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Strange new benefit for men from Panax ginseng

The most thoroughly studied natural product for diabetes is, perhaps, Panax ginseng.

Although its popularity stems largely from Asian countries being so prolific in publishing science, it’s also partly because it actually works.

And thankfully, the sheer number of articles about ginseng makes it easy to be confident about its safety and efficacy.

There is difficulty, however, in understanding exactly how it works.

There is no scientific consensus about ginseng’s mechanism of action, or the identity of the binding target responsible for its effects.

Moreover, a fair amount of science implies that ginseng would actually be counterintuitive for diabetics to take.

This is because many mRNA reporter assays demonstrate that ginseng activates glucocorticoid receptors (Lee, 1997):

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And this is the exact opposite of what’s needed in diabetes.

For nearly forty years, in fact, ginseng’s active compounds have been shown to strongly bind glucocorticoid receptors.

And glucocorticoids such as cortisol are well known to increase plasma glucose during times of stress.

In fact, they were named for this effect.

Elevated blood sugar is also a well‑known complication of prescription glucocorticoids, such as prednisone, often given for immunosuppression.

From a 1986 study:

“Glucocorticoid-induced diabetes mellitus usually resolves when glucocorticoids are stopped.”

For these reasons, you could rightly think ginseng would make diabetes worse, not better.

Yet ginseng does the complete opposite… It lowers plasma glucose, even in diabetics.

So, yes, its glucocorticoid activity could seem rather troubling upon first glance.

But there is a logical way to resolve this paradox… (More on that later.)

So it seems that clinical results always overturn theoretical predictions about this topic…

In fact, there are more studies supporting an anti‑diabetic role than not.

All of the studies done on living subjects, both animals and people, unambiguously demonstrate that ginseng acts to lower plasma glucose.

Many cell studies show that ginseng downregulates glucose‑producing enzymes.

And, again, that’s the exact opposite of what you’d expect from a glucocorticoid.

To get some idea about how consistent this glucose‑lowering effect is, here is a recently published meta‑analysis about ginseng and diabetes:

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This is the most thorough meta‑analysis published so far.

It includes the data from sixteen clinical trials on all species of Panax ginseng (not merely, for instance, Korean red ginseng.)

Half the studies were from Asia and the rest from either the United States or Europe.

A wide variety of different dosages of ginseng were included, both extracts and whole‑root powders.

Nonetheless, the results are fairly consistent:

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Only one of the studies they included did not show this change in plasma glucose.

That 2001 study was conducted by Reeds et al. in St. Louis, Missouri.

In that study, they used a sufficient dose of ginseng. And they had already proved their extract worked in rats.

Here’s the one difference between that Reeds study and the other studies: They used newly‑diagnosed subjects.

This could be why they didn’t see any change in plasma glucose from baseline…

Newly diagnosed diabetics are likely to progressively modify their eating habits upon hearing the news…

If so, they’d be consuming foods with lower glycemic indices by the time of the experiment’s conclusion.

From Reeds’ study:

“We confirmed that the batches of ginseng and ginsenoside Re used in this study had biological activity by demonstrating that incubation with ginseng and ginsenoside Re markedly improved insulin-mediated glucose uptake in isolated epitrochlearis muscles – obtained from diet-induced insulin-resistant rodents – and rectus abdominus strips obtained from obese subjects undergoing gastric bypass surgery.”

(Ginsenoside is the steroid glycoside compound in ginseng.)

The lack of effect seen in the Reeds study may only go to show that newly‑diagnosed diabetics are apt to change their diet.

Here’s another thing that may seem weird at face value:

Even though the subjects in all these studies were taking ginseng, the researchers couldn’t detect any ginsenosides in their plasma…

Nor can anyone else above the nanomolar range.

Yet this is actually no obstacle towards understanding ginseng’s effect because glucose regulation occurs primarily in the liver…

And the liver is also the precise organ where ginsenosides concentrate the most:

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Considering that the liver contains most of the body’s glycogen, this location is likely to be more consequential than the plasma.

“Among various pathological effects, the ability of hepatic control plays a vital role for maintaining the glucose homeostasis; the loss function will result in hyperglycemia.”

The liver is where blood glucose is controlled through balancing gluconeogenesis with glycogen breakdown.

And in cells taken from the liver, ginsenosides are shown to exert pronounced antidiabetic activity:

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This is a continuation of Chinese research on compound K, the main active ginseng metabolite within the body.

Compound K is simply what remains after ginsenosides are stripped of all but one of their attached glucose units.

This is primarily a product of bacteria residing in the small intestine. But it also occurs spontaneously in the stomach.

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And, coincidentally, that main metabolite – compound K – is also the most hypoglycemic one discovered.

Previous research also showed that compound K lowered plasma glucose in rats and downregulated two glucose‑producing enzymes – glucose‑6‑phosphatase (G6Pase) and phosphoenolpyruvate carboxykinase (PEPCK).

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Glucocorticoids are notorious for upregulating these two enzymes.

And the latter one (PEPCK) is commonly checked for because it’s rate‑limiting for gluconeogenesis.

The same effect was shown in isolated human hepatocytes – and to a similar degree, at a concentration of only 8 μM.

This concentration is achievable in the liver and nowhere else, after ginseng consumption.

Considering the distribution of ginsenosides within the body, this effect on hepatic glucose production must underlie their antidiabetic activity.

“In the present study, we can conclude that CK (carboxykinase) showed outstanding anti-diabetes effect, and its effect on inhibition of gluconeogenesis might be partially involved.”

Yet, according to Dr. Young Joo Lee (of the 1997 study mentioned above) and a few others, you would expect glucocorticoid effects at this concentration.

So what is going on?

Why does ginseng often cause the opposite effect than expected?

There are many possible ways to make sense of all this, such as concomitant MR or GR‑β activity (never mind what those are).

Yet only one possibility fits all the data.

And there’s actual proof of this…buried within a study published just two years ago:

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These researchers were inspired by the discovery of two rare but extremely potent natural inhibitors of 11β‑hydroxysteroid dehydrogenase‑1 (11β‑HSD).

This enzyme (11β‑HSD) is an important target for diabetes – as it converts inactive cortisone into active cortisol.

The two 11β‑HSD inhibitors are called hupehenol B and hupehenol E. The researchers set out to find a synthetic route to this enzyme.

On account of the inhibitors’ structural similarity to protopanaxadiol (PPD) – a compound in ginseng – and their low natural abundance, the researchers decided to use this as a starting source.

“Hupehenols [B and E] are the most potent and selective human 11β‑HSD inhibitors… Herein, the hupehenols were synthesized from PPD, the main component of Panax notoginseng.”

Protopanaxadiol (PPD) is the steroid‑like core of most ginsenosides.

It differs from compound K – the primary ginseng metabolite in humans – by only one attached glucose unit.

Besides all of the non‑hupehenol compounds tested, and the 11β‑HSD2 inhibitor glycyrrhizic acid, compounds 13 and 14 were the most potent:

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The potency of compound 13 approaches that of hupehenol B, the most potent selective 11β‑HSD1 inhibitor known.

Selectivity is an important consideration here, as 11β‑HSD2 catalyzes the opposite reaction and converts cortisol into cortisone.

This fact makes glycyrrhizic acid completely worthless for diabetes, and actually somewhat dangerous besides.

So what is the identity of this rather potent “compound 13”?

Well… It’s essentially just acetylated PPD, the starting source:

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This finding has some comedic value because the researchers would’ve been better off doing nothing. But that isn’t what’s important here.

This recent study demonstrates how potent PPD is in inhibiting 11β‑HSD1.

Again, this enzyme (11β‑HSD1) is responsible for transforming inactive cortisone into cortisol…

And cortisol is a potent glucocorticoid…

So this data hints towards ginseng’s elusive mechanism of action.

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This crucial enzyme (11β‑HSD1) is most highly expressed in the liver, exactly where ginsenosides concentrate the most.

“11β-HSD1 levels are highest in liver and adipose tissues as well as in the central nervous system…”

Let’s assume that compound K is approximately as effective as acetylated PPD (AKA compound 13).

Then it should inhibit 11β‑HSD1 at concentrations about 10 to 30 times less than what’s needed to activate glucocorticoid receptor‑α.

Just these two activities can explain all the seemingly paradoxical effects of ginseng.

For instance, when given to cells having a low expression of 11β‑HSD1 (e.g. endothelial cells), ginsenosides would be likely to induce a glucocorticoid effect through glucocorticoid receptor‑α.

Conversely, when given to cells having a high expression of 11β‑HSD1 (e.g. hepatocytes, adipocytes), you should get an antiglucocorticoid effect – as long as concentrations are held reasonable.

But at massive concentrations far in excess of those obtainable through normal ginseng supplementation, you could see glucocorticoid‑like effects even in hepatocytes (liver cells).

Yet, in humans taking normal human‑sized doses of ginseng, you always get an anti-glucocorticoid effect.

This makes ginseng useful for diabetes.

And that’s not the only benefit of this anti-glucocorticoid effect…

The additional glucose induced by glucocorticoids is synthesized at a price, deriving mostly from free amino acids.

And if the circulating pool of free amino acids is insufficient, glucocorticoids will even initiate protein breakdown to obtain them.

This is why cortisol promotes muscle wasting during chronic stress.

For this reason, ginseng should also have an anabolic effect…

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Matt Cook is editor-in-chief of Daily Medical Discoveries. Matt has been a full time health researcher for 26 years. ABC News interviewed Matt on sexual health issues not long ago. Matt is widely quoted on over 1,000,000 websites. He has over 300,000 daily newsletter readers. Daily Medical Discoveries finds hidden, buried or ignored medical studies through the lens of 100 years of proven science. Matt heads up the editorial team of scientists and health researchers. Each discovery is based upon primary studies from peer reviewed science sources following the Daily Medical Discoveries 7 Step Process to ensure accuracy.

Sievenpiper, John L. "The effect of ginseng on glycemic control: a systematic review and meta-analysis of randomized controlled clinical trials." PloS one (2014) https://pdfs.semanticscholar.org/ecc7/6bbd76930e0b55cf02a5c47aac70724d5975.pdf

Wei, Shengnan. "Ginsenoside Compound K suppresses the hepatic gluconeogenesis via activating adenosine-5′ monophosphate kinase: A study in vitro and in vivo." Life sciences (2015) 

https://www.sciencedirect.com/science/article/pii/S0024320515004464

Lee, Young Joo. "Ginsenoside-Rg1, one of the major active molecules from Panax ginseng, is a functional ligand of glucocorticoid receptor." Molecular and cellular endocrinology (1997) https://www.sciencedirect.com/science/article/pii/S0303720797001603

Shao, Li-Dong. "Synthesis of selective 11β-HSD1 inhibitors based on dammarane scaffold." European journal of medicinal chemistry (2017) http://ir.kib.ac.cn/bitstream/151853/54457/1/shao2017.pdf

Shao, Li-Dong. "Synthesis of hupehenols A, B, and E from protopanaxadiol." Royal Society of Chemistry: Advances (2016) https://www.researchgate.net/profile/Shao_Lidong2/publication/299652353_Synthesis_of_Hupehenols_A_B_and_E_from_Protopanaxadiol/links/5abde2b70f7e9bfc0457c986/Synthesis-of-Hupehenols-A-B-and-E-from-Protopanaxadiol.pdf