Sunday, March 23, 2014

Niacin (B3) & Glucose Management | Part V of the "There is More To Glucose Control Than Carbohydrates"-Series. Plus: Can You Use Niacin to Ramp Up Fat Burning During Fasts?

Some scientists speculate that the niacin could be the root cause of the diabesity epidemic. Others believe it's the solution.
After last the installments on vitamin D and calcium, I decided that it would be about time to talk about a nutrient with (purported) negative effects on blood glucose management. After some serious head-scratching I chose niacin aka nicotinic acid and it's innocent brother niacinamide for today's fifth installment of the  my choice "There is More To Glucose Control Than Carbohydrates"-Series.

Even if you haven't been following the SuppVersity articles over the last years, you will probably be aware of some of the health effects high and low vitamin B3... ha? Right! Niacin is the only vitamin with proven HDL boosting effects (van der Hoorn. 2008).
You can learn more about this topic at the SuppVersity

Proteins, Peptides & Blood Glucose

SFA, MUFA, PUFA & Blood Glucose

Vitamin D & Diabetes

Glucose Manager Calcium?

Flush & No-Flush Niacin & Diabesity

There is more to come!
The patented slow-release version "Niaspan" is often administered in conjunction with statins to patients with hypercholesteremia - quite successfully, actually... well, at least if you discard the debilitating effects both statins and slow release niacin can have on your musculature - as a series of case-reports from the Mayo Graduate School in Rochester and the Cardiovascular Institute in New York shows, even when niacin is administered without additional lipid-lowering drugs (Litin. 1989; Gharavi. 1994 | please keep in mind that all patients in these studies were well beyond 60 and high blood lipids were not their only health problems)... but I am losing sight of our actual topic.

It's not all about blood lipid management 

While the (albeit low) risk of niacin-induced myopathies have gained only minimal attention among the research community, early reports of niacin induced insulin resistance and an significant increases in fasting blood sugar in diabetes patients on Niaspan therapy (Garg. 1990), on the other hand, have lead to a marginalization of niacin as a standalone treatment of which more recent studies would suggest that they are more or less unwarranted (Grundy. 2002).

In a 16-week, double-blind, placebo-controlled trial with 148 patients who were randomized to placebo (n = 49) or 1000 (n = 45) or 1500 mg/d (n = 52) of extended release niacin (47% of the patients were on statins at the same time), Grundy et al. found that the "rates of adverse event rates other than flushing were similar for the niacin and placebo groups" and conclude that, even in type II diabetics, "[l]ow doses of ER niacin (1000 or 1500 mg/d) are a treatment option for dyslipidemia." (Grundy. 2002)

Niacin & glucose metabolism beyond metabolic syndrome

In view of the fact that I hope that only a small minority of you will (still) belong to the group of patients doctors ans scientists usually lump together as patients suffering from "metabolic syndrome", I would suggest we steer away from the niacin for cholesterol management issue and assume a more glucose-specific perspective to decide, whether or not niacin and/or niconamide supplements or fortified foods could compromise your glucose sensitivity.

To this ends, it may make sense to take a close look at the mechanism that's responsible for the previously described increase in blood glucose in type II diabetics and the significant reductions in of the glucose infusion rate Kelly et al. measured in a study with healthy 7 healthy volunteers who had been consuming 500 mg daily nicotinic acid (=regular niacin) for 7 days then 1 g daily for a further 7 days in euglycemic clamp scenario (Kelly. 2002).

What's the mechanism?

It is generally accepted that the negative effects of niacin are mediated by its interaction with the GPR109A receptor. What scientists still argue about is, whether the effects of the ingestion of high amounts of niacin (not niacinamide, by the way!) are of direct or indirect nature. 

Now, contrary to common believe, science is actually a very simple business. In physics, specifically, history has told us that it's usually the simpler of two competing hypothesis that's the right one. Against that background it's not unlikely that the negative effects of niacin aka nicotinic acid (pyridine-3-carboxylic acid, cf. Guyton. 2007) are nothing but the mechanistic profound changes in the amount and handling of blood lipids.
Figure 1: Illustration of the niacin induced changes in FFA (initial drop and rebound after 2h); levels were measured in healthy normolipidemic volunteers after the ingestion of 2g of regular niacin (Wang. 2000)
For you as a diligent reader of the SuppVersity it should not be too difficult to see that it's the FFA / TG pin-pong that's brought up by niacin's ability to suppress the release of free fatty acids via its interaction with the GPR109A receptor which is at the heart of the acute impairments in glucose uptake (Offermanns. 2006 | recent studies have shown that this effect is accompanied by a stimulation of adiponectin production, an adipokine with beneficial effects on glucose metabolism; cf. Plaisance. 2009).
Figure 2: Consider the growth hormone release in response to the administration of niacin and the drop of free fatty acids an "added bonus" - not a growth bonus, but certainly one that will increase the liberation of bound and oxidation of free fatty acids (data based on Quabbe. 1983).
Can you (ab-)use niacin during (intermittent) fasts? Actually, I have been thinking about ways to (ab-)use the rebound effect that occurs with large (>1,000mg of niacin - in people at risk of developing type II diabetes, even niacinamide; cf. Greenbaum. 1996) for quite some time now. Someone who is "intermittent fasting", for example, should be able to ingest a large amount of niacin before a low(-ish) fat, high carb meal (e.g. after a workout) should actually benefit from the low free fatty acid & triglyceride levels in the blood (Usman. 2012) and the corresponding increase in insulin sensitivity / glucose uptake (Boden. 1997) and give a damn about the free fatty acid rebound that occurs a couple of hours later (Kamanna. 2008). In healthy individuals, the sudden appearance of large amounts of free fatty acids in the blood stream would even ramp up fatty oxidation and thus increase the energy availability during the fast - wouldn't be too bad, don't you thinks so?
Blood lipids up, glucose tolerance down! It's as easy as that and in the end a result of the way our bodies react to the overabundance of a certain type of energy source by prioritizing its usage of that of another one; and during the free fatty acid rebound that occurs ~2-3h after the ingestion of nicotinic acid the overabundant energy source if fat.

As the words "temporary" and "adaptation" in the previous sentence already suggest, this does not necessarily have to be a bad thing. I mean, as long as you don't stuff yourself with carbs during this 3h+ "fat flood" (the actual length depends on the dosage and will vary from person to person), your fasting blood glucose levels will remain stable.
Figure 3: Correlation between diabetes & obesity prevalence (left) and per capita niacin intake (mg/day) and obesity prevalence in US adults (right) from 1920 to 2000 (Zhou. 2010)
Against that background it is in my humble opinion unwarranted to speculate about a causal nature of the the correlation between the increased diabetes and obesity ratesm on the one hand, and the average per capita niacin intake of the average American you can see in Figure 3 - and that in spite of rodent studies by the same researchers which suggest that "long-term high nicotinamide intake (e.g. induced by niacin fortification) may be a risk factor for methylation- and insulin resistance-related metabolic abnormalities" (Li. 2013).

In view of the fact that grains (flour and cereals) are the most widely used vehicles for niacin-fortification, it should be obvious that the over-consumption of over-processed, but fortified junk foods, and not the relatively small amounts of extra niacin in this "foods" are much more likely to explain the increased prevalence of obesity in US adults and children, Zhou et al. and Li et to explain by a "chronic niacin overload" in their 2010 papers in BMC Public Health (Zhou. 2010) and the World Journal of Gastroenerology (Li. 2010).

On the other hand...

Moreover, we are, as usual, dealing with conflicting evidence, some of you may actually remember from the SuppVersity Facebook News (like and make sure you always stay ahead of the game | read the corresponding news item on niacin). In a rodent model of obesity and type II diabetes, a group of scientists from South Korea observed small, albeit significant increases in glucose tolerance in response to the administration of both high dose niacin (NA) and niacinamide (with niacinamide > niacin; Yang. 2014).
Figure 4: Changes in blood glucose, insulin, HOMA-IR and triglyceride levels in response to 10/100mg of niacin (NA) or niacinamide (NAM) in a rodent model of obesity and type II diabetes (Yang. 2014)
And while both nicotinic acid (niacin) and niacinamide led to improvements in insulin sensitivity (= reduced HOMA-IR), the latter lead to significant increases in triglycerides which stand in contrast to the triglyceride lowering effects of nicotinic acid.

In addition to that, there is evidence that niacin and nicotinamide decreases high glucose-dependent oxidative stress (Ye. 2011; Torres-Ramírez. 2013). What we don't have though, is reliable evidence from controlled human studies to support this Janus-faced nature of "niacin" and the purported benefits of high dose niacinamide supplementation:
  • Reduced incidence of type I diabetes: Although this would appear to be rather an auto-immune issue, the net consequences of the results of a population‑based diabetes prevention trial that was conducted on school children aged 5‑7.9 years are obviously of utmost importance for glucose control (Elliott. 1996). The kids who received sustained‑release
    niacinamide 1.2 grams/m² (body surface area) per day for an average of 7.1 years had a
    lower incidence of T1DM versus controls.
  • Niacinamide may also have protective benefits in T2DM. A single blind study of 18 diabetic patients found that niacinamide improves C‑peptide release leading to a metabolic control similar to patients treated with insulin (Pozzilli. 1996).

    The patients had been assigned for 6‑month to either: (1) insulin plus nicotinamide (500 mg three tablets/day); (2) insulin plus placebo (3 tablets/day) and (3) current sulphonylureas plus nicotinamide (500 mg three tablets/day). Compared to the placebo group, C‑peptide release increased in both the insulin/niacinamide and sulphonylureas/niacinamide groups, while HbA1C, fasting and mean daily blood glucose levels improved in the three groups to the same extent.
Eventually, I would thus be hesitant to recommend using amounts of 1,500mg of niacinamide or niacin / nicotinic acid (the terms are used inter-changeably) per day as a strategy to prevent the development of type II diabetes. If you stay active and stay away from the niacin-fortified junk Zhou and Li failed to recognize as the common denominator of the increases in niacin intake, obesity and diabetes, you don't need it anyway.
Figure 5: The increases in HOMA-IR Westphal et al. observed in response to the administration of 1g/1.5g of niacin in patients with high LDL and low HDL levels look more severe than they actually are - in fact, they did not even achieve statistical significance. In contrast to the beneficial effects on adiponectin and HDL (Westphal. 2006)
Bottom line: Our regular niacin intake, as well as the comparatively low amounts of niacin and niacinamide in multi-vitamins and other useless supplements are not going to push you over the diabetic edge. As far as high dose supplements are concerned, we will probably have to distinguish between extended release (ET) preparations, which would be used for lipid management and immediate release forms of niacin and nicotinamide.

The extended release (ET) preparations appear to be useful as lipid lowering drugs. Their effects on blood glucose management are yet either neutral or negative (). High amounts of the "regular", flush-niacin, will produce a free fatty acid rebound and transient impairments in insulin sensitivity, of which I would like to see if you they cannot be used to your advantage (see infobox "Can you (ab-)use niacin during fasts?". Unlike ET and "flush" niacin, nicotinamide does not interact with the GPR109A receptor (Soga. 2003; Tunaru. 2003; Wise. 2003) and will thus neither produce free fatty acid rebounds nor will it raise your HDL, adiponectin and leptin levels (Westphal. 2006 & 2007; see Figure 5). In other words, it's benign, but useless - this is at least what we have to assume until there is convincing evidence from human studies outside of type-I-diabetes scenarios as they were described by Elliott (1996) or Pozzilli (1995).
  • Boden, Guenther. "Role of fatty acids in the pathogenesis of insulin resistance and NIDDM." Diabetes 46.1 (1997): 3-10.
  • Elliott, Robert B., et al. "A population based strategy to prevent insulin-dependent diabetes using nicotinamide." Journal of Pediatric Endocrinology and Metabolism 9.5 (1996): 501-510.
  • Fernandez-Mejia, Cristina. "Pharmacological effects of biotin." The Journal of nutritional biochemistry 16.7 (2005): 424-427. 
  • Garg, Abhimanyu, and Scott M. Grundy. "Nicotinic acid as therapy for dyslipidemia in non—insulin-dependent diabetes mellitus." Jama 264.6 (1990): 723-726.
  • Gharavi, Ali G., et al. "Niacin-induced myopathy." The American journal of cardiology 74.8 (1994): 841-842.
  • Greenbaum, Carla J., Steven E. Kahn, and Jerry P. Palmer. "Nicotinamide's effects on glucose metabolism in subjects at risk for IDDM." Diabetes 45.11 (1996): 1631-1634.
  • Guyton, John R. "Niacin in cardiovascular prevention: mechanisms, efficacy, and safety." Current opinion in lipidology 18.4 (2007): 415-420.
  • Grundy, Scott M., et al. "Efficacy, safety, and tolerability of once-daily niacin for the treatment of dyslipidemia associated with type 2 diabetes: results of the assessment of diabetes control and evaluation of the efficacy of niaspan trial." Archives of internal medicine 162.14 (2002): 1568-1576.
  • Kamanna, Vaijinath S., and Moti L. Kashyap. "Mechanism of action of niacin." The American journal of cardiology 101.8 (2008): S20-S26. 
  • Kelly, J. J., et al. "Effects of nicotinic acid on insulin sensitivity and blood pressure in healthy subjects." Journal of human hypertension 14.9 (2000).
  • Lauring, Brett, et al. "Niacin lipid efficacy is independent of both the niacin receptor GPR109A and free fatty acid suppression." Science translational medicine 4.148 (2012): 148ra115-148ra115. 
  • Li, Da, et al. "Chronic niacin overload may be involved in the increased prevalence of obesity in US children." World journal of gastroenterology: WJG 16.19 (2010): 2378. 
  • Li, Da, et al. "Nicotinamide supplementation induces detrimental metabolic and epigenetic changes in developing rats." British Journal of Nutrition 110.12 (2013): 2156-2164.
  • Litin, Scott C., and Carl F. Anderson. "Nicotinic acid-associated myopathy: a report of three cases." The American journal of medicine 86.4 (1989): 481-483.
  • McCarty, M. F. "High-dose biotin, an inducer of glucokinase expression, may synergize with chromium picolinate to enable a definitive nutritional therapy for type II diabetes." Medical hypotheses 52.5 (1999): 401-406. 
  • Offermanns, Stefan. "The nicotinic acid receptor GPR109A (HM74A or PUMA-G) as a new therapeutic target." Trends in pharmacological sciences 27.7 (2006): 384-390.
  • Plaisance, Eric P., et al. "Niacin stimulates adiponectin secretion through the GPR109A receptor." American Journal of Physiology-Endocrinology and Metabolism 296.3 (2009): E549-E558.
  • Pozzilli, P., et al. "Adjuvant therapy in recent onset type 1 diabetes at diagnosis and insulin requirement after 2 years." Diabete & metabolisme 21.1 (1995): 47-49.
  • Pozzilli, Paolo, Peter D. Browne, and Hubert Kolb. "Meta-analysis of nicotinamide treatment in patients with recent-onset IDDM." Diabetes Care 19.12 (1996): 1357-1363.
  • Quabbe, Hans-Jürgen, et al. "Growth Hormone, Cortisol, and Glucagon Concentrations during Plasma Free Fatty Acid Depression: Different Effects of Nicotinic Acid and an Adenosine Derivative (BM 11.189)*." The Journal of Clinical Endocrinology & Metabolism 57.2 (1983): 410-414. 
  • Soga, Takatoshi, et al. "Molecular identification of nicotinic acid receptor." Biochemical and biophysical research communications 303.1 (2003): 364-369. 
  • Torres-Ramírez, Nayeli, et al. "Nicotinamide, a glucose-6-phosphate dehydrogenase non-competitive mixed inhibitor, modifies redox balance and lipid accumulation in 3T3-L1 cells." Life sciences 93.25 (2013): 975-985.
  • Tunaru, Sorin, et al. "PUMA-G and HM74 are receptors for nicotinic acid and mediate its anti-lipolytic effect." Nature medicine 9.3 (2003): 352-355.
  • Usman, M. Haris U., et al. "Extended-release Niacin Acutely Suppresses Postprandial Triglyceridemia." The American journal of medicine 125.10 (2012): 1026-1035.
  • van der Hoorn, José WA, et al. "Niacin increases HDL by reducing hepatic expression and plasma levels of cholesteryl ester transfer protein in APOE* 3Leiden. CETP mice." Arteriosclerosis, thrombosis, and vascular biology 28.11 (2008): 2016-2022.
  • Wang, Wei, et al. "Effects of nicotinic acid on fatty acid kinetics, fuel selection, and pathways of glucose production in women." American Journal of Physiology-Endocrinology And Metabolism 279.1 (2000): E50-E59.
  • Westphal, Sabine, et al. "Extended-release niacin raises adiponectin and leptin." Atherosclerosis 193.2 (2007): 361-365. 
  • Wise, Alan, et al. "Molecular identification of high and low affinity receptors for nicotinic acid." Journal of Biological Chemistry 278.11 (2003): 9869-9874.
  • Yang, Soo Jin, et al. "Nicotinamide improves glucose metabolism and affects the hepatic NAD-sirtuin pathway in a rodent model of obesity and type 2 diabetes." The Journal of nutritional biochemistry 25.1 (2014): 66-72.
  • Ye, X., et al. "Niaspan reduces high-mobility group box 1/receptor for advanced glycation endproducts after stroke in type-1 diabetic rats." Neuroscience 190 (2011): 339-345.
  • Zhou, Shi-Sheng, et al. "B-vitamin consumption and the prevalence of diabetes and obesity among the US adults: population based ecological study." BMC public health 10.1 (2010): 746.