Type 2 Diabetes
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Reply To: How do you handle diabetes with niacin?
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THE TRUTH ABOUT NIACIN, BEGINNING WITH AN EXPLORATION OF ITS INTERSECTION IN THE DISEASE ETIOLOGY AND PATHOLOGY OF DIABETES
by Dmitry Kats, PhD, MPH
Flush niacin, immediate release nicotinic acid, at needed levels of supplementation (i.e., usually at least 1-2 g doses, though even higher is typically appropriate, common, and dose-responsive in terms of how much work is needed) ought to be COLLOQUIAL knowledge and understanding as being not only safe and effective but officially U.S. FDA approved–meaning consistently proved and (recently even re-)affirmed (as monotherapy) by the authority representative of the United States government, as THE standard, safest, and most effective treatment–to correct dyslipidemia as means for prevention (with evidence compiling also for therapeutic purposes) against cardiovascular disease outcomes, perhaps most particularly and importantly for individuals with type-2 diabetes. With scientific confidence, I project for flush niacin (and notably, noticeably more smoothly and efficiently combined with the other key, three B-vitamin precursor compounds at relevant levels, i.e., pyridoxine, folic acid, and cyanocobalamin) to provide not only comprehensive re-modification/correction of lipids/cholesterol/triglycerides but further–along with bestowing literally a halving of the likelihood of any future cardiovascular disease events (with any such occurrence itself likely an utter impossibility if flush niacin is continued beyond trial follow-up period; see paper below for what flush niacin as monotherapy actually was proven across three different double-blinded randomized controlled trials to do) in addition to likely complete regeneration of the cardiovascular architecture and system operations–efficient curative effects to be provided in those with diabetes (especially type 2). Early research and consistent clinical observation had all but proved this, but, naturally, it stayed under the wraps. Niacin, in fact, at the time, had been known to be a mimetic of insulin in a sense (after all, it does regulate glucose and lipid metabolism: https://pubmed.ncbi.nlm.nih.gov/25429652/). For those who are more insulin dependent, the only challenge will be realizing that you (and rather quickly as you go up dosing) will not need insulin anymore, likely even if as insulin dependent as needing to be clinically monitored daily. Individuals with more manageable diabetes should have zero issues and only enjoyable therapy within weeks.
Interestingly, despite already–albeit not formally for the actual disease outcome of type 2 (or 1) diabetes–evidenced (see more below), unfortunately only extended and not immediate release nicotinic acid aka flush niacin is being formally tested as monotherapy to cure type 2 diabetes in this currently ongoing double-blinded randomized controlled trial: https://journals.lww.com/md-journal/Fulltext/2021/03260/The_efficacy_of_niacin_supplementation_in_type_2.1.aspx. Even though I am sure actual (flush) niacin would outperform expectations to say the least if it (and not extended release niacin) was assessed in this upcoming trial, I also want to offer quell to ANY fears one may have based on the unfounded concerns of flush niacin in terms of the slight increases in glucose experienced (more noticeably) among those with type 2 diabetes, especially early-on as dosing is first-raised.On this note, before moving on, it is important to understand that any reports of “niacin” leading to or in any fashion being associated with insulin resistance (which you will from the information provided below realize is foolish to think, hint: TG/HDL-C ratio) are not actually for flush niacin aka immediate release nicotinic acid but for one of many alternatives. For instance, it is common for “niacin” to be reported for results pertinent to administration of not just flush niacin but flush niacin and interacting prescription Rx and/or OTC to inhibit/manipulate/interfere with/impede niacin’s therapeutic action(s). Often also is “niacin” being termed and reported (thus assumed to be flush niacin) as being the one to do with the release of findings in press (or social media) referring to results for an altered release version (e.g., sustained or extended release, the latter of which in fact made by Merck or Pfizer?) and so not just inferior to the natural (immediate release) form but even quite hepatotoxic (as the compound, niacin aka nicotinic acid (as crystalline powder in its natural form) is certainly not meant to be flowing in an altered way through the liver; note: flush niacin (i.e., immediate release nicotinic acid) is only amazing for the liver: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9274597/, https://www.jstage.jst.go.jp/article/jnsv/67/3/67_145/_article, https://jamanetwork.com/journals/jama/article-abstract/366299, https://www.lipidjournal.com/article/S1933-2874(19)30290-9/fulltext#secsectitle0015, https://academic.oup.com/jn/article/150/4/672/5681721?login=false, https://www.nature.com/articles/s41598-018-38002-7).
Not to forget, there is a study in rodents indicating insulin resistance associated with administration of high-dose flush niacin: However, not only does flush niacin turn into niacinamide (aka nicotinamide) in all rodents but the mice in that study were APOE*3-Leiden.CETP transgenic mice, meaning the subjects administered the flush niacin were mice in which flush niacin is not just turned into niacinamide (unlike as in humans) but that further also had a genetic mutation that made the turnover for extra NAD+ more constantly in greater demand. Thus, this genetic defect would contribute to acceleration of niacinamide overload by way of the overload of niacin (or chronic niacin supplementation as reported) in rodents (again, as remember, niacin turns into niacinamide, but not in humans).
Such a scenario, in humans (or other mammals for the most part) would be comparable to what manifests naturally over aging along the life epoch and/or in the face of exposure(s) that acutely or ultimately at last leads to too much energy induced into the body unaddressed and/or unprepared for as a result of insufficient flush niacin (turning into protons through its un-rate-limited biosynthesis of bigger molecules, i.e., NAD+ as well as NAADP+ in endolysosomes/T-cells for autophagy/debris clearance) through the body. Just as in rodents (especially those carrying the noted mutation), the regressing metabolic function overlapped into immune instability along DNA destruction that (often rapidly) develops into insulin resistance with further cardiometabolic dysfunction and potential cardiovascular disease, will be–upon accounting for any and all other factors involved that could be intervened upon–etiologically explained by the magnitude of the lack of flush niacin to have protected/countered sufficiently against incoming and/or accumulating energy induced into and through not in balance dynamically expended out. Experience of your body’s continuous momentum, in connection to the outside world, that is the lifespan will imminently with enough duration–without intervention (i.e., HOM3OSTASIS Protocol, as evoked from the body of evidence)–result in what is the consequences of the over-accumulating overload of niacinamide, which could be considered what then governs the course of the end of the existence within this extended progression of the body withering away into its end: disease pathology and aging. More so then, but still what simply physically- and mathematically-speaking comes down to being propelled forward as a function of the magnitude of how much flush niacin has been missed out on at that moment, if compounded with extra supplementation of niacinamide and/or nicotinamide riboside (NR) and/or nicotinamide mononucleotide (NMN) on top, then what will happen is in a nutshell as follows: in the face of the lack of flush niacin now and needing to compensate for needed NAD+ to be made, in correspondence to the extra energy accruing within/through the body, that can no longer be provided—the gut microbiome composition itself deliberately becoming dysbiosed as our cells, upon not being able to defend against the junction of too increasing of energy into the body, moves along the Warburg effect into more anerobic environments for tryptophan promiscuously but thankfully (or we would quickly die) to synthesize niacinamide (and in fact, NR too) amidst alternate routes through the kynurenine pathway.
This call it, trip-out of tryptophan becomes the only way to make NAD+ as its deficiency remains unaddressed beyond the time for it and so the pathology/aging itself to be pretty readily reversed via sufficient flush niacin supplementation as monotherapy. This stage presents usually within 3-4 months after the deficiency becomes clinically apparent, i.e., around when the folate stores become too depleted for comfort, which occurs once the saturation of niacinamide (in lieu of niacin) evolves into the point where meeting the need to provide sufficient SAMe from methionine to methylate overloading niacinamide in order for it to clear out the body without blowing up the liver (note again that ANY excess amount of flush niacin (and any of its metabolites) clears safely within hours the body through circulation and kidneys, as it does not need methylation) becomes more serious. Here, the dietary folic acid—which to make matters more complicated, needs not just NAD+ made by flush niacin, pyridoxal 5’-phosphate (PLP) through what appears to be its most favored precursor for us, pyridoxine, and predominately, methylcobalamin (in turn which does not become active until cyanocobalamin, its precursor, is coenzymated and converted into the methylcobalamin form within the body)—becomes unable to convert enough into the folate metabolites needed that it makes active to convert methionine to the growing amount (and rate) of SAMe needed as we progress to worse health status.
Meanwhile, too much strain is also hoarding on pyridoxine, i.e., vitamin B6 to continue to make the extra PLP (really, to supply the needed supply of the entire B6 cycling process) as the load for more SAMe builds, and interdependently, the already-limited (given its sensitive photolysis) content of vitamin B12, cyanocoblamin (as the initial precursor and thus actual vitamin needed to be exogenously administered through the oral down-the-GI to colon/liver route, akin to the other three B-vitamin molecules alongside at sufficient levels needed) to fuel continued aroused need for remethylation of homocysteine to make the extra needed methionine (… again, to keep making more SAMe to keep methylating perpetually and accumulatively overloading niacinamide). Putting further strain on vitamin B6, and ultimately, in concert, each of these four vitamins, the cycling of methionine through its own cycle (and in adjacency, folate’s) of 1-carbon transfer along with the preservation of sulfur beyond homocysteine into transsulfuration, as the appreciated demand for glutathione grows to counter oxidative stress that overdevelops along unaddressed inflammation (even more so along the already months-long flush niacin deficiency unaddressed without its previously-provided protection against environmental factors such as what should not be ignored, continuous more intense exposure each increment forward through it to the sun and electronics, meanwhile all as the body is already fighting against the junction of worsening sequelae progressing in the aftermath of the previously unaddressed over-accumulation of energy-accumulative exposures).
The downstream consequences of what occurs along evolving time and movement spent lacking flush niacin (and as that progresses, the other three B-vitamin compounds), is a compounding demand and detriment as a result of the lack of supply of each of these molecules then to sufficiently continue aforementioned conversions, among so many others, including each of these specific B vitamins holding mandatory, independent (but through-in-through interconnected) roles in converting each other into their what only then become active downstream intermediate forms through journey upon oral ingestion, along pit-stops operated upon by various gut microbiome species on the way down the GI and not just into and then of course within the intestine) is also ultimately expressed through disentanglement of the epidemiologic data as coming to light blatantly as well. Somewhat recently, it was unearthed in prospective data of the entire population-representative sample without missing data and in this way, much more minimal bias against association interpretation of causality (as opposed to most incoming results reported from longitudinal data from cohorts with the majority of data lost if over extended follow-up), after adjusting for all other covariates possible, it was unearthed how total (i.e., not just dietary but supplementation beyond levels provided in diet incorporated into the evaluation as well) intake of more of each of (and synergistically all of) ONLY these four B-vitamins (nicotinic acid, pyridoxine, folic acid, and cyanocobalamin) come up as not just preventative of cognitive decline but quite boosting of cognitive function from early adulthood into middle age: https://academic.oup.com/ajcn/article/106/4/1032/4652049. I hope it becomes more readily apparent how such is this case along our enrichment forward.
Not just flush niacin and these other B-vitamin molecules, but deficiency proceeds in all other nutrients, even the calories themselves, excreted out and not let through the body’s routes (this consequence primarily due to simply enough of a niacin deficiency developed), and with the others’ growing depletions along insufficient delivery coming from diet especially as niacin grows more deficient into declining health, the ability to produce enough erythrocytes (red blood cells) to empower and disperse niacin through the body, especially to the places most needed (and most arduous to reach), i.e., usually the brain/nerves. Therapy with flush niacin is in this way therefore not as comfortable and fast as it could be (https://www.sciencedirect.com/science/article/abs/pii/S0300483X09005228?via%3Dihub) until the other three B-vitamin precursor compounds are provided in sufficient amounts again to restore and regenerate from the damage of this niacinamide (in attempts to compensate for the lack of niacin) overload.
Please additionally recall that, as the salvage pathway is rate-limited and too much NAD+—upon niacin from diet reaching a threshold of insufficiency and being used up—is needed to counter the excess energy but that this rate-limited salvage biosynthesis remains perpetually then forward unable to make in time, is why niacinamide (as well as NR and NMN (what niacinamide and NR convert to as intermediate to their rate-limited emergency/salvage production of NAD+)) has repeatedly been demonstrated to induce insulin resistance and metabolic disturbances. Further, if you think about it, such is why indicated doses of these three salvage NAD+-precursors (i.e., niacinamide, NR, or NMN) are usually up to only 200-300 mg, as higher dosage has and will lead to not just insulin resistance but pretty much, comprehensive microcellular progression along further niacinamide overload (as supplementing NMN and/or NR will lead to even more niacinamide overload than niacinamide) and hence, along senescence / into disease pathology.
The biochemistry and arrangement of the NAD+ biosynthesis pathways are completely different in humans (and likely all mammals) versus rodents. In humans, all of the flush niacin converts down to NAD+ through nicotinic acid mononucleotide to NAAD, or its primary metabolite (and/or one or some of those of these intermediates on the way) simply does (do) not convert all the way to NAD+ and readily/safely clear(s) out circulation and kidney(s). If flush niacin is provided at the pharmacological-levels needed without further progress into full recovery in humans (and likely most if not all other mammals), this means it is not yet thermodynamically favorable (i.e., the gut species being provided enough of these other Bs that depleted over the continued niacin deficiency) for flush niacin to with NO rate limitation, swiftly start restoring the NAD+ deficiency and ultimately health. Such a situation would be accredited to a still-existing lack of pyridoxine, folic acid, and/or cyanocobalamin and so lack of their supplementation alongside flush niacin that is necessary for these conversions of niacin (and ditto for tryptophan, which if still being signaled to make niacinamide through the kynurenine pathway despite flush niacin now being provided at modest amounts, is also due to the lack of one or some combo of these other Bs) to have NAD+ be readily and systematically favorable through the body. Through all this disarray, flush niacin is also becoming less able to be processed, metabolized, and distributed through the gut and the liver appropriately to the rest of the body via enough red blood cells and hemoglobin metabolism—both of which are beyond focally regulated in cooperation by these Bs. Refer to this paper how folate stores were clinically shown markedly depleted in these middle-aged adult participants with mitochondrial disease pathology incoming at baseline (and with that, B6 and B12 used up more alongside and especially thereafter as the growing deficiencies for NAD+ and folate by flush niacin and folic acid, respectively, prolong), and how flush niacin still cured the diseases, though, as mentioned before, not as smoothly or expeditiously as it should have: https://www.sciencedirect.com/science/article/pii/S155041312030190X.
As also touched upon above, any excess/unused amount of flush niacin, its metabolites, and its particular main metabolite, nicotinuric acid, is streamlined safely through circulation and the kidney(s): https://academic.oup.com/ajhp/article-abstract/60/suppl_2/S9/5143532?redirectedFrom=fulltext. Therefore, despite reports of, for instance (even flush) “niacin being associated with glucose concerns and insulin resistance”, these statements are beyond misleading. The deliberate obfuscation, suppression, censorship, and in essence, withholding—in just this (albeit massive) sphere of cardiometabolic health—continues ongoing for generations to be responsible for unspoken, population-wide levels of healthy life years lost. With that, what follows below is some clarification and run-down of the most relevant clinical and research literature pertinent to the subject of diabetes and the defining intersection of flush niacin…
In the first formal double-blinded randomized controlled trial in humans of flush niacin as monotherapy in adults with type 2 diabetes, the Arterial Disease Multiple Intervention Trial (ADMIT) admitted 125 patients with hyperlipidemia and type 2 diabetes, and participants were assigned immediate-release niacin (preliminarily up to only 1 g per day) during a 12-week period. Patients were then randomly assigned to receive niacin or placebo for 48 additional weeks in which niacin doses averaged ~2.5 g daily. While niacin was associated with a slight increase in fasting glucose, the incremental gains in fasting glucose were most apparent during dose titration periods, with the glucose returning to baseline levels a few weeks later. Ultimately, these researchers concluded that flush niacin in doses less than 3 g per day is safely used in patients with type 2 diabetes.
Within a seminal follow-up analysis of the Coronary Drug Project in the mid-1980s, it was demonstrated that:
“Mortality in the niacin group was 11% lower than in the placebo group (52.0 versus 58.2%; p = 0.0004).”
https://www.sciencedirect.com/science/article/pii/S0735109786802935Notably, after treatment was discontinued, fasting glucose returned to baseline in the niacin-treated group but increased in the placebo group. Subsequent analysis pointed to the long-term cardiovascular benefits of niacin highly overpowering any supposed negative effects on glucose.
Synthesizing the data, when administered at doses of up to 2.5 g per day, flush niacin does not appear to have any type of clinically detrimental impact on glucose or HbA1c in most. The caution of flush niacin in those with diabetes pertaining to potential adverse glycemic effects appear to simply be the modification of the glucose control occurring during the initial segment of therapy during upward titration. Not only are the effects relatively transient, but the glucose levels return to near baseline levels after a few days to weeks (depending on dosing). These aforementioned modest early gains in blood sugar levels, I would argue, should be interpreted as positive glycemic effects representing restoration of glucose control and reversing of insulin resistance (after all, the TG/HDL-C ratio, which flush niacin is unsurpassed and causal intervention for keeping stable and/or improving, is the clinically standard metric for diagnosis of insulin resistance as well as perhaps the most potent indicator of incident cardiovascular disease [as well as COVID-19 morbidity and mortality]; see my paper and others’: https://www.ahajournals.org/doi/abs/10.1161/circ.133.suppl_1.mp37; https://www.ahajournals.org/doi/10.1161/ATVBAHA.119.313381, https://linkinghub.elsevier.com/retrieve/pii/S2352396422003474, https://www.nature.com/articles/s41598-021-86747-5, https://www.dovepress.com/triglyceridehigh-density-lipoprotein-cholesterol-ratio-is-associated-w-peer-reviewed-fulltext-article-IJGM) that are simply more pronounced as the progression along cardiometabolic dysfunction into type 2 diabetes presentation proceeds.
“This meta-analysis involved 2,110 patients with T2DM from 8 RCTs across a wide range of patients’ characteristics. The results of this study suggested that niacin supplementation significantly reduced TC, TG, & LDL, and increased the level of HDL.”
https://journals.lww.com/md-journal/fulltext/2020/07170/effectiveness_of_niacin_supplementation_for.94.aspx
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“Niacin use significantly increased HDL-C by 29% and 29% and decreased triglycerides by 23% and 28% and LDL-C by 8% and 9%, respectively, in participants with and without diabetes.”
https://jamanetwork.com/journals/jama/fullarticle/193064
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“niacin therapy had typical effects on routine clinical lipids (HDL-C + 16%, q < 0.01; LDL-C − 20%, q < 0.01; and triglyceride − 15%, q = 0.1)”
https://lipidworld.biomedcentral.com/articles/10.1186/s12944-020-01350-3
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“niacin retains an FDA-approved indication as monotherapy for treating dyslipidemia, a main risk factor for cardiovascular events and myocardial infarction”
“Stratified meta-analysis showed an association of niacin monotherapy with reduction of some cardiovascular events among patients WITHOUT statin treatment (acute coronary syndrome: relative risk, 0.68; 95% CI, 0.58-0.96; stroke: 0.69; 95% CI, 0.59-0.94; revascularization: 0.51; 95% CI, 0.37-0.72). These results were mainly derived from 2 trials conducted in the 1970s and 1980s”
https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2730481
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“Our study concludes that lipid-modifying dosages of niacin can be safely used in patients with diabetes and that niacin should be used for patients with diabetes to sufficiently correct hypertriglyceridemia or low HDL-C levels.”
https://read.qxmd.com/read/10979113/effect-of-niacin-on-lipid-and-lipoprotein-levels-and-glycemic-control-in-patients-with-diabetes-and-peripheral-arterial-disease-the-admit-study-a-randomized-trial-arterial-disease-multiple-intervention-trial
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P.S.
As I have been reporting with passion for several years now, the expression of the framework of the GPR109A receptor—for which flush niacin is the innate, most powerful and genetically preserved fashion of binding as ligand/agonist to this receptor—serving as a dynamically accountant-like barometer measurement, indicator, and target for anti-inflammation, really how much niacin is needed to reach the receptor expressed in each cell of the body in order to institute a reversal of the junction in pathology towards metabolic + cellular restoration, applies ubiquitously across the disease spectrum, and so follows the same script for the endocrinologic regions along diabetic pathogeneses: https://www.sciencedirect.com/science/article/pii/S0016648016302507. To add insult to injury to uninformed (or well-acted) niacin-naysayers, check out this very recent finding published of the GPR109A receptor for even type 1 diabetes:
“The findings reveal that macrophage GPR109a deficiency accelerates the development of T1D. Activation of GPR109a on macrophage by dietary components may provide a new strategy for preventing or treating T1D.”
https://onlinelibrary.wiley.com/doi/10.1002/mnfr.202200300
Dynamically recouping to clear the damage and/or providing sufficient flush niacin (along with relevant levels addressed in deficiencies and needs of the other key B vitamin compounds alongside) of which diet (especially mother’s while in her womb or depending on her (or surrogate) breast milk for many months) is well-beyond just unequipped (and now most especially while ever growingly forward these days)—is also underlying to prevention and basis for therapeutic regimen of the type 1 presentation of diabetes instituted earlier in the life course, not just to the more environmentally-induced type 2 disposition experienced in adulthood (as is the case for any disease, condition, etc).
Here are some more relevant papers…
https://iovs.arvojournals.org/article.aspx?articleid=2188684
https://pubmed.ncbi.nlm.nih.gov/23701262/
^ yet another bioharma attempt of a fake thus not just inferior but toxic niacin analogue/derivative… oh, and on that note, look what else tries (unsuccessfully, of course, as always) niacin-GPR109A power for therapy (as they just completely “ignore” flush niacin’s most innate, potent, needed binding that is intrinsically meant to be the compound to do this through its own receptor), metfoformin: http://www.annclinlabsci.org/content/47/5/556.long … and not only does it fail in this, but it also even DOWNREGULATES the GPR109A after the fact of trying to attach to it!
Enjoy!