Does Niacinamide contribute to diabetes and insulin resistance?

Vitamin B3 comes in a few forms, with niacin (nicotinic acid (NA)), niacinamide (NAM), nicotinamide riboside (NR) and inositol hexanicotinate being the most famous.

Nicotinamide N-methyltransferase: more than a vitamin B3 clearan

As you can see from the picture, vitamin B3 can come in three forms from the diet, namely NA, NAM and NR, whereas an endogenous pathway can also synthesize NAM from tryptophan. NAM is converted to nicotinamide mononucleotide (NMN) by the enzyme nicotinamide phosphoribosyltransferase (NAMPT). NAMPT is the rate-limited step in NAD+ synthesis and regulates Sirt1 (sirtuins)-mediated function by modulating NAD+ availability (higher NAD+ levels means higher Sirt1 activity). NMN is then converted to NAD+ via the enzyme nicotinamide mononucleotide adenylyltransferase (NMNAT).

Nicotinamide adenine dinucleotide (NAD) is a classic coenzyme that exerts its biological effects via many redox and non-redox reactions.

NAD+ can then be broken down/reconverted back to niacinamide (NAM) by Sirt1 (which regulates fat and glucose metabolism), PARPs (mono- and poly-ADP ribosyltransferases; which regulates genes and is involved in DNA repair and cellular function) and ADP-ribose cyclases (CD38, CD158) (which regulates intracellular calcium), which then inhibits their enzymatic activity when NAD levels drop too low.

NAM metabolism2

As you can see from this picture, NAD+ increases energy metabolism, and sirt1 can actually decrease energy metabolism, by converting NAD+ back to NAM.

The important pathway that I want to talk about, the one this blog is based on, is NNMT (Nicotinamide N-Methyltransferase). NNMT converts NAM to N1-methylniacinamide (MNAM), and s-adenosylmethionine (SAM) donates a methyl group. SAM and is converted to SAH, which in turn is converted to homocysteine. The higher NNMT activity is, the more MNAM and homocysteine you will have.

This is where everyone starts to think NAM is bad for you, because it depletes SAM, raises homocysteine, which increases inflammation, lowers methylation of estrogen, serotonin, histamine, adrenaline, DNA, etc., and contributes to diabetes and obesity.

But why only niacinamide (NAM)? Because NAM increases the activity of NNMT to a greater extent than nicotinic acid (NA).

But let me tell you that vitamin B3 is not the only substance methylated via NNMT, but also pyridine. (1) From the study:

“Around 1980 a mini-epidemic that involved a different pyridine, MPTP, occurred again in extreme circumstances. Drug addicts took the compound parenterally and gave themselves acute Parkinsonism.”

MPTP is produced from 4-phenylpyridine known to be present in diet and to form MPPC
directly using the same enzyme that is involved with NAM catabolism, NNMT. Pyridine occurs in any compound that has a pyridine ring structure, and these include some pharmaceutical drugs, bactericides and herbicides.

But before I explain more in-depth, let’s discuss how the body deals with MNAM, why it NNMT is elevated and that MNAM is actually protective.

The clearance pathway for MNAM, as can be seen in picture 1, is via aldehyde oxidase (Aox, which produces reactive oxygen species in the process). Aox requires vitamin B2 and molybdenum as cofactors. A deficiency in vitamin B2 and molybdenum could result in a rise in MNAM levels. The two end-products of Aox, N1-methyl-2-pyridone-5-carboxamide (2py) and N1-methyl-4-pyridone-3-carboxamide (4py), together with MNAM are eventually excreted in the urine.

The secondary clearance pathway for excess NAM starts with the direct oxidation of NAM to NAM N-oxide by cyp2E1, followed by elimination in the urine.

Sweating is a major excretion pathway for excess NAM. This study shows that there is a more than x5 increase in sweat NAM with no change in MNAM levels after an oral NAM dose of 100mg. (2)

Under most conditions, methylation is quantitatively by far the predominant NAM clearance pathway with the exception of an acute pharmacological dose of NAM, which is mainly converted to NAM N-oxide. As a result of increased NAM methylation, it reduces SAM and the size of betaine pool; which subsequently inhibits the methylation of endogenous substrates (e.g., catecholamines and DNA), leading to an increase in plasma norepinephrine levels and DNA hypomethylation. (3)

It’s highly unlikely that NAM will cause DNA hypomethylation, unless someone isn’t eating real food, and is severely deficient in methionine, betaine, choline, folate, vitamin B12, etc.

Estimates suggest that less than 1% of the total urinary loss of methyl groups can be attributed to NNMT activity. (1) Plus, when niacinamide is ingested in very high amounts, the major metabolite is Nam N-oxide (via CYP2E1) and not metabolites from methylation. (4)

Another pathway that can reduce excessive methyl donors, is the enzyme glycine N-methyltransferase (GNMT). GNMT is a major liver methyltransferase that methylates glycine to form sarcosine. (Sidenote: retinoic acid/vitamin A, increases GNMT activity)

When SAM is high, GNMT activity is high, and vice versa. When GNMT is not working properly (genetic mutation/glycine deficiency), SAM stays elevated. This can lead to DNA hypermethylation, cancer and tumor growth (increase in polyamines), liver disease (fatty liver and fibrosis), etc. (5) Luckily NAM through diet or supplementation can lower liver SAM content when GNMT isn’t sufficient.

As a side note, nicotinic acid is converted to trigonelline (MNA) via NNMT and not to MNAM. (1)

 

NNMT, MNAM on insulin resistance and obesity

MNAM levels and NNMT expression are almost two-fold elevated in diabetes and obesity and are thought the be the causative factor. (6, 7, 8)

Niacinamide supplementation increases NNMT expression directly, so it contributes to the hypothesis that NAM can contribute to insulin resistance.

But…NAM, NNMT and MNAM are not the cause or reason for insulin resistance or diabetes because CYP2E1 and NNMT are equally upregulated in diabetes and those are upregulated in the absence of any NAM supplementation. (9, 10) Also as mentioned above, niacinamide is not the only substrate for NNMT. This shows that another factor must be regulating NNMT expression and MNAM levels.

First off, NAM lowers methyl groups slightly, thus reducing catechol-O-methyltransferase (COMT) activity. COMT is one of several enzymes that degrade catecholamines, catecholestrogens, and various drugs and substances having a catechol structure.

So basically less COMT will lead to more catecholamines, such as adrenaline, and this is exactly what we see with NAM and NA supplementation. An increase in adrenaline and noradrenaline. (11) The problem with these catecholamines is that it stimulates lipolysis, which is the enzyme that liberates fatty acids from fat stores. This is important because basal plasma free fatty acids (FFAs) can lead to hyperinsulinemia in normoglycemic obese subjects, contributing to insulin resistance (12).

NA supplementation increases circulating FFAs, due to a fatty acid rebound. Initially, it suppresses lipolysis, with FFA levels reaching a nadir in as little as 1.5 hours after NA treatment, but then subsequently rebounds as early as 3 hours after NA. (13) Higher catecholamines, cortisol and growth hormone leads to higher FFAs, which leads to hyperinsulinemia and a reduction in insulin sensitivity.

Niacinamide, and not niacin, decreases 11β-HSD1, which is the enzyme that converts cortisone into the active hormone, cortisol, thus making it anti-cortisol, unlike niacin.

This is all because of a drop in methyl donors, which reduces COMT activity. Supplementing betaine (which converts homocysteine to methionine), will prevent the increase in homocysteine and also provide new methyl donors to prevent the decrease in COMT activity. Taking extra vitamin B6 (<10mg) will also reduce homocysteine levels by converting it so cysteine.

Niacin also spikes growth hormone, which is known to increase the release of FFAs, thus causing an FFA rebound.

Nicotinamide does not affect insulin secretion and glucose kinetics in normal subjects, confirming its suitability for trials designed to delay or prevent the onset of Type 1 diabetes, whereas nicotinic acid, structurally similar to nicotinamide, induces insulin resistance and increases insulin secretion in healthy individuals. (14)

This study (15) shows that niacinamide supplementation reduced fasting glucose, insulin levels and triglycerides and increased adiponectin, indicating improved insulin sensitivity.

NAM also increase NAMPT (the rate-limited step in NAD+ synthesis), total NAD+ levels, the NAD:NADH ratio, Sirt1, 2, 3, and 6 mRNA expressions, Sirt1 activity, proliferator-activated receptor gamma (PPARγ), coactivator 1 alpha (PGC-1α) and mitochondrial DNA.

NAM will increase the production of new, proper working mitochondria while improving glucose oxidation and insulin sensitivity. NAM was also better than NA at doing all this. The human equivalent dose is 1-1.5g daily.

If you want to avoid a rise in GH, cortisol and free fatty acid rebound, don’t take it on an empty stomach.

 

So how do niacinamide affect fat loss

A high NAD:NADH increases AMPK, which improves glucose and fatty acid oxidation. (16) Improper oxidation of fats and glucose leads to oxidative stress, inflammation and fat gain.

An increase in NNMT activity increases the formation of new fats and subsequent fat gain, and inhibiting NNMT (with methylquinolinium) reduces lipogenesis and reduces body weight. (17) Although NAM increases NNMT, the effect is minimal and other factors, such as oxidative stress and inflammation increases NNMT activity to a greater extent and contributes to insulin resistance and fat gain. Coffee, nicotine and copper are natural NNMT inhibitors. (18, 19)

Also, MNAM works in a negative feedback loop and inhibits NNMT activity, and increases oxygen consumption and fat loss. (20) Yes, you read that right. MNAM actually contributes to fat loss and inhibits excessive NNMT activity.

MNAM increases the tyrosine:phenylalanine ratio by increasing the enzyme phenylalanine hydroxylase. It does so by inhibiting free radical production through NADPH oxidase (NAM inhibit excessive NADPH oxidase activity) and thus stabilizing Tetrahydrobiopterin (BH4), which is involved in neurotransmitter synthesis. This leads to an increase in dopamine production, which inhibits prolactin and serotonin, which are metabolic inhibitors. (21)

An increase in NNMT can rather be seen as a protective measure, by reducing the risk for cancer and tumors, protect against cardiovascular disease, etc., instead of a causative effect of diabetes and obesity.

 

A few things to know about NNMT and MNAM:

  • NNMT increases ATP synthesis (22).
  • Blocking NNMT does not lead to an accumulation of NAM or NAD. (1)
  • Blocking NNMT does not change SAM/SAH ratio in the livers of mice or primary hepatocytes.
  • MNAM lowers liver inflammation (IL-4 and TNFα) by a prostacyclin-dependent mechanism, thus lowering NNMT activity. (23)
  • MNAM reduces secretion of homocysteine in white adipose tissue. (24)
  • MNAM protects against cardiovascular disease, by increasing prostacyclin (PGI2), nitric oxide (NO) and lipid droplet formation. PGI2 inhibits platelet aggregation and is anti-thrombotic. Nitric oxide induces vasodilation. Lipid droplet formation lowers circulating toxic arachidonic acid.
  • MNAM is an angiotensin-converting enzyme (ACE) inhibitor, which lowers blood pressure and reactive oxygen species formation. (Angiotensin increases NADPH oxidase, which oxidizes BH4, hence lowering NO and dopamine levels)

 

Factors that increase NNMT activity:

  • STAT3 (induced by inflammatory cytokines) and hepatocyte nuclear factor-1beta (HNF1β) increase NNMT promoter activity in cancer cells (1)
  • IL-6, TNFα, TGFβ (promotes fibrosis), interferon-gamma (IFNγ) all increase NNMT expression. This might be because inflammation increases cortisol and phospholipase, which cleaves phospholipids, such as phosphatidylcholine from cell membranes, thus increasing methyl donors. More methyl donors = more SAM = more NNMT. (25)
  • A reduction in ATP and energy failure induced by hypoxia or metabolic stress increase NNMT (26)
  • MNAM positively correlates with C-reactive protein (CRP; which is a marker of inflammation). Keeping polyunsaturated fats (PUFAs) as low as possible will keep inflammation and CRP low. (27)
  • A high-fat diet, possibly via a decreasing in ATP and NAD+ and an increase in Sirt1, increases NNMT. (28)
  • Manganese excess increase NNMT. (29)
  • Fasting and stress, which is similar to the drop in ATP, increase NNMT. The newly formed MNAM then stimulates lipolysis. So it goes like this: Eating enough glucose for oxidative metabolism lowers NNMT, as there is little need for lipolysis, and fasting increase NNMT to stimulate lipolysis because there is a lack of glucose. Diabetics have impaired glucose oxidation, so are almost constantly in a “fasted” state, which contributes to the elevated NNMT. (30)

 

Conclusion

NAM does not cause insulin resistance or lead to obesity, but is successfully used to prevent type I diabetes and reverse type II diabetes, and it might also actually aid in fat loss. If NAM is causing problems, it could be that you are under stress and have inflammation somewhere in the body. But luckily, NAM is also anti-inflammation.

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