spreading the words that niacinamide on its own or especially in combination with inosine may very well give Mildronate a run or its money, and it is also unbannable and probably undetectable even if abused.

Excellent, thank You

 

[bdawg]

It's not a good weight gain, it is mostly fat. Anti-dopaminergic drugs are notorious for causing weight gain due to lowered metabolism and if SSRI have systemic anti-dopamine effects then this weight gain is to be expected. The weight gain from serotonin antagonists is usually not just fat. Many bodybuilders use ketotifen and cypro to gain muscle.

lowered metabolism, thats true.

I know this isnt related to the main topic, but do you suspect SSRIs also paradoxically work as anti-serotonin agents because of everyday doses causing serotonin downregulation for a long period of time?

This kind of mirrors their therapeutic effects kicking in after a month or so, which is enough time for the receptors to downregulate after being bombarded on a daily basis

 

[haidut]

lowered metabolism, thats true.

I know this isnt related to the main topic, but do you suspect SSRIs also paradoxically work as anti-serotonin agents because of everyday doses causing serotonin downregulation for a long period of time?

This kind of mirrors their therapeutic effects kicking in after a month or so, which is enough time for the receptors to downregulate after being bombarded on a daily basis

Many of the successful SSRI drugs are actually proven antagonists on the 5-HT2C receptor. I posted a thread on this long time ago. So, their antidepressant effects are probably due to the antagonism of 5-HT2C even though their systemic effect is still serotonergic.

 

[Wagner83]

..

I'm not sure what you read in my post, but I was only replying to the idea that Peat did not have any troubles with foods or metabolism. I think he did and that's partly what got him curious about it, I highlighted a few things. As you said (and I can only agree with that) he doesn't sound like he ever got addicted and that fits quite well with his anti authoritarian personnality.
Anyways, I won't derail the thread further.

 

[whodathunkit]

He was susceptible to many problems similar to women

No prob. :)