Berberine May Reduce Cardiovascular Risk

Berberine (which I wrote about here) is a herbal supplement obtained from a number of different plants, which Chinese medicine has used for perhaps thousands of years. Its physiological mechanism most resembles metformin, the world’s most prescribed diabetes drug. It lowers blood glucose, activates AMPK, and does a seemingly endless number of other beneficial things. And berberine may reduce cardiovascular risk.

Endothelial cells

Endothelial cells are those cells that line arteries and are very important for cardiovascular health. When the cells lining arteries don’t function well, this is known as endothelial dysfunction.

The vascular endothelium, which regulates the passage of macromolecules and circulating cells from blood to tissues, is a major target of oxidative stress, playing a critical role in the pathophysiology of several vascular diseases and disorders.

Vascular endothelial cells have a finite lifespan and can enter a state of senescence and promote atherosclerosis. Maintaining youthful and healthy endothelial cells in the lining of arteries is essential for cardiovascular health.

Older or senescent endothelial cells produce lower amounts of nitric oxide, the important signaling molecule that inititates the relaxation of blood vessels and keeps them youthful.

So how do we keep our arteries youthful?

Berberine increases endothelial progenitor cells

Berberine increases the production of nitric oxide, which in turn plays a key role in the regulation of endothelial progenitor cells (EPCs). These cells mature and replace older endothelial cells, ensuring the arteries stay flexible and youthful.

Researchers took a look at the effect of berberine on EPCs: Berberine-Induced Upregulation of Circulating Endothelial Progenitor Cells Is Related to Nitric Oxide Production in Healthy Subjects.

First, what I liked about this study. It was done in humans, so we know that this works and not just in rats or mice. Second, berberine is not well-absorbed into the circulation. I’ve seen a number of studies in which berberine was injected at high doses into rats or mice, and I doubt we can meaningfully extrapolate those results to humans taking oral doses. This study used healthy people taking berberine orally.

The subjects were 20 healthy people, average age 54, with no cardiovascular disease and taking no medication. They took 400 mg of berberine 3 times a day for 30 days. Then they looked at EPCs, as well as their activity, and the level of nitric oxide in the blood.

Berberine therapy resulted in a dramatic increase in EPCs. See chart below.

The number of EPCs rose 50%.

Results for proliferative, adhesive, and migratory activity of EPCs were similar.

Also, blood glucose, LDL cholesterol, and blood pressure all declined.

The researchers found that EPC numbers and activity were strongly correlated with increased nitric oxide in blood, so that may be how berberine works to promote EPCs.

Importance

As noted, EPCs are strongly and negatively correlated with cardiovascular risk. An article in the New England Journal of Medicine tells the story: Circulating Endothelial Progenitor Cells, Vascular Function, and Cardiovascular Risk.

“…endothelial progenitor cells may provide a circulating pool of cells that could form a cellular patch at the site of denuding injury or serve as a cellular reservoir to replace dysfunctional endothelium…

To test this hypothesis, we measured the activity of endothelial progenitor cells in relation to cardiovascular risk factors and endothelial function in a group of healthy volunteers. These subjects had no symptoms associated with atherosclerosis or active ischemia.”

For the result, see chart below.

“The nature and size of our study do not permit us to determine whether low levels of endothelial progenitor cells can accurately predict subsequent cardiovascular events… Establishing a definitive cause-and-effect relation requires studies in which the levels of endothelial progenitor cells are experimentally manipulated and the biologic or therapeutic effects assessed. Rather, we believe our data suggest that circulating endothelial progenitor cells have a role in vascular homeostasis. We further speculate, but cannot prove, that continuous risk-factor–induced injury may lead to the eventual depletion of circulating endothelial progenitor cells. Interestingly, recent studies in animals have suggested that the exhaustion of stem cells may be an important determinant of a number of age-related conditions. Future studies will therefore be needed to determine whether this postulated risk-factor–induced exhaustion of circulating endothelial progenitor cells is a factor in the pathogenesis of cardiovascular disease.”

While the effect of berberine appears important, we can only say that the number and activity of EPCs is associated with lower cardiovascular risk. That seems important enough. Berberine’s additional actions on blood glucose, LDL, and blood pressure certainly seem to substantiate that.

You can read a review of the metabolic and cardiovascular effects of berberine here.

PS: Berberine is just one of the supplements I discuss in my new book, Best Supplements for Men.

PPS: Check out my Supplements Buying Guide for Men.

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21 comments
Bill says May 31, 2017

PD I have been taking berberine to promote autophagy. So the news that it is good for preventing or healing CVD is great to know.

I .am on my second container of Tribiotics berberine from Nutricology.

It was the one I could readily access via Iherb on line. Berberine sulfate 400 mg; Artemisinin 60mg; Citrus seed extract 400mg & Black walnut hulls 100 mg. Not sure what to make of the other ingredients as supplements. But I have noted no nasty side affects at all…

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Sean Sadler says May 31, 2017

Interesting post. Do you have any thoughts on whether berberine interferes with hypertrophy?

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    P. D. Mangan says May 31, 2017

    In the study in which berberine caused muscle atrophy in mice, they were injected intraperitoneally with high doses of berberine. Since humans don’t do this, and berberine has low bioavailability, that’s unlikely to happen in people. The authors of the study note that it’s never been seen in humans, and there’s quite a bit of clinical data on berbberine (as well as metformin).

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Anthony says May 31, 2017

Would adding metformin to my supplements be redundant if I’m already taking 900mg of berberine daily?

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    P. D. Mangan says May 31, 2017

    Probably. Either one or the other.

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peter connor says May 31, 2017

I notice that some companies are promoting Berberine with Silymarin…what do you think?

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    P. D. Mangan says May 31, 2017

    Probably fine but unnecessary.

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Andreas says May 31, 2017

Hi P.D.,

I follow a variation of Asprey’s BulletProof diet, essentially: coffee in the morning (8 AM) with MCT Oil and butter or cream (and most of my day’s supplements); several hours later (1pm-3pm) a meal of good protein, healthy fat, and maybe(certainly not always) a low glycemic vegetable or fruit (like cantaloupe); and dinner similar to lunch with maybe a bit more low glycemic carbs and occasionally some white rice to replace glycogen stores. Note, I often add MCT to meals with carbs because I’ve found it helps to maintain ketosis.

This works pretty well.

On your recommendation I’ve added berberine to all of this and have started to take it at the beginning of meals with which I plan to consume some carbs (and especially if I think I might consume more carbs or higher glycemic indexed carbs than I probably should;-)

I seem to have pretty good results from doing this, but wondered if I can optimize the use of berberine further.

Could/should I take berberine:

– sometime before having a meal?
– Twice a day even if I only plan to consume < 100 grams of low glycemic carbs?
-some other way or on some other schedule?

Just wondering.

Happy to get a response of, "It's all in the new book".

Best,
A

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    P. D. Mangan says May 31, 2017

    Hi Andreas – some of that is in the new book. Maybe I can answer your questions by saying that I take it only once a day, almost always with morning coffee (i.e. no food). Actual diabetics would normally take it 3 times a day, with each meal. (These are ~500 mg doses.) I look at berberine like I do with many of my supplements: insurance. If you are as lean as you want, have no blood sugar issues, eat relatively low carb, berberine may get into the realm of diminishing returns, especially at more than once daily.

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Brandon says May 31, 2017

Dennis, I was wondering, in the hypothetical scenario metformin was available cheaply OTC and you were not adhering to a low carb diet, but you weren’t overweight or diabetic, would you take it and if so at what dosage? IE, half that of what diabetics take?

FYI they think metformin may cause b12 deficiency: “In fact, the risk for Parkinson’s disease or Alzheimer’s dementia went up over 50 percent during a 12 year period in those who took metformin when compared to those who did not.”

https://www.diabetesdaily.com/blog/study-metformin-linked-to-higher-risk-of-alzheimers-and-parkinsons-393789/

Another study I found also:
“Researchers at BioMarker Pharmaceuticals have discovered that metformin can mimic changes in gene expression found in calorically-restricted mice, which live longer than normally-fed mice. Metformin has also been found to extend life span in mice by 20%. ”

https://www.thefreelibrary.com/Scientists+Discover+Anti-Aging+Effects+of+Diabetes+Drug-a0100504403

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    Brandon says May 31, 2017

    I was just doing more research on this, apparently it is a new study that contradicts previous findings that metformin is protective against alzherimers. This is something I really hate about having infinite information, much of it is contradictory and its hard to tell which one to believe.

    “A Taiwanese study presented yesterday at an international conference on Alzheimer’s and Parkinson’s diseases suggested that long-term use of the popular diabetes medication Metformin may increase the risk of neurodegenerative disease in patients with type 2 diabetes mellitus, contradicting the results of a large study published just last year following US-based subjects that seemed to show that Metformin exerts a protective effect against the same diseases.”

    http://www.biotecheast.com/2017/03/31/new-taiwan-research-contradicts-earlier-findings-on-metformins-neurodegenerative-disease-protective-effects/

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    P. D. Mangan says May 31, 2017

    Hi Brandon, I might take metformin in lieu of berberine if it were OTC; while berberine seems to have fewer side effects, it’s hard to say which is more effective. In one study, however, berberine was possibly more effective in diabetics than metformin. Dose is hard to say, but as with my reply to Andreas above, if you’re lean already, more than a little may be superfluous. Sorry to be so vague, but so much of this is necessarily speculation. BTW, stomach upset and diarrhea are common metformin side effects, and I’m not aware of berberine having any effects like that.

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Sixkiller says May 31, 2017

PD,

One of the many positives of supplementing with berberine is the increased nitric oxide production. L-Citrulline also does this. Are there other similarities between the two?

Thanks.

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    P. D. Mangan says May 31, 2017

    Not that I’m aware of. Berberine activates AMPK, promotes autophagy, chelates iron, whereas citrulline generates NO through the citrulline-arginine cycle. Very different mechanisms and generating NO may be the only thing they both do.

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Stefan says June 3, 2017

Hello PD,

I read that Berberine activates AMBP by blocking a component of the mitochondria (Complex I to be precise). This doesn’t sound good to me at all. On one hand, I understand how blocking ATP producing mitochondria activates AMPK to induce autophagy. But, on the other, blocking mitochondria, beside being detrimental to muscle growth and other organs energy needs can switch healthy cells to cancer, based on the metabolic theory of cancer, as demonstrated by Dr. Seyfried. I am very interested in your opinion on this.

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    Stefan says June 4, 2017

    One last post on this issue. I am not a biochemist, so I am only based on what can be understood from the study as read by a non-professional. Here is the study: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4114874/
    It basically says this: Berberine lowers ATP (i.e. cellular energy) production in the mitochondria by inhibiting Complex I (one of the complexes in the electron transport chain – the mechanism used by mitochondria to create energy from glucose and oxygen). This inhibitory action has 2 effects: 1) activates AMPK, because the ATP/AMP level, monitored by AMPK, decreases and AMPK gets signaled to switch the cell into mitochondria repair mode. AMPK activated promotes autopahgy and mitogenesys. And 2) mitochondrial inhibition increases glycolysis, which is the anaerobic (i.e. outside mitochondria) way to create ATP from glucose. Glycolysis increase is the cell’s mechanism to compensate the loss of respiratory capacity (i.e the loss of ATP production in mitochondria by using oxygen + glucose, as that path is now blocked by berberine). As a result of glycolysis becoming a main producer of enerygy in the cell, the cell is much less efficient in creating ATP and it consumes much more glucose than with normal repsiration. This is why you see the blood glucose level drop faster with berberine (or metformine). Also, the lactic acid (a product of glycolysis) raises much more with berberine – showing the rais ein glycolysis. All this mechanism, actually, is very similar with the cancer cells metabolism, the same increase in glycolysis and decrease in repiration, as shown in the Warburg effect.

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      P. D. Mangan says June 4, 2017

      Hi Stefan – I note that in the article you linked, metformin did the exact same thing as berberine, and metformin use is associated with lower cancer rates in humans. The glucose lowering effect and consequent lowering of insulin is probably responsible for this. In the study, the researchers used an in vitro system, and I don’t know how the concentration they used compared to a concentration that would result from oral dosing. Berberine is poorly absorbed, even more so than metformin, and some have speculated that their main mechanisms of action are the affect on the gut microbiome, changing the types and numbers of different bacterial species.

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        Stefan says June 4, 2017

        Hi PD,
        Indeed, the anti-cancer effect of metformin is apparently due to the lowering of blood glucose and lowering insulin, which, in turn, lowers general inflamation. Lowering blood glucose and activating AMPK is beneficial. But I was concerned by the way it is done, via inhibiton of a key mitochondrial component. I read this exceptional book https://www.amazon.com/Life-Mitochondria-original-probiotic-dictates-ebook/dp/B00NLQQ8PG/ref=sr_1_1?s=books&ie=UTF8&qid=1496604008&sr=1-1&keywords=life+mitochondria about mitochondria and how we need to supplement with CoQ10 (ubiquinol – a key component ofthe mitichondrial electron transport chain) as we produce less as we age. And other substrate for mitochondrial health like B complex, L-carnitine, PQQ, etc. Now, comes berberine and does exactly the oposite, disables something in the electron transport chain which I am trying to enable and amplify with the other supplements. And this triggered my question, as these supplements are antagonic to each other..

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Stefan says June 3, 2017

A typo: AMPK not AMBP

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    Bill says June 4, 2017

    Stefan, the article you cite nhas this conclusion :
    In conclusion, the results from the current study demonstrated that berberine inhibited mitochondrial respiratory chain complex I, which led to the suppression of ATP synthesis, and the enhancement of glycolysis. The elevated glycolysis may be a primary cause for increased glucose consumption in hepatocytes and myotubes by berberine. Furthermore, all these effects are independent of AMPK activation. Berberine and metformin showed identical effects in vitro. We suggest complex I inhibition may replace AMPK activation as a major molecular mechanism of berberine and metformin.”

    There is no discussion of this process being similar to ‘cancer cell metabolism”

    Reply
      Stefan says June 4, 2017

      Hi Bill,

      What I reffered to is the Warburg Effect: In oncology, the Warburg effect is the observation that most cancer cells predominantly produce energy by a high rate of glycolysis followed by lactic acid fermentation in the cytosol, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate in mitochondria as in most normal cells. Here is the link: https://en.wikipedia.org/wiki/Warburg_effect

      Also, Thomas Seyfried work, which shows that cancer is a defect of mitochondria and not a random somatic mutation.

      Reply
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