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:
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.
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.
[...]
Perhaps most mechanistically worrisome are the recent studies linking niacin's activation of the "niacin receptor" GPR109A/PUMA-G:
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.
Michael,
niacin cant be converted into nicotinamide, so then into N-methylnicotinamide. Only the opposite can happen. So this is a concern only related with niacinamide and NR.
On the other hand, if the GPR109A is the part involved for Niacin increasing fasting glucose, then it explains why the long term study done on it showed a return to normal at the end of the study unlike the short term ones.
I believe this is a dose dependant response and THE answer for its method of action :
https://www.ncbi.nlm...les/PMC4586547/
"enterocyte GPR109a is expressed and functional in the local control of intestinal glucose absorption, and that type 2 diabetic and high glucose conditions upregulate the GPR109a expression, thus enhancing niacin-induced intestinal glucose uptake in the mice. Our laboratory has recently reported the novel role of niacin, via its activation of GPR109A, in pancreatic islets [10]. In that study, niacin was found to increase fasting glucose concentrations, reduce glucose-stimulated insulin secretion (GSIS) and insulin secretion, and impair glucose tolerance, thereby inducing pancreatic islet dysfunctions in high-fat diet (HFD) induced obese mice [10]. In this regard, the present study establishes a previously undiscovered role of niacin in local regulation of glucose homeostasis at the level of the small intestine in normal and diabetic states."
"In conclusion, the present study is the first to report that niacin is able to bind to the niacin receptor GPR109a to stimulate SGLT1- and GLUT2-mediated jejunal glucose uptake in hyperglycemia observed in diabetes."
So we clearly want to avoid high dose (above 500mg maybe even..) and avoid time released.
Back to this receptor : it is also a positive thing since its anti inflamatory and has cntrol on sleep quality / circardian rythm :
https://www.ncbi.nlm...les/PMC4201464/
things gets more complicated when we read that butyrate is also an agonist for this receptor, but we know butyrate control glucose (it decreases fasting glucose) :
"Butyrates (GPR109A agonists) are also known to inhibit inflammation through inhibiting NFκB in Crohn’s disease [57]. Butyrates decrease pro-inflammatory cytokine (TNFα, IL-6 and IL-1β) expression via inhibition of NFκB activation and IκB degradation [58]. Butyrates also inhibit NFκB activation via GPR109A and increases IκB levels in-vitro in intestinal epithelial cell lines [59]."
and :
https://www.ncbi.nlm...pubmed/24412617
"GPR109A (encoded by Niacr1) is a receptor for butyrate in the colon. GPR109A is also a receptor for niacin, which is also produced by gut microbiota and suppresses intestinal inflammation. Here we showed that Gpr109a signaling promoted anti-inflammatory properties in colonic macrophages and dendritic cells and enabled them to induce differentiation of Treg cells and IL-10-producing T cells. Moreover, Gpr109a was essential for butyrate-mediated induction of IL-18 in colonic epithelium. Consequently, Niacr1(-/-) mice were susceptible to development of colonic inflammation and colon cancer. Niacin, a pharmacological Gpr109a agonist, suppressed colitis and colon cancer in a Gpr109a-dependent manner. Thus, Gpr109a has an essential role in mediating the beneficial effects of gut microbiota and dietary fiber in colon.
So your comment here are welcome, but to me it start to over complicated the picture. My today conclusion for this is that all has to come in balance, why take such high amount vitamin B3 ? I know our end goal is to increase NAD+ but isnt low dose long run a better strategy to keep the balance under control ?
Also, some of the last studies you quoted mentions they dont have full data access and they dont even speak about the dosages used, and it look like the dosage used for cholesterol treatment means in g...
Most people here wouldnt use even a dose close to 1g and avoid the time released form. Personally I use 100mg (wich is like to take 200mg NR) daily along a mult B because if you look at well, all the others data done on biotin, P5P etc show a glucose balance with them. So maybe there is also a methylation cycle to respect, and this is true also for NR users probably
Edited by Michael, 11 September 2018 - 06:49 PM.
trim quotes
This topic is locked
. Re: these specific sources, note that butyrate here as in most studies is acting in the GI tract itself, which doesn't address the evidence for MeNAM and/or NA proper inhibiting or being toxic to beta-cells.
