43 replies to this topic

[jwilcox25]

Is there a reason to avoid combining these?  I currently take 500mg nicotinic acid (full flush variety) in the morning together with 250mg NR.  Wondering if there is reason not to combine or to change dosing schedule

[PeaceAndProsperity]

NR is useless. Nicotinic acid is all you need of the vitamin B3 vitaminers. NR is an overhyped, patented "drug." It does nothing good.

NA is even superior to NR's supposed benefits, in many respects

[able]

Good question - I hope it generates some discussion.

 

I've been taking 250-500 mg NR for 18 months.

 

Added NA and NAM about 4 months ago myself.

 

Started with 250 mg NA, and built tolerance up to 750mg twice a day before flush gets too much.

 

It makes a HUGE difference in energy for me.  

 

Maybe NR would do the same, but I can't afford that much.

 

From all I've read, it makes sense to me to combine them.

 

 

[stefan_001]

 

From all I've read, it makes sense to me to combine them.

 

Where did you read that?

[Michael]

I wouldn't so much comment on the wisdom of combining NA with NR, as council against the use of NA. After all these years, it's still not clear whether NA reduces risk of cardiovascular events in people at high risk (ie, in the people in whom you'd most expect it to benefit) — and, in the meantime, it's now pretty clear that it raises the risk of diabetes:
 

Niacin therapy and the risk of new-onset diabetes: a meta-analysis of randomised controlled trials
 
... We included trials with ≥50 non-diabetic participants and average follow-up of ≥24 weeks. Published data were tabulated and unpublished data sought from investigators. We calculated risk ratios (RR) for new-onset diabetes with random-effects meta-analysis. ...
 
Results In 11 trials with 26,340 non-diabetic participants, 1371 (725/13,121 assigned niacin; 646/13,219 assigned control) were diagnosed with diabetes during a weighted mean follow-up of 3.6 years. Niacin therapy was associated with a RR of 1.34 (95% CIs 1.21 to 1.49) for new-onset diabetes, with limited heterogeneity between trials (I²=0.0%, p=0.87). This equates to one additional case of diabetes per 43 (95% CI 30 to 70) initially non-diabetic individuals who are treated with niacin for 5 years. Results were consistent regardless of whether participants received background statin therapy (p for interaction=0.88) or combined therapy with [anti-flushing medication] laropiprant (p for interaction=0.52). ... [N]o difference was observed when comparing the trials that had or had not used background statin treatment (p=0.84 for interaction; see online supplementary eFigure 4). We performed an analysis with the largest trial, HPS2-THRIVE (which provided 65% of the overall weighting of the main analysis), excluded. In the remaining 10 trials, the RR of new-onset diabetes on niacin was similarly elevated at 1.38 ...
 
The mechanism that explains niacin's detrimental effect on glycaemic control and diabetes risk remains unclear. The observation that statins also increase diabetes risk and that this appears to be an on-target effect suggests that a specific lipid-modifying effect warrants particular attention. ... The data from HPS2-THRIVE also confirm that clinically significant deteriorations in glucose control in patients with diabetes are substantially increased on niacin. In those known to have diabetes at baseline in this major trial, there was a 55% increase in serious disturbances in glucose control for patients with diabetes, most of whom required hospital admission as a result. These findings contrast with earlier and smaller trials with shorter follow-up which suggested that the detrimental effect of niacin on glucose may only be temporary and therefore of potentially limited clinical importance. Additionally, the Coronary Drug Project showed that the relative risk of developing diabetes on niacin was similar regardless of whether patients had impaired fasting glycaemia (IFG) or normoglycaemia though the absolute risk was higher in IFG due to the increased rate of progression to diabetes.
 
Even with the discovery that statins modestly increase diabetes risk, their cardiovascular benefits still greatly outweigh any such metabolic risk. With niacin, the risk:benefit ratio appears far less favourable. Recent major niacin trials have now confirmed a lack of cardiovascular benefit when niacin is added to statin therapy ... In HPS2-THRIVE, gastrointestinal events, musculoskeletal events and infectious adverse events were increased on niacin. The results from HPS2-THRIVE and AIM-HIGH differ from the historical Coronary Drug Project, a clinical trial of niacin monotherapy which suggested modest cardiovascular benefit with similar effects across all glycaemic categories.

PMID: 26370223

 
A possible mechanism linked to lipid metabolism is niacin's effects on free fatty acids, which it initially suppresses but leads to a later rebound. Such a rebound would axially induce transient insulin resistance via the Randle cycle. That would seem to be more consistent with a transient, reversible effect.

A somewhat obscure second possible mechanism is through metabolic conversion of niacin to N-methylnicotinamide, the major metabolite of nicotinamide, whose function is still unclear.
 

Diabetic subjects had significantly higher plasma N(1)-methylnicotinamide levels 5 h after a 100-mg nicotinamide load than the non-diabetic subjects (0.89 +/- 0.13 micromol/L vs 0.6 +/- 0.13 micromol/L, P < 0.001). Cumulative doses of nicotinamide (2 g/kg) significantly increased rat plasma N(1)-methylnicotinamide concentrations associated with severe insulin resistance, which was mimicked by N(1)-methylnicotinamide. Moreover, cumulative exposure to N(1)-methylnicotinamide (2 g/kg) markedly reduced rat muscle and liver NAD contents and erythrocyte NAD/NADH ratio, and increased plasma H(2)O(2) levels. Decrease in NAD/NADH ratio and increase in H(2)O(2) generation were also observed in human erythrocytes after exposure to N(1)-methylnicotinamide in vitro. Sweating eliminated excessive nicotinamide (5.3-fold increase in sweat nicotinamide concentration 1 h after a 100-mg nicotinamide load).
PMID 19960564

In human and rodent urine, it was previously found that 'species demonstrated profound changes in nucleotide metabolism, including that of NMN [here N-methylnicotinamide, not nicotinamide mononucleotide ...], which may provide unique biomarkers for following type 2 diabetes progression' In diabetic individuals, decreased urinary levels and slower plasma clearance of NMN after nicotinamide overload have been observed. Nicotinic acid and nicotinamide have been reported to induce insulin resistance and NMN is thought to trigger this effect. In light of these previous findings and our results, NMN might therefore represent an interesting biomarker for prednisolone-induced insulin resistance.
PMID 23199229

Trammell and Brenner (2016a) found that 100 and 300 mg of oral NR had little effect on levels of N-methylnicotinamide in human PBMC, but 1000 mg/d caused a substantial increase; in mouse liver, nicotinamide riboside elevated N-methylnicotinamide close to twice as much as niacin does.
 
("But wait!" you say. "NR has been shown in several studies to prevent or partly reverse diabetes!" Yes, but those studies used C57BL/6J mice with the NNT mutation, where you'd expect that NAD precursors would improve the impaired glucose tolerance caused by the mutation and/or diabetes by eg. reducing oxidative stress in the beta-cells and increasing metabolism. Indeed, Trammel and Brenner(2016b) find that in prediabetic and diabetic C57BL/6 mice "NR supplementation significantly boosted hepatic NADP+ and tended to elevate NADPH but did not fully correct either metabolite." If the NNT concern is correct, then humans would not get the metabolic benefits seen in these mice.  In any case, human clinical trial results are a much more inherently powerful source of data for humans, an must not be ignored, especially for nicotinic acid itself).

Perhaps most mechanistically worrisome are the recent studies linking niacin's activation of the "niacin receptor" GPR109A/PUMA-G:
 

Eight-week niacin treatment elevated blood glucose concentration in obese mice with increased areas under the curve at oral glucose and intraperitoneal insulin tolerance tests. Additionally, niacin treatment significantly decreased glucose-stimulated insulin secretion (GSIS) but induced peroxisome proliferator-activated receptor gamma (Pparg) and GPR109a expression in isolated pancreatic islets; concomitantly, reactive oxygen species (ROS) were transiently increased, with decreases in GSIS, intracellular cyclic adenosine monophosphate (cAMP) accumulation and mitochondrial membrane potential (ΔΨm), but with increased expression of uncoupling protein 2 (Ucp2), Pparg and Gpr109a in INS-1E cells. Corroborating these findings, the decreases in GSIS, ΔΨm and cAMP production and increases in ROS, Pparg and GPR109a expression were abolished in INS-1E cells by GPR109a knockdown.

PMID 25622782

High levels of PUMA-G transcripts and protein were detected in all β cells, and about 40% of α cells. PUMA-G transcripts increased more than 3-fold in islets incubated with [the inflammatory cytokine] interferon γ. Cyclic adenosine monophosphate accumulation, induced by IBMX/forskolin, was inhibited by [nicotinic acid/niacin] .... Static incubation of islets with NA led to an approximately 30% reduction of GSIS. The results indicated that PUMA-G stimulation by NA in islet β cells inhibited GSIS likely via activation of the Gi signaling pathway.
PMID: 21441844

GPR109A was significantly reduced in islets from diabetic individuals and animal model of db/db mice as compared to their respective controls. Further, GPR109A levels in insulinoma were also reduced dramatically as compared to islets found in corresponding non-tumor normal tissues. Quantitative RT-PCR analysis demonstrated that GPR109A transcripts were severely down-regulated in rodent insulinoma cell lines as compared to that of freshly isolated islets from mice. Finally, human and murine GPR109A expression cassettes were transfected into INS-1 cells, which resulted in reduced accumulation of cAMP and insulin secretion after incubation with niacin.
PMID 27570060

If this is correct, then it's important to know that nicotinamide riboside does not engage the niacin receptor.

The effect of niacin on beta-cells could also be an acute and reversible effect, but seems more intuitively likely to be durable than something as clearly related to metabolic flux as an FFA-mediated effect, particularly granted that "GPR109A was significantly reduced in islets from diabetic individuals and animal model of db/db mice". It would be interesting to see islets from diet-induced diabetic mice transplanted into healthy syngeic mice to see if function recovered. On the other hand, this is evidence of impaired function, not actually of the death of beta-cells.

[PeaceAndProsperity]

^What a load of junk. Citing studies about a theoretical possibility does nothing to change reality. How about consulting with people who take 4g of NA a day? Even Wikipedia makes it clear that although it ever so slightly may raise blood glucose levels, this is a completely insignificant effect.

It certainly does not cause those issues.

[Michael]

Oooh, Wikipedia! Well, that settles it, then.

 

I've just documented from a meta-analysis of randomized, placebo-controlled clinical trials in humans that niacin use substantially increases the risk of diabetes. There's nothing theoretical about that. The only theoretical aspects of my post related to the mechanism of action, which is still unclear.

Edited by Michael, 30 August 2017 - 02:23 PM.

[Turnbuckle]

No one has ever shown that NR is absorbed as NR, and in fact, in rats it has been shown that NR has to be broken down into N+R. So taking N+R should get you the same results for 1/10 the cost, and without having to wait hours for it to be digested. As pharmacological agents, niacin and nicotinamide have quite different effects and different half-lives. Each can be converted into the other in the body, but this happens in relatively small amounts.

 

 

Digestion and Absorption of NAD by the Small Intestine of the Rat

 

Perfused or intact intestine rapidly hydrolyzed NMN to nicotinamide riboside, which accumulated, but was not absorbed. It was slowly cleaved by an enzyme associated with the mucosal cells to nicotinamide, which was the major if not the only labeled compound absorbed.

 

http://nadh.wiki/wp-...-of-the-Rat.pdf

 

 

 

 

If you use NR, keep in mind that the peak of NAD+ is reached only after several hours (delayed by digestion), while with N+R, it could be an hour or so. Niacin can peak in a matter of minutes. ER niacin would match the peak of NR derived NAD+ better than immediate release, if you took them at the same time. If you took immediate release niacin with NR, it would likely be gone by the time an increase of NR derived NAD+ was detectable.

 

Average half-lives--

 

Niacin -- 45 minutes

Nicotinamide -- 5 hours

 

 

Edited by Turnbuckle, 30 August 2017 - 06:09 PM.

[Michael]

No one has ever shown that NR is absorbed as NR, and in fact, in rats it has been shown that NR has to be broken down into N+R. So taking N+R should get you the same results for 1/10 the cost, and without having to wait hours for it to be digested. As pharmacological agents, niacin and nicotinamide have quite different effects and different half-lives. Each can be converted into the other in the body, but this happens in relatively small amounts.
 

Digestion and Absorption of NAD by the Small Intestine of the Rat
 
Perfused or intact intestine rapidly hydrolyzed NMN to nicotinamide riboside, which accumulated, but was not absorbed. It was slowly cleaved by an enzyme associated with the mucosal cells to nicotinamide, which was the major if not the only labeled compound absorbed.
 
http://nadh.wiki/wp-...-of-the-Rat.pdf

 

That doesn't seem to be the case, as I explained previously here. Your cited study (Gross & Henderson PMID 6218262) used NR that was only labeled at its carbonyl group (and thus could not trace the fate of the ribosyl moiety) and that didn't track its fate in target tissues. Both Frederick & Baur  PMID 27508874 and Trammell & Brenner PMID 27721479, using doubly-labeled NR (with deuterium at the ribosyl C2 and ¹³C at the NAM carbonyl group), find that at least in the liver, NR is utilized intact.

 

As I've indicated previously, however, it does appear likely that NR is broken down into NAM prior to entering the systemic circulation.

[jwilcox25]

 

High levels of PUMA-G transcripts and protein were detected in all β cells, and about 40% of α cells. PUMA-G transcripts increased more than 3-fold in islets incubated with [the inflammatory cytokine] interferon γ. Cyclic adenosine monophosphate accumulation, induced by IBMX/forskolin, was inhibited by [nicotinic acid/niacin] .... Static incubation of islets with NA led to an approximately 30% reduction of GSIS. The results indicated that PUMA-G stimulation by NA in islet β cells inhibited GSIS likely via activation of the Gi signaling pathway.
PMID: 21441844

GPR109A was significantly reduced in islets from diabetic individuals and animal model of db/db mice as compared to their respective controls. Further, GPR109A levels in insulinoma were also reduced dramatically as compared to islets found in corresponding non-tumor normal tissues. Quantitative RT-PCR analysis demonstrated that GPR109A transcripts were severely down-regulated in rodent insulinoma cell lines as compared to that of freshly isolated islets from mice. Finally, human and murine GPR109A expression cassettes were transfected into INS-1 cells, which resulted in reduced accumulation of cAMP and insulin secretion after incubation with niacin.
PMID 27570060

If this is correct, then it's important to know that nicotinamide riboside does not engage the niacin receptor.

The effect of niacin on beta-cells could also be an acute and reversible effect, but seems more intuitively likely to be durable than something as clearly related to metabolic flux as an FFA-mediated effect, particularly granted that "GPR109A was significantly reduced in islets from diabetic individuals and animal model of db/db mice". It would be interesting to see islets from diet-induced diabetic mice transplanted into healthy syngeic mice to see if function recovered. On the other hand, this is evidence of impaired function, not actually of the death of beta-cells.

 

 

Thanks for bringing these up - they are very helpful.  PMID 21441844 seems to imply that niacin's MOA is inhibition of GSIS in beta-cells, which I personally would not mind, as I have good glycemic control (especially postprandial).  But to clarify, are you hypothesizing the possibility that persistent agonism (i.e. by niacin) could lead to GPR109A downregulation (and therefore increased GSIS and eventual cell death)?  The downregulation in PMID 27570060 seems to be a result of compensatory mechanism with respect to low insulin or high blood glucose due to beta-cell death.  I don't see evidence that receptor agonism is causing the downregulation (and the transient nature of nicotinic acid makes me feel incrementally less worried about that).  The test would be GSIS function in long-term niacin supplementation.  If it is impaired, then I would not be worried about downregulation.

 

Separately, I take niacin because I have bad lipid numbers despite being very thin and exercising caloric restriction (likely due to genetic factors including rs662799, confirmed by a family history of early heart attacks in thin individuals).  Would you favor a statin or another intervention over niacin?

[Turnbuckle]

 

No one has ever shown that NR is absorbed as NR, and in fact, in rats it has been shown that NR has to be broken down into N+R. So taking N+R should get you the same results for 1/10 the cost, and without having to wait hours for it to be digested. As pharmacological agents, niacin and nicotinamide have quite different effects and different half-lives. Each can be converted into the other in the body, but this happens in relatively small amounts.
 

Digestion and Absorption of NAD by the Small Intestine of the Rat
 
Perfused or intact intestine rapidly hydrolyzed NMN to nicotinamide riboside, which accumulated, but was not absorbed. It was slowly cleaved by an enzyme associated with the mucosal cells to nicotinamide, which was the major if not the only labeled compound absorbed.
 
http://nadh.wiki/wp-...-of-the-Rat.pdf

 

That doesn't seem to be the case, as I explained previously here. Your cited study (Gross & Henderson PMID 6218262) used NR that was only labeled at its carbonyl group (and thus could not trace the fate of the ribosyl moiety) and that didn't track its fate in target tissues. Both Frederick & Baur  PMID 27508874 and Trammell & Brenner PMID 27721479, using doubly-labeled NR (with deuterium at the ribosyl C2 and ¹³C at the NAM carbonyl group), find that at least in the liver, NR is utilized intact.

 

As I've indicated previously, however, it does appear likely that NR is broken down into NAM prior to entering the systemic circulation.

 

 

From the NR paper: The minute amount of dual-labeled NAD observed in muscle indicates that direct utilization of NR by the muscle does occur. However, oral NR dosing increased circulating NAM ~40-fold while NMN remained unchanged and NR was detected only at trace levels in the blood. Thus, the majority of the orally administered NR that reaches the muscle appears to enter in the form of liberated NAM or as NMN.

 

 

This is consistent with most of an NR dose being digested and any small amount absorbed without digestion being processed by the liver so that it is not available to other tissues. Thus it makes sense to use N+R and not NR.

 

BTW, I don't agree with the paper's statement that "a minute amount of dual-labeled NAD observed in muscle indicates that direct utilization of NR by the muscle does occur," as some doubly labeled NAD will occur by chance. So this statement is not warranted without some further argument based on the relative availability of unlabeled N and R.

Edited by Turnbuckle, 30 August 2017 - 08:00 PM.

[able]

 

 

If you use NR, keep in mind that the peak of NAD+ is reached only after several hours (delayed by digestion), while with N+R, it could be an hour or so. Niacin can peak in a matter of minutes. ER niacin would match the peak of NR derived NAD+ better than immediate release, if you took them at the same time. If you took immediate release niacin with NR, it would likely be gone by the time an increase of NR derived NAD+ was detectable.

 

Average half-lives--

 

Niacin -- 45 minutes

Nicotinamide -- 5 hours

 

This is why I take all three.  

 

Niacin - super fast peak in liver

Nicotinamide - slower

 

NR - peaks 4-8 hours, but shows significant levels of all metabolites up to 24 hours later.

 

It seems like they have different pathways and impact on different organs, so see them as possibly all having some benefit in raising NAD at different times and different tissues.

 

As for Niacin raising blood glucose - Not an issue for me since Keto diet and intermittent fasting dropped fasting blood glucose from 110 to 75.

[jwilcox25]

If you use NR, keep in mind that the peak of NAD+ is reached only after several hours (delayed by digestion), while with N+R, it could be an hour or so. Niacin can peak in a matter of minutes. ER niacin would match the peak of NR derived NAD+ better than immediate release, if you took them at the same time. If you took immediate release niacin with NR, it would likely be gone by the time an increase of NR derived NAD+ was detectable.

 

Average half-lives--

 

Niacin -- 45 minutes

Nicotinamide -- 5 hours

Good point!  It's more convenient to take them together because I take most supplements at two time points, one on empty stomach and the other with a meal.  I take NR on empty (for better absorption if I remember correctly) and it sounds like niacin would be better on empty too for an even more immediate PK, avoiding possible receptor sensitization (if I interpreted Michael's post correctly).

[Michael]

 

 

No one has ever shown that NR is absorbed as NR, and in fact, in rats it has been shown that NR has to be broken down into N+R.

That doesn't seem to be the case, as I explained previously here. Your cited study (Gross & Henderson PMID 6218262) used NR that was only labeled at its carbonyl group (and thus could not trace the fate of the ribosyl moiety) and that didn't track its fate in target tissues. Both Frederick & Baur  PMID 27508874 and Trammell & Brenner PMID 27721479, using doubly-labeled NR (with deuterium at the ribosyl C2 and ¹³C at the NAM carbonyl group), find that at least in the liver, NR is utilized intact.
 
As I've indicated previously, however, it does appear likely that NR is broken down into NAM prior to entering the systemic circulation.

 
From the NR paper [ie, Frederick & Baur  PMID 27508874]: The minute amount of dual-labeled NAD observed in muscle indicates that direct utilization of NR by the muscle does occur. However, oral NR dosing increased circulating NAM ~40-fold while NMN remained unchanged and NR was detected only at trace levels in the blood. Thus, the majority of the orally administered NR that reaches the muscle appears to enter in the form of liberated NAM or as NMN.

Right: as I said, "it does appear likely that NR is broken down into NAM prior to entering the systemic circulation."
 

This is consistent with most of an NR dose being digested and any small amount absorbed without digestion being processed by the liver so that it is not available to other tissues. Thus it makes sense to use N+R and not NR.

Agreed that "most of an NR dose [is] digested." That's not the same as the categorical assertion that "No one has ever shown that NR is absorbed as NR". A small amount of doubly-labeled NR does become incorporated into NAD+ in the liver, as reported by Trammell & Brenner PMID 27721479:

54% of the NAD+ and 32% of the NADP+ contained at least one heavy atom, while 5% of the NAD+ and 6% of the NADP+ incorporated both heavy atoms. Because >50% of hepatic NAD+ incorporates label before a rise in NAD+ accumulation, it is clear that the NAD+ pool is dynamic. As shown in Fig. 7c,d, the majority of hepatic Nam and MeNam following gavage of double-labelled NR incorporated a heavy atom, necessarily the ¹³C in Nam. Because NR drives increased NAD+ synthesis and ADPR production (Fig. 5), the liberated singly labelled Nam becomes incorporated into NMN and NAD+ in competition with double labelled NR, thereby limiting subsequent incorporation of both labels into the NAD+ pool.

 
It's similarly over-broad to say that "any small amount absorbed without digestion being processed by the liver so that it is not available to other tissues," since some doubly-labeled NR does appear in the blood (even if it's "trace") and in muscle (even if it's "minute"). If only ≈5% of ingested NR is incorporated intact in hepatic NAD, it's unsurprising that an even lower percent would reach the systemic circulation and thence the muscle.
 
And, this isn't the full story on the ultimate effect on tissue NAD+ levels: as Frederick & Baur  PMID 27508874 report, despite only "minute" amounts of intact NR being incorporated into muscle NAD+,

To test whether NAM itself might account for some of the beneficial effects of NR treatment, we performed an additional experiment that included 3 weeks of NAM treatment. NAM-treated mice exhibited To test whether NAM itself might account for some of the beneficial effects of NR treatment, we performed an additional experiment that included 3 weeks of NAM treatment. NAMtreated mice exhibited intermediate phenotypes with regard to muscle performance and NAD levels [as compared with NR-supplemented and vehicle-treated animals] (Figures S5A–S5I).

 Indeed, to a rough approximation the effects of NAM are here about half those of NR.
 
Now, I hasten to add that this can't be extrapolated to indicate the relative effects of NAM vs. NR in normal mice or humans: these were mice with the gene for NAMPT knocked out in their muscles, so they couldn't synthesize NAD from NAM directly in their muscles. Still, it shows that NR had a functional effect that goes substantially beyond what can be accounted for by breakdown into NAM alone, and is disproportionate to the amount of local doubly-labeled NAD.
 
"But wait!" you say,

Turnbuckle wrote: BTW, I don't agree with the paper's statement that "a minute amount of dual-labeled NAD observed in muscle indicates that direct utilization of NR by the muscle does occur," as some doubly labeled NAD will occur by chance. So this statement is not warranted without some further argument based on the relative availability of unlabeled N and R.
 
On a sheer stoichiometry and volume of distribution basis, that seems unlikely to explain all of the differential effect of NR over and above NAM. The authors propose several possible mechanisms in addition to direct muscle use of intact NR:
 

The correlation between the NAD content and the respiratory capacity of isolated mitochondria, even in cultured myotubes (Figure 4), supports the model that subtle changes in NAD can disproportionately modulate aerobic metabolism. It is important to note that NAD turnover may vary independently from NAD concentration and that small changes in average tissue concentration might reflect larger changes in specific cells or subcellular compartments.
 
It is also possible that intramuscular conversion of NAD into secondary messengers potently influences calcium homeostasis, which is both essential to muscle contraction and can independently modulate mitochondrial respiration (Cárdenas et al., 2010). Our results leave open the possibility that some of the functional improvements in NR-treated mNKO muscles are secondary to effects in other cell types. ... The observation that NAM treatment was sufficient to confer a partial effect in mNKO muscle supports the model that effects outside of differentiated fibers contribute to the benefits of NR. Such indirect activities may help to explain how oral NR administration clearly mitigates the severity of insults to a growing list of tissues in which robust NAD decrements were not observed before treatment (Brown et al., 2014; Cerutti et al., 2014; Khan et al., 2014; Xu et al., 2015). We also cannot exclude the possibility that NAM contributes slightly to the NAD pool in mNKO myofibers by inhibition of NAM-sensitive NAD consumers or via residual Nampt activity in fibers or fusing myoblasts.

 I will myself note that effects on NADP(H) in C57BL/6 mice could also "help to explain how oral NR administration clearly mitigates the severity of insults to a growing list of tissues in which robust NAD decrements were not observed before treatment".
 
Turnbuckle wrote: If you use NR, keep in mind that the peak of NAD+ is reached only after several hours (delayed by digestion), while with N+R, it could be an hour or so.

... or any other figure you care to speculate. Again, we have no data on NR + ribose. You've put forward an mechanism-based hypothesis about breakdown and resynthesis of NR, and therefore of the benefit of NAM + ribose as an NAD+-boosting supplement, but it will remain an hypothesis until someone actually doses up some mice (or people) to see. It would be helpful to all concerned if you would be consistent and clear in describing your ideas about NAM + ribose in such terms.

Edited by Michael, 31 August 2017 - 03:31 AM.

[PeaceAndProsperity]

Oooh, Wikipedia! Well, that settles it, then.

 

I've just documented from a meta-analysis of randomized, placebo-controlled clinical trials in humans that niacin use substantially increases the risk of diabetes. There's nothing theoretical about that. The only theoretical aspects of my post related to the mechanism of action, which is still unclear.

Oh does it really? How about the hundreds of thousands of people who have taken many grams a day for many years and never had diabetes? I've never heard of anyone getting diabetes from it. It's a load of junk based upon a proposed possibility.

[Turnbuckle]

...

 

 
And, this isn't the full story on the ultimate effect on tissue NAD+ levels: as Frederick & Baur  PMID 27508874 report, despite only "minute" amounts of intact NR being incorporated into muscle NAD+,

To test whether NAM itself might account for some of the beneficial effects of NR treatment, we performed an additional experiment that included 3 weeks of NAM treatment. NAM-treated mice exhibited To test whether NAM itself might account for some of the beneficial effects of NR treatment, we performed an additional experiment that included 3 weeks of NAM treatment. NAMtreated mice exhibited intermediate phenotypes with regard to muscle performance and NAD levels [as compared with NR-supplemented and vehicle-treated animals] (Figures S5A–S5I).

 Indeed, to a rough approximation the effects of NAM are here about half those of NR.
 
...

 

 I will myself note that effects on NADP(H) in C57BL/6 mice could also "help to explain how oral NR administration clearly mitigates the severity of insults to a growing list of tissues in which robust NAD decrements were not observed before treatment".
 
Turnbuckle wrote: If you use NR, keep in mind that the peak of NAD+ is reached only after several hours (delayed by digestion), while with N+R, it could be an hour or so.

... or any other figure you care to speculate. Again, we have no data on NR + ribose. You've put forward an mechanism-based hypothesis about breakdown and resynthesis of NR, and therefore of the benefit of NAM + ribose as an NAD+-boosting supplement, but it will remain an hypothesis until someone actually doses up some mice (or people) to see. It would be helpful to all concerned if you would be consistent and clear in describing your ideas about NAM + ribose in such terms.

 

 

 

I am not comparing N (NAM) to NR, and I am not comparing NR+R to NR. I am comparing N+R to NR. The paper never made that obvious comparison, only comparing N to NR. Ribose is not plentiful in the body and without sufficient ribose NR will not be created in the same amount from a dose of N as with a dose of NR. The same can be said for taking NR and expecting it to be reconstituted as NR in the same amount. Some ribose will be lost to other processes, so it only makes sense to take a greater than stoichiometric amount of R. The failure of the paper to compare N+R  to NR would be inexplicable were there a no-conflict-of-interest statement, but in fact there is a conflict of interest--"R.W.D. [ Ryan W. Dellinger] is an employee and stockholder of Chromadex Inc., which manufactures and distributes NR." So given the millions being made selling this stuff, they would not want to indicate that one could simply take N+R at a small fraction of the cost. 

 

I have personally compared (1g of NR) with (1g of N + 2g of R) and found the latter to be more effective. This is not a fair comparison as the N+R was comparable to 2g of NR, however, I wasn't interested in NR if one had to take huge doses of it. It is way too expensive. For my purposes, I take a dose of (2g N + 5g R) once or twice a week--equivalent to at least 4g NR.

Edited by Turnbuckle, 31 August 2017 - 11:59 AM.

[Ibbz]

 

 

 

 

I have personally compared (1g of NR) with (1g of N + 2g of R) and found the latter to be more effective. This is not a fair comparison as the N+R was comparable to 2g of NR, however, I wasn't interested in NR if one had to take huge doses of it. It is way too expensive. For my purposes, I take a dose of (2g N + 5g R) once or twice a week--equivalent to at least 4g NR.

 

 

 

What were the differences you noticed between the two? Did you do blood testing before / after or some other measurement, or is it more anecdotal? (I'm not doubting you may have found it more effective, I'm more interested in the effect of N+R / NR in general)

[Turnbuckle]

 

 

 

 

 

I have personally compared (1g of NR) with (1g of N + 2g of R) and found the latter to be more effective. This is not a fair comparison as the N+R was comparable to 2g of NR, however, I wasn't interested in NR if one had to take huge doses of it. It is way too expensive. For my purposes, I take a dose of (2g N + 5g R) once or twice a week--equivalent to at least 4g NR.

 

 

 

What were the differences you noticed between the two? Did you do blood testing before / after or some other measurement, or is it more anecdotal? (I'm not doubting you may have found it more effective, I'm more interested in the effect of N+R / NR in general)

 

 

 

I compared the two during exercise. NR increases NAD+ and a high NAD+/NADH ratio fissions mitochondria and sets the QC mitophagy process running, and while that is valuable in itself, I wanted to make it do double duty in the gym. See Exercise like a girl -- a protocol. 

[Michael]

 

Turnbuckle wrote: If you use NR, keep in mind that the peak of NAD+ is reached only after several hours (delayed by digestion), while with N+R, it could be an hour or so.

... or any other figure you care to speculate. Again, we have no data on NR + ribose. You've put forward an mechanism-based hypothesis about breakdown and resynthesis of NR, and therefore of the benefit of NAM + ribose as an NAD+-boosting supplement, but it will remain an hypothesis until someone actually doses up some mice (or people) to see. It would be helpful to all concerned if you would be consistent and clear in describing your ideas about NAM + ribose in such terms.

I am not comparing N (NAM) to NR, and I am not comparing NR+R to NR. I am comparing N+R to NR. The paper never made that obvious comparison, only comparing N to NR.

To be precise, you are comparing your speculations about NAM+R to NAR. This paper never made that obvious comparison, and neither has any other paper. We have data on NAM vs. NR, and we have zero data on NAM+R — just your speculation.
 
Turnbuckle wrote: Ribose is not plentiful in the body and without sufficient ribose NR will not be created in the same amount from a dose of N as with a dose of NR. The same can be said for taking NR and expecting it to be reconstituted as NR in the same amount. Some ribose will be lost to other processes, so it only makes sense to take a greater than stoichiometric amount of R.

That's an interesting and non-crazy expectation. And some day, we'll hopefully have data on it. Very little is known about NR biosynthesis, and the main known route is via breakdown of NNM by two 5′-nucleotidases in yeast, not de novo biosynthesis. Indeed, in their paper on the discovery of the two known enzymes responsible for the production of NR and nicotinic acid riboside, the authors wrote:

 

We set out to determine the enzymes responsible for NR and NAR production. Because there is no biological precedent for nucleoside synthesis de novo and because NR and NAR accumulation appear to occur at the expense of NAD⁺ (Figs. 1 and 2), we considered the mechanisms by which NAD⁺ and related compounds could be broken down to NR.

 

In the meantime, as I said, it would be helpful to all concerned if you would be clearer in stating that you're speculating on the effects of NAM + R, rather than stating your hypotheses as if they were known facts.
 
Turnbuckle wrote: The failure of the paper to compare N+R  to NR would be inexplicable were there a no-conflict-of-interest statement, but in fact there is a conflict of interest--"R.W.D. [ Ryan W. Dellinger] is an employee and stockholder of Chromadex Inc., which manufactures and distributes NR." So given the millions being made selling this stuff, they would not want to indicate that one could simply take N+R at a small fraction of the cost.

That's also speculation on your part. It could also be that it hasn't occurred to them, or that they're limited by money, or that they don't think a de novo route exists in the relevant tissue or is efficient enough to bother testing. 
 

 

Turnbuckle wrote: I have personally compared (1g of NR) with (1g of N + 2g of R) and found the latter to be more effective. This is not a fair comparison as the N+R was comparable to 2g of NR, however, I wasn't interested in NR if one had to take huge doses of it. It is way too expensive. For my purposes, I take a dose of (2g N + 5g R) once or twice a week--equivalent to at least 4g NR.
 
What were the differences you noticed between the two? Did you do blood testing before / after or some other measurement, or is it more anecdotal? (I'm not doubting you may have found it more effective, I'm more interested in the effect of N+R / NR in general)

 
I compared the two during exercise. NR increases NAD+ and a high NAD+/NADH ratio fissions mitochondria and sets the QC mitophagy process running, and while that is valuable in itself, I wanted to make it do double duty in the gym. See Exercise like a girl -- a protocol.

 

That's an interesting anecdote. But of course, while your performance results might be due to higher NAD+ levels, they could also be due to use of ribose for other biosynthetic purposes, or its effects on glucoregulation, or the power of placebo. We don't even have NAD+ data from your n-1 experiment, let alone from a proper scientific study. Again: it would be helpful to all concerned if you would be clear about this.

Edited by Michael, 31 August 2017 - 04:26 PM.

[Turnbuckle]

I tried the OP idea this morning, using 500 mg of niacin, 1.5 g of niacinamide and 5 g of ribose, along with AMPK activators (all in one dose) and went out to the gym an hour and a half later. I think the results were at least as good as 2g/5g of N+R with the same activators. Perhaps better, but hard to tell until I try it a few more times. One difference (other than a flush) was a slightly unpleasant head feeling that developed several hours later--which was similar to what I get from taking large amounts of niacinamide without ribose. So I took another 5 g of ribose and the feeling went away after a few minutes. Ribose has a short half-life--

 

Following consumption, ribose is rapidly absorbed and reaches its highest concentration in the blood after around 45 minutes. The half-life in the bloodstream is around half an hour. Moreover, ribose does not accumulate in the tissues and is not stored in cells in free form. 

http://www.naturafou...fie/Ribose.html

 

 

Still, this seems odd as niacin has such a short half-life compared to niacinamide. 

 

 

[stefan_001]

 

 

 

 

 

 

I have personally compared (1g of NR) with (1g of N + 2g of R) and found the latter to be more effective. This is not a fair comparison as the N+R was comparable to 2g of NR, however, I wasn't interested in NR if one had to take huge doses of it. It is way too expensive. For my purposes, I take a dose of (2g N + 5g R) once or twice a week--equivalent to at least 4g NR.

 

 

 

What were the differences you noticed between the two? Did you do blood testing before / after or some other measurement, or is it more anecdotal? (I'm not doubting you may have found it more effective, I'm more interested in the effect of N+R / NR in general)

 

 

 

I compared the two during exercise. NR increases NAD+ and a high NAD+/NADH ratio fissions mitochondria and sets the QC mitophagy process running, and while that is valuable in itself, I wanted to make it do double duty in the gym. See Exercise like a girl -- a protocol. 

 

 

Have you done this test with only taking Ribose (disclaimer, I didnt bother to read the cited studies)?

http://www.ironmanma...-energy-switch/

In a recent study reported in The Journal of Current Therapeutic Research, bodybuilders who supplemented with 10 grams of ribose for four weeks dramatically improved their muscle strength and overall workout performance. In a related study, 16 bodybuilders were randomly given 10 grams of ribose a day for four weeks. At the beginning of the trial researchers recorded the ability of the ribose group and the group not supplementing with ribose to do 10 consecutive sets of lifts before muscle fatigue set in. At the end of four weeks the bodybuilders who were taking D-ribose had a 29.8 percent increase in maximum lift capacity vs. 7.4 percent for the placebo group.

Suggested dose: Take three to five grams of D-ribose before and after exercise every day to maintain constant ATP production and regeneration.

 

Edited by stefan_001, 31 August 2017 - 07:16 PM.

[Turnbuckle]

 

 

 

 

 

 

 

I have personally compared (1g of NR) with (1g of N + 2g of R) and found the latter to be more effective. This is not a fair comparison as the N+R was comparable to 2g of NR, however, I wasn't interested in NR if one had to take huge doses of it. It is way too expensive. For my purposes, I take a dose of (2g N + 5g R) once or twice a week--equivalent to at least 4g NR.

 

 

 

What were the differences you noticed between the two? Did you do blood testing before / after or some other measurement, or is it more anecdotal? (I'm not doubting you may have found it more effective, I'm more interested in the effect of N+R / NR in general)

 

 

 

I compared the two during exercise. NR increases NAD+ and a high NAD+/NADH ratio fissions mitochondria and sets the QC mitophagy process running, and while that is valuable in itself, I wanted to make it do double duty in the gym. See Exercise like a girl -- a protocol. 

 

 

Have you done this test with only taking Ribose (disclaimer, I didnt bother to read the cited studies)?

http://www.ironmanma...-energy-switch/

In a recent study reported in The Journal of Current Therapeutic Research, bodybuilders who supplemented with 10 grams of ribose for four weeks dramatically improved their muscle strength and overall workout performance. In a related study, 16 bodybuilders were randomly given 10 grams of ribose a day for four weeks. At the beginning of the trial researchers recorded the ability of the ribose group and the group not supplementing with ribose to do 10 consecutive sets of lifts before muscle fatigue set in. At the end of four weeks the bodybuilders who were taking D-ribose had a 29.8 percent increase in maximum lift capacity vs. 7.4 percent for the placebo group.

Suggested dose: Take three to five grams of D-ribose before and after exercise every day to maintain constant ATP production and regeneration.

 

 

 

I haven't tried it with ribose alone as I am not aware that ribose alone contributes to mito fission. What I'm looking for is a temporary reduction in muscle strength combined with elimination of dysfunctional mitochondria. So when I say I got better results, I mean that I got a burn faster with fewer reps and/or less weight. See Exercise like a girl. 

[stefan_001]

 

 

I compared the two during exercise. NR increases NAD+ and a high NAD+/NADH ratio fissions mitochondria and sets the QC mitophagy process running, and while that is valuable in itself, I wanted to make it do double duty in the gym. See Exercise like a girl -- a protocol. 

 

 

Have you done this test with only taking Ribose (disclaimer, I didnt bother to read the cited studies)?

http://www.ironmanma...-energy-switch/

In a recent study reported in The Journal of Current Therapeutic Research, bodybuilders who supplemented with 10 grams of ribose for four weeks dramatically improved their muscle strength and overall workout performance. In a related study, 16 bodybuilders were randomly given 10 grams of ribose a day for four weeks. At the beginning of the trial researchers recorded the ability of the ribose group and the group not supplementing with ribose to do 10 consecutive sets of lifts before muscle fatigue set in. At the end of four weeks the bodybuilders who were taking D-ribose had a 29.8 percent increase in maximum lift capacity vs. 7.4 percent for the placebo group.

Suggested dose: Take three to five grams of D-ribose before and after exercise every day to maintain constant ATP production and regeneration.

 

 

 

I haven't tried it with ribose alone as I am not aware that ribose alone contributes to mito fission. What I'm looking for is a temporary reduction in muscle strength combined with elimination of dysfunctional mitochondria. So when I say I got better results, I mean that I got a burn faster with fewer reps and/or less weight. See Exercise like a girl. 

 

 

Perhaps there is no mito fusion and you simply notice the same as the ribose alone effect that those atheletes observe

 

[Turnbuckle]

 

 

 

 

 

Perhaps there is no mito fusion and you simply notice the same as the ribose alone effect that those atheletes observe

 

 

 

 

Fission, not fusion, and you are saying that athletes take ribose to have less strength?

[stefan_001]

 

 

 

 

 

 

Perhaps there is no mito fusion and you simply notice the same as the ribose alone effect that those atheletes observe

 

 

 

 

Fission, not fusion, and you are saying that athletes take ribose to have less strength?

 

 

I am saying that the effect you observe may not be because of your theory, anyways it seems you benefit from what you do so its all good

 

Edited by stefan_001, 31 August 2017 - 08:35 PM.

[Michael]

 

 

High levels of PUMA-G transcripts and protein were detected in all β cells, and about 40% of α cells. PUMA-G transcripts increased more than 3-fold in islets incubated with [the inflammatory cytokine] interferon γ. Cyclic adenosine monophosphate accumulation, induced by IBMX/forskolin, was inhibited by [nicotinic acid/niacin] .... Static incubation of islets with NA led to an approximately 30% reduction of GSIS. The results indicated that PUMA-G stimulation by NA in islet β cells inhibited GSIS likely via activation of the Gi signaling pathway.
PMID: 21441844

GPR109A was significantly reduced in islets from diabetic individuals and animal model of db/db mice as compared to their respective controls. Further, GPR109A levels in insulinoma were also reduced dramatically as compared to islets found in corresponding non-tumor normal tissues. Quantitative RT-PCR analysis demonstrated that GPR109A transcripts were severely down-regulated in rodent insulinoma cell lines as compared to that of freshly isolated islets from mice. Finally, human and murine GPR109A expression cassettes were transfected into INS-1 cells, which resulted in reduced accumulation of cAMP and insulin secretion after incubation with niacin.
PMID 27570060

If this is correct, then it's important to know that nicotinamide riboside does not engage the niacin receptor.

The effect of niacin on beta-cells could also be an acute and reversible effect, but seems more intuitively likely to be durable than something as clearly related to metabolic flux as an FFA-mediated effect, particularly granted that "GPR109A was significantly reduced in islets from diabetic individuals and animal model of db/db mice". It would be interesting to see islets from diet-induced diabetic mice transplanted into healthy syngeic mice to see if function recovered. On the other hand, this is evidence of impaired function, not actually of the death of beta-cells.

 
Thanks for bringing these up - they are very helpful.  PMID 21441844 seems to imply that niacin's MOA is inhibition of GSIS in beta-cells, which I personally would not mind, as I have good glycemic control (especially postprandial).

I put it to you that you should not take this good postprandial glycemic response for granted.
 

But to clarify, are you hypothesizing the possibility that persistent agonism (i.e. by niacin) could lead to GPR109A downregulation (and therefore increased GSIS and eventual cell death)?

I wouldn't go so far as to speculate on beta-cell death (that's really going well beyond the data), but it does seem reasonable to worry about persistent stimulation leading to downregulation and this leading to a more persistent loss of first-phase insulin response.
 
jwilcox25 wrote: The downregulation in PMID 27570060 seems to be a result of compensatory mechanism with respect to low insulin or high blood glucose due to beta-cell death.  I don't see evidence that receptor agonism is causing the downregulation (and the transient nature of nicotinic acid makes me feel incrementally less worried about that). 

I agree that the downregulation in PMID 27570060 is not caused by nicotinic acid, and the fact that "human and murine GPR109A expression cassettes were transfected into INS-1 cells, which resulted in reduced accumulation of cAMP and insulin secretion after incubation with niacin" seems to argue in favor of an acute effect.
 
However, granted that (a) the meta-analysis does confirm a substantial increase in diabetes risk, (b) nicotinic acid stimulates the GPR109A receptor, and © GPR109A is downregulated in diabetes and insulinoma, that the mechanism might be due to compensatory downregulation in response to chronic stimulation by nicotinic acid.

Note that the downregulation in diabetes is more likely to relate to hyperinsulinemia or persistent cell-autonomous insulin output than hyperglycemia, since it is also observed in insulinoma cells (at both the transcriptional and the protein levels).
 
Certainly, we should worry more about the fact of the risk than the mechanism, except that a MoA via GPR109A would be specific to nicotinic acid, whereas other mechanisms might apply equally to NAM or NR (which have been studied far less).
 
jwilcox25 wrote: The test would be GSIS function in long-term niacin supplementation.  If it is impaired, then I would not be worried about downregulation.
 
Certainly agree that that's the best test; however, that doesn't help any of us trying to make decisions now, and one doesn't want to find out by personal experience.
 
jwilcox25 wrote: Separately, I take niacin because I have bad lipid numbers despite being very thin and exercising caloric restriction (likely due to genetic factors including rs662799, confirmed by a family history of early heart attacks in thin individuals).  Would you favor a statin or another intervention over niacin?

As I indicated in my first post in this thread, "After all these years, it's still not clear whether NA reduces risk of cardiovascular events in people at high risk (ie, in the people in whom you'd most expect it to benefit)", whereas statins very clearly do work. If it were me, I'd take a statin way before I considered NA for either hyperlipidemia per se or prevalent CVD events or death (compare .this meta analysis with this, but also this (from the same authors as the latter) and this). The latter two were conducted before AIM-HIGH, and all but Garg et al were conducted before HPS2-THRIVE, which latter two certainly seem to me to have put the benefit of combination therapy to bed; it still seems to me to be possible that NA alone is beneficial vs. no therapy, but it seems pretty clear it does not work as well as statins and is of little or no use adjunctively.
 
Reinforcing this interpretation,
 

Our analysis suggesting a lack of clinical benefit with niacin is in agreement with studies involving other HDL-raising drugs.^53,54 Recently published trials investigating fibrates and cholesteryl ester transfer protein inhibitors have added to a growing consensus against the hypothesis that HDL-C–raising therapies would be atheroprotective.^54,55 Notably, among statin-treated patients, the ACCORD (Action to Control Cardiovascular Risk in Diabetes) and dal-OUTCOMES (Study of the Effect of Dalcetrapib on Atherosclerotic Disease in Patients with Coronary Artery Disease) trials failed to show any reduction in recurrent cardiovascular events, with the addition of fenofibrate and dalcetrapib, respectively. (Garg et al again).

 

A lot of other studies have also emphasized the notion that a simplistic "higher HDL is better" understanding of the effects of interventions is mistaken: see here and here, eg.

[jwilcox25]

[Discussion of possible mechanisms whereby NA increases diabetes risk; lack of clear effect of NA on risk of hard events in CVD]

 

Thanks - I largely agree with your viewpoint.  In addition, I dug up some old clinical data showing that chronic (4 wk) NA admin increases GSIS in nondiabetics which lends a lot of credence to your hypothesis of downregulation.  Full papers include postprandial curves.  They use a higher dose of NA than I do and tid, but it is immediate release, so this is really troublesome.
 
DOI: 10.1016/0026-0495(71)90026-6The influence of antilipemic doses of nicotinic acid on carbohydrate tolerance, plasma insulin levels after oral glucose administration, serum uric acid levels, and renal excretion and clearance of uric acid was investigated in man. After a stabilization period of 1 wk, five subjects were given nicotinic acid, 1.5 g three times daily for 4 wk, under dietetically controlled conditions. Two of the subjects had normal oral glucose tolerance tests and the others, abnormal, prior to drug administration. Oral glucose (75 g) tolerance tests were performed twice prior to and weekly during drug administration and 1 wk after drug discontinuation. Twice weekly, throughout the 6 wk study, fasting plasma levels of uric acid, glucose, cholesterol, triglycerides, and immunoreactive insulin were determined. Insulin levels were also determined on each plasma sample during glucose tolerance tests. Rates of uric acid excretion were measured daily in two subjects. During drug administration, all subjects sustained increases, above predrug values, of plasma uric acid and of glucose after glucose tolerance tests. Glucosuria and ketonuria also ensued. Since plasma insulin levels increased along with glucose in nondiabetics, the data suggest that inhibition of insulin release is not the mechanism by which carbohydrate intolerance is produced or intensified. Renal excretion and clearance of uric acid decreased 50% and 75%, respectively; hence, the increases in plasma uric acid concentrations may be due, in whole or in part, to diminished renal clearance. Such diminished clearance may result from altered tubular handling of m-ate by keto acids and/or nicotinic acid and its metabolites.

DOI: 10.1111/j.0954-6820.1969.tb01473.x

Abstract. Since nicotinic acid is known to interfere with the glucose metabolism, a detailed study was made to establish whether insulin secretion is involved in this action. On chronic administration of nicotinic acid to hyperlipidemic subjects the fasting blood glucose and plasma immunoreactive insulin (IRI) concentrations rose significantly. The elimination rate constant (K) of intravenous glucose decreased from an average of 1.88 to 1.07. The plasma IRI response increased, but only in relation to blood glucose level. Biguanide treatment did not improve the glucose utilization during nicotinic acid treatment. A short-term effect of the drug given as intravenous infusion to control subjects was a decrease of K-value of iv. glucose, a slight increase of basal plasma IRI level and an unchanged plasma IRI response to glucose load. In subjects maintained on total calory restriction or on highfat low-carbohydrate diet nicotinic acid did not cause any further decrease of the primarily low K-value. A similar lack of effect was present in patients with liver cirrhosis. Also in these instances the IRI response was not modified by nicotinic acid. It is suggested that nicotinic acid impairs the hepatic glucose assimilation by increasing both glycogenolysis and gluconeogenesis through some action which is not related to antilipolysis. Insulin secretion is slightly stimulated by the drug.

Edited by Michael, 04 September 2017 - 03:28 AM.
Trim quotes, wrap abstracts

[zorba990]

I tried the OP idea this morning, using 500 mg of niacin, 1.5 g of niacinamide and 5 g of ribose, along with AMPK activators (all in one dose) and went out to the gym an hour and a half later. I think the results were at least as good as 2g/5g of N+R with the same activators. Perhaps better, but hard to tell until I try it a few more times. One difference (other than a flush) was a slightly unpleasant head feeling that developed several hours later--which was similar to what I get from taking large amounts of niacinamide without ribose. So I took another 5 g of ribose and the feeling went away after a few minutes. Ribose has a short half-life--

Following consumption, ribose is rapidly absorbed and reaches its highest concentration in the blood after around 45 minutes. The half-life in the bloodstream is around half an hour. Moreover, ribose does not accumulate in the tissues and is not stored in cells in free form.
http://www.naturafou...fie/Ribose.html

Still, this seems odd as niacin has such a short half-life compared to niacinamide.

This brings up an interesting point. Since ribose has a much shorter half life than nicotinamide, it might help to sip a drink with more ribose over the course of a workout in case the original dose was metabolized into other uses before being used in the intended pathway.

[able]

I wouldn't so much comment on the wisdom of combining NA with NR, as council against the use of NA. After all these years, it's still not clear whether NA reduces risk of cardiovascular events in people at high risk (ie, in the people in whom you'd most expect it to benefit) — and, in the meantime, it's now pretty clear that it raises the risk of diabetes:

 

 

I Finally had a little time to look into some of the recent research on Niacin and am surprised how mixed it is.  

 

But I do see the 2 reviews below that examine/rebut the earlier meta-analysis that showed no clear benefit for Niacin on cardiovascular events.

 

The first agrees no significant impact when used with statins for all cause mortality, but still finds benefit when used without statins on cardiovascular events that don't result i death.

 

The second finds some flaws in the analysis of the earlier review and argue Niacin is effective when not used with statins.

 

Clearly not a ringing endorsement for Niacin use, but refutes some of the more negative reviews I think.

 

Since I don't take statins, and have excellent blood glucose levels now, I will continue to take it,  mostly just going on the fact that Niacin does clearly elevate NAD+ per Trammell.

 

 

 

 

 

 

 

Concerning Niacin in Current Clinical Practice 

“Niacin, either by itself or combined with a bile acid sequestrant or a fibrate, did not reduce all-cause mortality, cardiovascular mortality, or coronary deaths. 

When not used in conjunction with a statin, niacin or niacin combined with a bile acid sequestrant or a fibrate reduces the risk of nonfatal MIs, strokes, and revasculari- zation procedures. Consequently, there is a role for niacin by itself, or niacin combined with clofibrate, colestipol, or gemfibrozil, in patients who are intolerant of statins. “

 

Role of Niacin in Cardiovascular Prevention: The Debate Continues 

 

“our meta-analysis showed that niacin treatment was associated with a 41% reduction in any revascularization, whereas Garg et al’s analysis1 reported a nonsignificant 17%. 

What could be the possible explanation for this striking difference? First, we incorporated data from the individual primary end point events of the AIM-HIGH trial, whereas Garg et al1 took the data from the tertiary end points.5 Second, we included results from the Coronary Drug Project, which showed a 67% reduction in the rate of coronary bypass surgery.6 

Therefore, our findings suggest that niacin could still be a cost-effective therapeutic option for cardiovascular prevention, especially among those patients who do not respond adequately to statins with or without the addition of ezetimibe. “

Edited by able, 04 September 2017 - 04:10 PM.

[Michael]

 

I wouldn't so much comment on the wisdom of combining NA with NR, as council against the use of NA. After all these years, it's still not clear whether NA reduces risk of cardiovascular events in people at high risk (ie, in the people in whom you'd most expect it to benefit) — and, in the meantime, it's now pretty clear that it raises the risk of diabetes:

 

I Finally had a little time to look into some of the recent research on Niacin and am surprised how mixed it is.  

 

But I do see the 2 reviews below that examine/rebut the earlier meta-analysis that showed no clear benefit for Niacin on cardiovascular events.

 

The first agrees no significant impact when used with statins for all cause mortality, but still finds benefit when used without statins on cardiovascular events that don't result i death.

 

The second finds some flaws in the analysis of the earlier review and argue Niacin is effective when not used with statins.

 

Clearly not a ringing endorsement for Niacin use, but refutes some of the more negative reviews I think.

 

Since I don't take statins, and have excellent blood glucose levels now, I will continue to take it,  mostly just going on the fact that Niacin does clearly elevate NAD+ per Trammell.

 

That's a good summary of the rebuttals — which I think make some pretty good arguments. See also the response to the rebuttals, which doesn't really refute their most important findings. Still, (a) it's uncertain either way, and if your life depends on it I'd want to be confident; (b) the population risk factor profile has changed quite a bit since the older niacin-only trials; © as you note, even the rebuttals' analysis find no reduction in CVD or total deaths from niacin alone, which if you're actually taking it for CVD risk is a pretty damned important outcome; and most importantly (d) they don't rebut the finding that niacin substantially increases the risk of diabetes in the Garg meta-analysis and in the more specific meta-analysis on niacin and the risk of new-onset diabetes I cited in my earlier post — which last should give everyone pause, no matter why they're taking it. As with jwilcox, I would not take your excellent blood glucose levels for granted.